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The testosterone metabolite and neurosteroid 3α-androstanediol may mediate the effects of testosterone on conditioned place preference
Abstract
The abuse of androgens may be related to their ability to produce positive, hedonic interoceptive effects. Conditioned Place Preference (CPP) has been used in many experiments to examine hedonic effects of drugs. This review is focused on studies from our laboratory that utilized CPP to examine potential positive hedonic effects of testosterone (T), and its androgenic metabolite dihydrotestosterone (DHT), and its metabolite 3alpha-androstanediol (3alpha-diol). We hypothesized that administration of a high concentration of 3alpha-diol would produce a CPP, pharmacological concentrations of plasma androgens, and alter androgen receptors (AR) and the function of GABA(A)/benzodiazepine receptor complexes (GBR). In our studies, we observed that systemic 3alpha-diol (1.0 mg/kg) prior to exposure to the non-preferred side of a CPP chamber significantly increased preference for the non-preferred side of the chamber compared to baseline preference and homecage controls. Furthermore, administration of T, DHT, or 3alpha-diol increased levels of these androgens, decreased ARs (decreased seminal vesicle weight and intrahypothalamic AR) and GBR function (decreased GABA-stimulated chloride influx in cortical synaptoneurosomes, and muscimol binding in the hippocampus compared to control groups). With systemic administration of 3alpha-diol that enhanced CPP, concentrations of 3alpha-diol were increased in the nucleus accumbens (NA). Central implants of T, DHT, or 3alpha-diol to the NA also produced a CPP compared to baseline preference and vehicle controls. These data indicate that systemic 3alpha-diol is more effective at enhancing CPP and increasing circulating 3alpha-diol levels than is T or DHT and that central administration of 3alpha-diol to the NA can condition a place preference. These findings indicate that 3alpha-diol produces positive hedonic effects and suggest that T's variable effects on CPP may be due in part to T's metabolism to 3alpha-diol.
... In a recent study, we observed that progesterone-derived 3α-5α-reduced metabolites exerted potent neuroprotective effects against oxaliplatin-or vincristineinduced peripheral neuropathy in rats, suggesting that 3α-5αneurosteroid-based strategies may offer serious opportunities to develop effective therapies against anticancer drug-evoked painful neuropathic symptoms [24,25]. Among the family of 3α-5α-neurosteroids are naturally-produced molecules such as allopregnanolone and 3α-androstanediol (3α-DIOL) which activate allosterically the GABA A receptor and potentiate the central inhibition [26][27][28][29][30][31][32][33][34]. While allopregnanolone has extensively been investigated in several experimental models and in humans as a neuroprotective, neurogenic, anaesthetic, anxiolytic or analgesic compound, the neurosteroid 3α-DIOL has received little attention [26,[35][36][37][38][39][40][41][42]. ...
... Although previous dose-response studies have identified 1 to 4 mg/kg as an effective dose range for 3α-androstanediol neuroactivity in vivo [29,32,56,57], we investigated in the present work the dose-and injection frequency-dependent effects of 3α-DIOL (by testing 2 or 4 mg/kg every 2 or 4 days) on the mechanical nociceptive thresholds of vehicle-and PACtreated rats ( Figure 5). In vehicle-treated animals, corrective 3α-DIOL treatments at 2 or 4 mg/kg every 2 days ( Figure 5A) or at 4 mg/kg every 4 days ( Figure 5B) significantly decreased the percent of responses to 26 g (p<0.05), ...
... Altogether, these results suggest that CNPase gene expression may be highly sensitive to 3α-DIOL-evoked intracellular signaling while the sensitivity of NF200 and PGP9.5 genes to 3α-DIOL may increase only under pathophysiological situations thanks to the activation of various transcription factors evoked by PAC treatment [71][72][73]. Also, 3α-DIOL is known to stimulate the central inhibitory system via the GABA A receptor, suggesting that 3α-DIOL may exert an analgesic action which may contribute to suppress PAC-evoked painful symptoms [26][27][28][29][30][31]46]. Another important point is the fact that 3α-DIOL may be inter-converted into 5α-DHT by the enzyme 3αhydroxysteroid oxido-reductase abundantly expressed in the nervous system [39,74,75]. ...
Painful peripheral neuropathy belongs to major side-effects limiting cancer chemotherapy. Paclitaxel, widely used to treat several cancers, induces neurological symptoms including burning pain, allodynia, hyperalgesia and numbness. Therefore, identification of drugs that may effectively counteract paclitaxel-induced neuropathic symptoms is crucial. Here, we combined histopathological, neurochemical, behavioral and electrophysiological methods to investigate the natural neurosteroid 3α-androstanediol (3α-DIOL) ability to counteract paclitaxel-evoked peripheral nerve tissue damages and neurological symptoms. Prophylactic or corrective 3α-DIOL treatment (4 mg/kg/2days) prevented or suppressed PAC-evoked heat-thermal hyperalgesia, cold-allodynia and mechanical allodynia/hyperalgesia, by reversing to normal, decreased thermal and mechanical pain thresholds of PAC-treated rats. Electrophysiological studies demonstrated that 3α-DIOL restored control values of nerve conduction velocity and action potential peak amplitude significantly altered by PAC-treatment. 3α-DIOL also repaired PAC-induced nerve damages by restoring normal neurofilament-200 level in peripheral axons and control amount of 2',3'-cyclic-nucleotide-3'-phosphodiesterase in myelin sheaths. Decreased density of intraepidermal nerve fibers evoked by PAC-therapy was also counteracted by 3α-DIOL treatment. More importantly, 3α-DIOL beneficial effects were not sedation-dependent but resulted from its neuroprotective ability, nerve tissue repairing capacity and long-term analgesic action. Altogether, our results showing that 3α-DIOL efficiently counteracted PAC-evoked painful symptoms, also offer interesting possibilities to develop neurosteroid-based strategies against chemotherapy-induced peripheral neuropathy. This article shows that the prophylactic or corrective treatment with 3α-androstanediol prevents or suppresses PAC-evoked painful symptoms and peripheral nerve dysfunctions in rats. The data suggest that 3α-androstanediol-based therapy may constitute an efficient strategy to explore in humans for the eradication of chemotherapy-induced peripheral neuropathy.
... T is of particular interest because most studies examining behavioral correlates of the mesocorticolimbic system use male rodents. Moreover, T microinjected into the brain affects motivated behaviors (26) and decreases dopamine release in the NAc (27). However, it still remains unclear whether steroid concentrations differ between mesocorticolimbic nodes and the circulation, and if steroids are locally produced in these regions. ...
... T and CORT can have dramatic effects on the mesocorticolimbic system, and these results will inform future studies that examine the roles of neurosteroids in motivated behaviors. For instance, microinjections of T or its metabolites into the NAc elicit conditioned place preference (26), which is attenuated by a dopamine receptor antagonist (69). In addition, GDX affects dopaminesynthesizing cells in the VTA and dopamine-sensitive cells in the NAc and mPFC (70). ...
As males age, systemic testosterone (T) levels decline. T regulates executive function, a collection of cognitive processes that are mediated by the mesocorticolimbic system. Here, we examined young adult (5 months) and aged (22 months) male Fischer 344 × Brown Norway rats, and measured systemic T levels in serum and local T levels in microdissected nodes of the mesocorticolimbic system (ventral tegmental area (VTA), nucleus accumbens (NAc), medial prefrontal cortex (mPFC), and orbitofrontal cortex (OFC)). We also measured androgen receptor (AR) immunoreactivity (-ir) in the mesocorticolimbic system. As expected, systemic T levels decreased with age. Local T levels in mesocorticolimbic regions - except the VTA - also decreased with age. Mesocorticolimbic T levels were higher than serum T levels at both ages. AR-ir was present in the VTA, NAc, mPFC, and OFC and decreased with age in the mPFC. Taken together with previous results, the data suggest that changes in androgen signaling may contribute to changes in executive function during aging.
... Androgens will condition a place preference [15]. The pattern of these effects in humans has been modeled in rodents [16,17]. It is notable that some neurodevelopmental (e.g., autism spectrum disorders), neuropsychiatric [18], and neurodegenerative (i.e., Alzheimer's, all-cause dementia, and seizure) [19][20][21][22][23][24] disorders are associated with differences in androgen levels. ...
Purpose of Review
Here, we summarize current knowledge of androgens’ action gained over the recent years.
Recent Findings
Neurosteroids are produced in the brain and peripheral nerves, independent of endocrine glands have been investigated for how they are regulated, and have actions via non-steroid receptor targets to mediate social, affective, and cognitive behavior and to protect the brain. Androgens’ organizing actions in the peri-natal period have effects throughout the lifetime that may be recapitulated later in life during critical periods and at times of challenge. Developmental changes in androgens occur during mid-childhood, adrenarche, puberty, adolescence, young adulthood, middle age, and andropause. Changes in androgens with a 5α-reductase inhibitor, such as finasteride, result in disruptions in organizational and activational functions of androgens that can be unremitting.
Summary
Normal developmental or perturbation in androgens through other means can cause changes in androgen-sensitive phenotypes throughout the lifespan, in part through actions of neurosteroids.
... This hormonal response can be conditioned to become associated with an odor so that the odor itself produces the response in male rats (Graham & Desjardins, 1980). Interestingly, an exogenously induced increase in testosterone can be used as an unconditioned stimulus to induce conditioned place preference in male rats (Alexander, Packard, & Hines, 1994;Rosellini, Svare, Rhodes, & Frye, 2001). Increases in circulating testosterone after exposure to female urine are more pronounced in sexually experienced male mice when they have been deprived of sexual stimulation for at least 3 days before being exposed to female urine (Clancy, Singer, Macrides, Bronson, & Agosta, 1988). ...
Although sex drive is present in many animal species, sexual behavior is not static and, like many other behaviors, can be modified by experience. This modification relies on synaptic plasticity, a sophisticated mechanism through which neurons change how they process a given stimulus, and the neurophysiological basis of learning. This review addresses the main plastic effects of steroid sex hormones in the central nervous system (CNS) and the effects of sexual experience on the CNS, including effects on neurogenesis, intracellular signaling, gene expression, and changes in dendritic spines, as well as behavioral changes.
... Es posible que las discrepancias encontradas entre los reportes se deban a diferencias metodológicas, tales como la especie de roedor, el tipo de andrógeno utilizado, la duración del tratamiento y las variaciones en la PNF. Por ejemplo, Bernardi et al. 11 utilizaron ratones Swiss-Webster cuatro semanas después de la castración, que recibieron un tratamiento breve (cuatro administraciones) de T, mientras que Frye et al. [12][13][14][15][16] usaron tratamientos de T, dihidrotestosterona y 3-diol administrados de forma aguda, así como una versión modificada de la PNF, en la cual se prescinde de la preprueba. Otros resultados del laboratorio sugieren que al menos para la depresión, la T tiene una relevancia fisiológica que depende de la edad. ...
It has been proposed that gonadal hormones participate in regulation of mood and emotion in men as well as in the effect of psychoactive drugs, such as antidepressants. However, evaluation of this type of interactions has been poorly studied in clinic and basic studies. The objective of the present study was to determine the role of gonadal hormones, testosterone (T) and 17 beta-estradiol (E-2), one of its main metabolites, in the effect of two antidepressant drugs: desipramine and fluoxetine. The former is a tricyclic antidepressant that inhibits noradrenaline reuptake in a preferential manner, while the second is a serotonin selective reuptake inhibitor (SSRI) and the most prescribed antidepressant. Behavioral evaluations were conducted in adult male rats, intact or orchidectomized (Orx), treated with T (0-2 mg/rata), E-2 (0-40 mu g/rata), desipramine (0-20 mg/kg), fluoxetine (0-20 mg/kg) and their combinations. Forced swimming test was used as an animal model to detect antidepressant-like effect induced by treatments, on the basis of its predictive validity. We found that desipramine and fluoxetine produced an antidepressant-like effect in gonadally intact male rats. However, the antidepressant-like effect of both treatments was cancelled in Orx males. Treatment with E-2, but not with T, produced antidepressant-like actions in Orx males. Interestingly, treatment with E-2 restored the antidepressant-like effect of desipramine and fluoxetine, while supplementation with T only reestablished the antidepressant-like action of desipramine, evidencing that gonadal hormones have a differential participation in regulation of neurotransmitter systems involving in the antidepressant effect. In conclusion, the main testicular androgen T, participates in the expression of the effect of antidepressant drugs, mainly via conversion to its estrogenic metabolite E-2. These results give support to the idea that a combined therapy of gonadal hormones and antidepressant drugs may be more convenient to treat depressive disorders in hypogonadal men resistant to conventional antidepressant drugs.
... Conditioned place preference (CPP) and self-administration are relevant experimental paradigms used to study reward in an experimental condition (Wood, 2004;Koob, 2006). Several studies in adult rodents have reported that systemic testosterone injections induced CPP in male rats and mice (de Beun et al., 1992;Alexander et al., 1994;Arnedo et al., 2000Arnedo et al., , 2002Frye et al., 2001). In another animal model, it has been demonstrated that 15 days of administration of an AAS cocktail consisting of testosterone cypionate, nandrolone decanoate, and boldenone undecylenate, increased the rate of self-administration and enhanced the sensitivity to amphetamine challenge (Clark et al., 1996). ...
Androgens are mainly prescribed to treat several diseases caused by testosterone deficiency. However, athletes try to promote muscle growth by manipulating testosterone levels or assuming androgen anabolic steroids (AAS). These substances were originally synthesized to obtain anabolic effects greater than testosterone. Although AAS are rarely prescribed compared to testosterone, their off-label utilization is very wide. Furthermore, combinations of different steroids and doses generally higher than those used in therapy are common. Symptoms of the chronic use of supra-therapeutic doses of AAS include anxiety, depression, aggression, paranoia, distractibility, confusion, amnesia. Interestingly, some studies have shown that AAS elicited electroencephalographic changes similar to those observed with amphetamine abuse. The frequency of side effects is higher among AAS abusers, with psychiatric complications such as labile mood, lack of impulse control and high violence. On the other hand, AAS addiction studies are complex because data collection is very difficult due to the subjects' reticence and can be biased by many variables, including physical exercise, that alter the reward system. Moreover, it has been reported that AAS may imbalance neurotransmitter systems involved in the reward process, leading to increased sensitivity toward opioid narcotics and central stimulants. The goal of this article is to review the literature on steroid abuse and changes to the reward system in preclinical and clinical studies.
... Likewise, DHT administered either systemically (1 mg/kg; 10 mm capsule) or intrahippocampally (1200 ng) into the dorsal hippocampus was nearly or just as effective as testosterone and 3α-androstanediol (a metabolite of DHT) at attenuating gonadectomy-induced impairments in crossover latencies in a inhibitory avoidance task Edinger and Frye, 2007). Interestingly, 3α-androstanediol (1 mg/kg) increased the cross-over latency in young adrenalectomized, GX male rats responding in a shuttlebox avoidance task (Frye and McCormick, 2000), and was more effective than testosterone or DHT in establishing a conditioned place preference (see Rosellini et al., 2001;Frye et al., 2002). ...
The primary role of the gonadal steroid hormones in mammals is to regulate reproduction and related behaviors; however, both androgens and estrogens are also integrally involved in mediating higher brain function and processes including cognition, neural development, and neural plasticity. In particular, a number of studies show that estradiol modulates dendritic spine growth and synapse density (synaptic plasticity) in the hippocampus of females, and that increased estradiol levels are generally associated with improvements on a variety of learning and memory tasks. While the majority of research has focused on the beneficial effects of estradiol in females, much less attention has been given to testosterone and its effects on learning and memory in males. Similar to estradiol titers in females, testosterone titers in males decline with age, albeit more gradually, and this decline has been correlated with impairment of certain cognitive tasks. Moreover, studies involving both humans and animals indicate that testosterone and its metabolites can augment responding on certain behavioral tasks, depending on the subject's current hormonal state, the response required, and the stimuli involved (e.g., those involving spatial or nonspatial stimuli). While the exact mechanisms by which testosterone exerts its effects on learning and memory are not fully understood, recent findings suggest that testosterone modulates learning and memory in males through an interaction with the cholinergic system. The overall objective of this review is to discuss studies investigating the role of the gonadal hormones in mediating learning and memory processes in male mammals.
... A preponderance of self-administration studies published in peer-reviewed scientific journals have definitively proven that androgenic steroids have acute reinforcing effects that are independent of the route of administration (p.o., i.v., i.c.v.) or the species tested (mice, rats, NHPs, or hamsters; Alexander et al., 1994;Ballard and Wood, 2005;DeBeun et al., 1992;Wood, 2004, 2006;Frye et al., 2002;Frye and Seliga, 2001;Johnson and Wood, 2001;Jorge et al., 2005;King et al., 1999;Packard et al., 1997;Packard et al., 1998;Peters and Wood, 2004;Rosellini et al., 2001;Schroeder and Packard, 2000;Triemstra and Wood, 2004;Wood, 2002;Wood et al., 2004). These data clearly demonstrate that the interoceptive stimulus events induced by delivery of steroids are capable of initiating and maintaining behaviors that preceded it; that is, serve as positive reinforces. ...
... It must be said that some studies have implicated the positive role of 3␣-diol on memory. For example , systemically administration of 3␣-diol to gonadectomized rats enhances cognitive performance in the inhibitory avoidance, place learning and object recognition tasks [19] [20] [21]. Further, blocking testosterone metabolism to 3␣-diol with indomethacin decreases cognitive performance and increases anxiety behavior of gonadally intact or DHT-replaced rats [5]. ...
... Es posible que las discrepancias encontradas entre los reportes se deban a diferencias metodológicas, tales como la especie de roedor, el tipo de andrógeno utilizado, la duración del tratamiento y las variaciones en la PNF. Por ejemplo, Bernardi et al. 11 utilizaron ratones Swiss-Webster cuatro semanas después de la castración, que recibieron un tratamiento breve (cuatro administraciones) de T, mientras que Frye et al. [12][13][14][15][16] usaron tratamientos de T, dihidrotestosterona y 3-diol administrados de forma aguda, así como una versión modificada de la PNF, en la cual se prescinde de la preprueba. Otros resultados del laboratorio sugieren que al menos para la depresión, la T tiene una relevancia fisiológica que depende de la edad. ...
Se ha propuesto que las hormonas gonadales participan en la regulación del estado de ánimo en los varones, y en el efecto de los fármacos psicoactivos, tales como los antidepresivos. Sin embargo, la evaluación de este tipo de interacciones ha sido estudiada escasamente. El objetivo del presente trabajo fue determinar el papel que cumplen las hormonas testosterona (T) y 17β-estradiol (E2), uno de sus principales metabolitos, en el efecto de dos fármacos antidepresivos utilizados en la práctica clínica, desipramina y fluoxetina. El primero es un tricíclico con acciones sobre el sistema noradrenérgico, mientras que la fluoxetina es un inhibidor selectivo de la recaptura de serotonina. Las evaluaciones se llevaron a cabo utilizando ratas macho adultas jóvenes, gonadalmente intactas u orquidectomizadas (Orx), bajo tratamiento con T (0-1 mg/rata), E2 (0-40 µg/rata), desipramina (0-20 mg/kg), fluoxetina (0-20 mg/kg) y sus respectivas combinaciones. Se utilizó la prueba de nado forzado (PNF) para detectar las acciones antidepresivas de los tratamientos. Encontramos que desipramina y fluoxetina redujeron la conducta de depresión en los machos gonadalmente intactos; sin embargo, el efecto de ambos tratamientos fue abolido por la orquidectomía. El tratamiento de restitución hormonal con E2, pero no con T, indujo acciones antidepresivas en los machos Orx. A su vez, cuando los animales Orx recibieron la restitución con T se produjo la recuperación del efecto antidepresivo de la desipramina, mientras que el E2 restableció las acciones antidepresivas de ambos fármacos. En conclusión, el principal andrógeno de origen testicular, la T, participa en la expresión del efecto de los fármacos antidepresivos explorados en el presente estudio, principalmente a través de su metabolito estrogénico, el E2. Estos resultados apoyan la idea de que una terapia adjunta de tratamientos hormonales y antidepresivos sería de beneficio para varones hipogonadales que cursen con depresión resistente a los fármacos antidepresivos convencionales.
... Peripheral injections of T and central implants of T, dihydrotestosterone, or 3alpha-diol can induce a conditioned place preference (CPP) in rats (e.g. Alexander et al., 1994;Rosellini et al., 2001). Androgeninduced CPPs are blocked by dopamine receptor antagonists. ...
We thank Professor Wingfield for his commentary in this issue and the interesting questions he raises about the challenge effect and its functions in the control of aggressive behavior. He suggests several intriguing ideas that are worth pursuing, particularly in relation to the temporal nature of the testosterone (T) changes that occur in response to a competitive encounter. Testosterone changes can be short term, long term and the timing of the change can vary. Furthermore, some of these changes may be modulated by learning processes.
... For example, 3α-diol is a neuroactive steroid and, similar to other 3α tetrahydrosteroids, is a potent allosteric modulator of GABAa receptors. As a result, 3α-diol has been implicated in the regulation of a several behaviors (61)(62)(63)(64). By contrast, 3β-diol cannot bind the benzodiazepine receptor (M. ...
Activation of the hypothalamic-pituitary-adrenal (HPA) axis is a basic response of animals to environmental perturbations that threaten homeostasis. These responses are regulated by neurones in the paraventricular nucleus of the hypothalamus (PVN) that synthesise and secrete corticotrophin-releasing hormone (CRH). Other PVN neuropeptides, such as arginine vasopressin and oxytocin, can also modulate activity of CRH neurones in the PVN and enhance CRH secretagogue activity of the anterior pituitary gland. In rodents, sex differences in HPA reactivity are well established; females exhibit a more robust activation of the HPA axis after stress than do males. These sex differences primarily result from opposing actions of sex steroids, testosterone and oestrogen, on HPA function. Ostreogen enhances stress activated adrenocorticotrophic hormone (ACTH) and corticosterone (CORT) secretion, whereas testosterone decreases the gain of the HPA axis and inhibits ACTH and CORT responses to stress. Data show that androgens can act directly on PVN neurones in the male rat through a novel pathway involving oestrogen receptor (ER)beta, whereas oestrogen acts predominantly through ERalpha. Thus, we examined the hypothesis that, in males, testosterone suppresses HPA function via an androgen metabolite that binds ERbeta. Clues to the neurobiological mechanisms underlying such a novel action can be gleaned from studies showing extensive colocalisation of ERbeta in oxytocin-containing cells of the PVN. Hence, in this review, we address the possibility that testosterone inhibits HPA reactivity by metabolising to 5alpha-androstane-3beta,17beta-diol, a compound that binds ERbeta and regulates oxytocin containing neurones of the PVN. These findings suggest a re-evaluation of studies examining pathways for androgen receptor signalling.
... However, when implanted bilaterally into the nucleus accumbens shell, all three substances produced CPP [82]. Based on these results, the temporal onset of CPP for the individual substances, and brain as well as plasma levels, the authors conclude that the testosterone metabolite and neurosteroid 3α-androstanediol is responsible for the CPP [80][81][82]216]. Testosterone administerd s.c. to mice have also been shown to produce CPP at doses ranging from 0.8-2 mg/kg [2,3]. ...
... Con relación a la T y su efecto ansiolítico se plantea la posibilidad de que los metabolitos reducidos de la hormona (3-alfa-diol, androsterona, DHT), los cuales son considerados como andrógenos "débiles" pero potentes agonistas de GABA, sean los que causen el efecto ansiolítico en los animales, ya que se necesitan menores dosis de los mismos que de T para causar el mismo fenómeno (Aikey, et al., 2002;Bitran et al., 1993;, 2007Fernández-Guasti & Martínez-Mota, 2003;Frye, Babson & Walf, 2006;Frye, Park, Tanaka, Rosellini & Svare, 2001;Frye, 2007;Rosellini, Svare, Rhodes & Frye, 2001). A nivel cortical se encontró que el tratamiento con T disminuye la concentración de GABA, mientras que incrementa la sensibilidad de los receptores de GABAA en la corteza (Bitran et al., 1993;Zhang et al., 1999). ...
The present work reviews the research about the relation between sexual behavior and anxiety in animals. The most relevant results suggest that sexual behavior has an anxiolytic-like effect. This phenomenon is expressed on the subject's behavior, besides the physiological and neuroendocrine levels. Also, the review includes studies about the opposite relation, it means, how the stress affects the animal's sexual behavior.
... In rodents, administration of T creates conditioned placepreferences that can be inhibited by dopaminergic antagonists, suggesting that the heightened place-preference due to T is partly modulated through its effects on dopaminergic processes (Alexander et al., 1994; Caldarone et al., 1996; Packard et al., 1998; Arnedo et al., 2000; Schroeder and Packard, 2000). These positive hedonic effects of T have been found to be mediated by actions of its metabolites, especially 3a-androstanediol, in the nucleus accumbens (Rosellini et al., 2001; Frye et al., 2002). Chronic exposure to T has shown to alter sensitivity to DA by increasing DA metabolism in the cerebral cortex (Kurling et al., 2005). ...
Life-course persistent antisocial behavior is 10 to 14 times more prevalent in males and it has been suggested that testosterone levels could account for this gender bias. Preliminary studies with measures of fetal testosterone find inconsistent associations with antisocial behavior, especially studies that use the 2D:4D ratio as a proxy for fetal testosterone. However, circulating testosterone consistently shows positive associations with antisocial behaviors throughout childhood, adolescence, and adulthood, particularly in males. It is suggested that high fetal/circulating testosterone interactively influence the maturation and functionality of mesolimbic dopaminergic circuitry, right orbitofrontal cortex, and cortico-subcortical connectivity, resulting in a strong reward motivation, low social sensitivity, and dampened regulation of strong motivational/emotional processes. The link between these testosterone induced endophenotypes and actual display of antisocial behavior is strongly modulated by different social (e.g., social rejection, low SES) and genetic (e.g., MAOA, 5HTT) risk factors that can disturb socio-, psycho-, and biological development and interact with testosterone in shaping behavior. When these additional risk factors are present, the testosterone induced endophenotypes may increase the risk for a chronic antisocial lifestyle. However, behavioral endophenotypes induced by testosterone can also predispose towards socially adaptive traits such as a strong achievement motivation, leadership, fair bargaining behaviors, and social assertiveness. These adaptive traits are more likely to emerge when the high testosterone individual has positive social experiences that promote prosocial behaviors such as strong and secure attachments with his caregivers, affiliation with prosocial peers, and sufficient socioeconomic resources. A theoretical model is presented, various hypotheses are examined, and future venues for research are discussed.
... For example, enhancing the function of dopaminergic neurons (Kimmel, Gong, Vechia, Hunter, & Kuhar, 2000) or glutamate receptors in the VTA or the NA evoked dose-dependent increases in motor activity (Swanson & Kalivas, 2000). Also, steroids in the VTA and the NA modulate other behaviors characterized by dramatic changes in motoricity, such as social behavior (Frye, 2001b) and place learning (Frye, Rhodes, Rosellini, & Svare, 2001). ...
Blocking progesterone’s metabolism to 5α -pregnan-3α -ol-20-one (3α ,5α -THP) with finasteride, a 5α -reductase inhibitor,
and effects on anxiolytic, exploratory, and antinociceptive behaviors of rats in behavioral estrus were examined. Rats in
behavioral estrus received finasteride systemically (SC), to the hippocampus, or to control implant sites, the nucleus accumbens
(NA) or ventral tegmental area (VTA), and were tested in horizontal crossing, open-field, elevated plus-maze, emergence, holeboard,
social interaction, tailflick, pawlick, and defensive freezing tasks. Finasteride, SC or intrahippocampally, reduced 3α ,5α
-THP in the hippocampus relative to vehicle implants or finasteride to the NA or VTA. Systemic or intrahippocampal finasteride
decreased central entries in the open field and open-arm time on the elevated plus-maze and increased freezing in response
to shock relative to vehicle. Finasteride to the hippocampus decreased emergence latencies and increased social interaction,
pawlick, and tailflick latencies relative to all other groups. Finasteride to the hippocampus of rats in behavioral estrous
decreased anxiolysis and enhanced exploration and analgesia. In summary, these data demonstrate that decreases in anxiolytic
behavior of behavioral estrous rats can be produced by reductions in 3α ,5α -THP in the hippocampus, which suggest that elevations
in 3α ,5α -THP in the hippocampus may give rise to anxiolysis seen during behavioral estrus.
... Male rodents permitted access to an estrous female in a place preference apparatus have consistently shown a preference for the chamber in which mating occurred [15,61,82,84]. Likewise, peripheral injections of T, DHT or 3a-diol also induce place preferences in rats [4,107]. As discussed above [75], the role of T elevations in sexual contexts remains poorly understood. ...
The functions of rapid increases in testosterone seem paradoxical because they can occur in response to different social contexts, such as male–male aggressive encounters and male–female sexual encounters. This suggests that context may impact the functional consequences of changes in testosterone, whether transient or long term. Many studies, including those with California mice (Peromyscus californicus), have addressed these issues using manipulations and species comparisons, but many areas remain to be investigated. We report a study here that suggests transient increases in testosterone after social competition influence future competitive behavior, but social experience alone may also be critical in determining future behavior. In other rodents, a comparable testosterone surge occurs in response to sexual stimulation, but the function is not entirely understood. In addition to competitive and sexual behavior, testosterone impacts other systems instrumental to social behaviors, including paternal behavior and degree of monogamy. Thus, mechanisms regulated by testosterone, such as the vasopressin and aromatase systems, may also be influenced by rapid surges of testosterone in aggressive or sexual contexts. We discuss how the functions of testosterone may overlap in some contexts.
... Both opioids and anabolic steroids produce hedonic effects in rodents, which are mediated by the dopaminergic system (Rosellini et al., 2001). Moreover, there is a growing literature demonstrating an interaction between androgens and opioids in the mechanisms mediating their effects (Wood, 2008). ...
Opioid administration in males results in opioid-induced androgen deficiency which persists throughout the treatment. In adults, this quickly reverses once opioid administration is suspended. However, less is known about the duration of the effect following drug discontinuation in adolescents. Given the significant implications to sexual maturation in adolescent males, this study examined plasma testosterone levels in both morphine withdrawn mice and their drug-naïve (saline-injected) cage-mates as compared to drug-naïve mice housed physically and visually separate from the morphine-treated mice ('saline only'). Consistent with the literature, plasma testosterone levels in morphine withdrawn adults were reduced on withdrawal day 1 (WD1) and returned to baseline levels by WD9. No significant effects were observed in their saline cage-mates. In the adolescents, no significant differences were observed on WD1 between the morphine withdrawn mice, their saline cage-mates, and the saline only mice - all of which had significantly lower plasma testosterone levels than adults. By WD9, testosterone levels in the saline only adolescent mice had reached adult levels. Notably, plasma testosterone levels were reduced in both the morphine withdrawn adolescent mice and their saline cage-mates, as compared to saline only mice. The effect was not a drug effect per se, given that reduced plasma testosterone levels were not observed in individually housed morphine withdrawn mice. Moreover, our results also suggest that these social effects are not solely explained by stress. These results have numerous implications to the short term and long term health of both adolescents requiring pain management and of adolescent drug addicts.
... Neurosteroids may have reinforcing properties via actions in the VTA. Foremost, neurosteroids are rewarding as they readily condition a place preference (Finn et al. 1997; Rosellini et al. 2001) and are systemically self-administered by rodents preferentially over vehicle (Frye et al. 2007a; Sinnott et al. 2002). The paced mating paradigm allows the female the opportunity to " self-administer " her copulatory contacts as occurs in the natural environment (Calhoun 1962). ...
In the midbrain ventral tegmental area (VTA), actions of neurosteroids, such as the progesterone metabolite, 5α-pregnan-3α-ol-20-one (3α,5α-THP), can facilitate mating and influence stress-related processes. Some actions of 3α,5α-THP may occur via positive modulation of GABA(A) receptors (GBRs), or negative modulation of N-methyl-D: -aspartate receptors (NMDARs), to influence anxiety-like behavior; but this is not known.
We aimed to assess the role that neurosteroids and stress factors play on intra-VTA NMDAR- and/or GBR-mediated anxiety-like and mating behavior.
Estradiol-primed, ovariectomized rats, which were partially or completely adrenalectomized (ADX), received infusions of vehicle, an NMDAR blocker (MK-801; 200 ng), or a GBR antagonist (bicuculline, 100 ng) to the VTA. Rats then received intra-VTA vehicle or a neurosteroidogenesis enhancer (N,N-Dihexyl-2-(4-fluorophenyl)indole-3-acetamide, FGIN 1-27, 5 μg) and anxiety-like and sexual behavior was assessed.
Complete, compared to partial, ADX significantly reduced open arm exploration on an elevated plus maze, the proportion of females that engaged in mating, lordosis quotients, pacing of sexual contacts, and defensive aggression towards a sexually vigorous male. Intra-VTA MK-801 enhanced open arm investigation and the proportion of females that engaged in mating. Infusions of either, MK-801 or FGIN 1-27, enhanced lordosis and, when co-administered, FGIN 1-27 attenuated MK-801's lordosis-enhancing effects. Intra-VTA infusions of bicuculline, prior to FGIN 1-27, blocked FGIN 1-27's effects to enhance lordosis.
Together, these data suggest that reduced NMDAR activity in the VTA may influence motivation to explore and engage in sexual behavior. These data suggest that neurosteroid actions at NMDARs and GBRs in the VTA are important for exploration and/or sexual behavior.
... This four hour delay would allow for slow genomic effects, both by direct actions of testosterone or metabolites such as dihydrotestosterone (DHT) on intracellular androgen receptors and after aromatization to estradiol. Indeed, research has shown that both DHT (Rosellini et al., 2001) and estradiol (Jorge et al., 2005) have reinforcing properties similar to testosterone (DiMeo and Wood, 2006b), and there is evidence in humans showing menstrual cycle-dependent changes in reward processing that are likely associated with estradiol (Dreher et al., 2007). Although genomic effects presumably contribute strongly to effects of androgens on sexual behavior (Wood, 2008), nuclear an-drogen receptors are relatively scarce in NAcc and VTA (Stumpf and Sar, 1976), suggesting that other, nongenomic, effects may be implicated. ...
Changing social environments such as the birth of young or aggressive encounters present a need to adjust behavior. Previous research examined how long-term changes in steroid hormones mediate these adjustments. We tested the novel concept that the rewarding effects of transient testosterone pulses (T-pulses) in males after social encounters alters their spatial distribution on a territory. In free-living monogamous California mice ( Peromyscus californicus ), males administered three T-injections at the nest spent more time at the nest than males treated with placebo injections. This mimics T-induced place preferences in the laboratory. Female mates of T-treated males spent less time at the nest but the pair produced more vocalizations and call types than controls. Traditionally, transient T-changes were thought to have transient behavioral effects. Our work demonstrates that in the wild, when T-pulses occur in a salient context such as a territory, the behavioral effects last days after T-levels return to baseline.
Background:
Age-dependent alterations of hormonal states have been considered to be involved in age related decline of cognitive abilities. Most of the studies in animal models are based on hormonal substitution in adrenal- and/or gonadectomized rodents or infusion of steroid hormones in intact rats. Moreover, the manipulations have been done timely, closely related to test procedures, thus reflecting short-term hormonal mechanisms in the regulation of learning and memory. Here we studied whether more general states of steroid and thyroid hormone profiles, independent from acute experiences, may possibly reflect long-term learning capacity. A large cohort of aged (17-18 months) intact male rats were tested in a spatial hole-board learning task and a subset of inferior and superior learners was included into the analysis. Young male adult rats (16 weeks of age) were also tested. Four to 8 weeks after testing blood plasma samples were taken and hormone concentrations of a variety of steroid hormones were measured by gas chromatography-tandem mass spectrometry or radioimmunoassay (17β-estradiol, thyroid hormones).
Results:
Aged good learners were similar to young rats in the behavioral task. Aged poor learners but not good learners showed higher levels of triiodothyronine (T3) as compared to young rats. Aged good learners had higher levels of thyroid stimulating hormone (TSH) than aged poor learning and young rats. Both aged good and poor learners showed significantly reduced levels of testosterone (T), 4-androstenedione (4A), androstanediol-3α,17β (AD), dihydrotestosterone (DHT), 17-hydroxyprogesterone (17OHP), higher levels of progesterone (Prog) and similar levels of 17β-estradiol (E2) as compared to young rats. The learning, but not the memory indices of all rats were significantly and positively correlated with levels of dihydrotestosterone, androstanediol-3α,17β and thyroxine (T4), when the impacts of age and cognitive division were eliminated by partial correlation analyses.
Conclusion:
The correlation of hormone concentrations of individuals with individual behavior revealed a possible specific role of these androgen and thyroid hormones in a state of general preparedness to learn.
Major depressive disorder (MDD) is a debilitating chronic illness that is two times more prevalent in women than in men. The mechanisms associated with the increased female susceptibility to depression remain poorly characterized. Aberrant neuronal oscillatory activity within the putative depression network is an emerging mechanism underlying MDD. However, innate sex differences in network activity and its contribution to depression vulnerability have not been well described. In this review, current evidence of sex differences in neuronal oscillatory activity, including the influence of sex hormones and female cycling, will first be described followed by evidence of disrupted neuronal circuit function in MDD and the effects of antidepressant treatment. Lastly, current knowledge of sex differences in MDD-associated aberrant circuit function and oscillatory activity will be highlighted, with an emphasis on the role of sex steroids and female cycling. Collectively, it is clear that there are significant gaps in the literature regarding innate and pathologically associated sex differences in network activity and that the elucidation of these differences is invaluable to our understanding of sex-specific vulnerabilities and therapies for MDD.
Drug use influences sexual behavior, performance, and can be associated with increased sexual risk-taking. Our prior results using an animal model indicate that progestogens contribute to hormonally-mediated changes in sexual behavior of female rodents during acute cocaine exposure. Androgens, such as testosterone, and its metabolite 3ɑ-androstanediol (3α-diol), and estradiol, are known to influence male sexual behavior, but can also alter the expression of sexual behavior of female rodents. As such, we investigated the influence of endogenous androgen and estradiol fluctuations on cocaine-mediated changes in motor behavior and sexual receptivity of rats during diestrous or proestrous phases of the estrous cycle. Female rats were administered saline or cocaine (5, 10, or 20mg/kg, i.p.). Motor behavior was observed in the first 30min following drug administration, and then sexual responding was assessed for 15min. Cocaine decreased aggressive behavior in response to attempted mounts by a male among non-receptive (diestrous) rats and inhibited sexual behavior among sexually receptive (proestrous) rats. Cocaine dose-dependently altered concentrations of testosterone metabolites (estradiol and 3α-diol), but not testosterone, which correlated to motor and sexual behaviors of diestrous and proestrous rats, respectively. These data suggest that actions of 3α-diol may be involved in female sexual and motor behavior in response to cocaine, in a cycle-dependent manner.
One of the hallmarks of drug abuse is a reduction in the salience of, and motivation for, natural rewards, such as mating. The effects of psychostimulants on male sexual interest and performance are conflicting; use of psychostimulants can produce increases in risky sexual behaviors but have detrimental effects on sexual ability. We hypothesize that these conflicting effects on sexual behavior are due to interactions between cocaine and androgens, such as testosterone and its neuroactive metabolite, 3α-androstanediol (3α-diol). Male rats were administered saline or cocaine (5, 10, or 20mg/kg, i.p.). Motor behavior was observed in the first 30min following drug-administration, and then sexual responding was assessed for 15min. Levels of androgens (T, 3ɑ-diol, and T's aromatized metabolite, estradiol (E2)) were measured in circulation and brain regions (frontal cortex, hippocampus, hypothalamus/striatum (hypo/str), and midbrain). Cocaine had no effect on measures of sexual interest (i.e. anogenital investigation). However, cocaine had substantial effects on consummatory sexual behaviors, such as the latency to mount/intromit and the number of sexual contacts. Frontal cortex and hypo/str 3α-diol levels were strongly correlated with consummatory behaviors in saline administered rats; however, this relationship was disrupted by cocaine at all dosages, concomitant with impaired sexual behaviors. Additionally, there was a shift in metabolism at low dosages of cocaine to push T metabolism in the midbrain towards 3α-diol. On the contrary, moderate and high dosages of cocaine shifted T metabolism towards E2. These data demonstrate that the association between cortical and hypo/str 3α-diol levels and sexual behavior of male rats is disrupted by non-contingent cocaine and that there may be dose-dependent effects of acute cocaine on androgen metabolism.
Neuroanatomical and neurotransmitter changes in the ageing brain
Risky decision making is prominent during adolescence, perhaps contributed to by heightened sensation seeking and ongoing maturation of reward and dopamine systems in the brain, which are, in part, modulated by sex hormones. In this study, we examined sex differences in the neural substrates of reward sensitivity during a risky decision-making task and hypothesized that compared with girls, boys would show heightened brain activation in reward-relevant regions, particularly the nucleus accumbens, during reward receipt. Further, we hypothesized that testosterone and estradiol levels would mediate this sex difference. Moreover, we predicted boys would make more risky choices on the task. While boys showed increased nucleus accumbens blood oxygen level-dependent (BOLD) response relative to girls, sex hormones did not mediate this effect. As predicted, boys made a higher percentage of risky decisions during the task. Interestingly, boys also self-reported more motivation to perform well and earn money on the task, while girls self-reported higher state anxiety prior to the scan session. Motivation to earn money partially mediated the effect of sex on nucleus accumbens activity during reward. Previous research shows that increased motivation and salience of reinforcers is linked with more robust striatal BOLD response, therefore psychosocial factors, in addition to sex, may play an important role in reward sensitivity. Elucidating neurobiological mechanisms that support adolescent sex differences in risky decision making has important implications for understanding individual differences that lead to advantageous and adverse behaviors that affect health outcomes.
Anabolic androgenic steroids (AAS) are substances that mimic the hormone testosterone, and primarily act via the androgen receptor. In addition to their physiological effect on muscle tissue and growth, research from the last decade has shown that AAS have a pronounced impact on the central nervous system. A large number of studies have demonstrated that AAS affect the mesolimbic reward system in the brain. However, whether the direct effects of AAS on endorphins, dopamine, serotonin and GABA etc. and on the corresponding and related systems lead to dependence needs to be further elucidated. According to recent studies, the prevalence of AAS dependence among AAS users has been estimated to be approximately 30%, and polysubstance use, of both pharmaceutical drugs and narcotics, within this group is common. The present review primarily discusses AAS in the context of addiction and dependence, and further addresses the issue of using multiple substances, i.e. stimulants and opiates in combination with AAS. In addition, aspects of the treatment of AAS dependence, the connection between AAS abuse and cognition, and AAS-induced neurotoxicity are presented. Currently, performance enhancing drugs are frequently used in combination with AAS. Therefore, a large section on growth hormone and insulin-like growth factor is also included.
3alpha-Androstanediol is synthesized from testosterone in peripheral tissues and in the brain, but the clinical importance of this neurosteroid remains unclear. This study evaluated the effects of 3alpha-androstanediol on seizure susceptibility in mouse models of epilepsy. 3alpha-Androstanediol protected mice against seizures induced by GABA(A) receptor antagonists pentylenetetrazol, picrotoxin, and beta-carboline ester in a dose-dependent fashion. However, 3alpha-androstanediol was inactive against seizures induced by glutamate receptor agonists kainic acid, NMDA and 4-aminopyridine. Pretreatment with the androgen receptor antagonist flutamide had no effect on seizure protection by 3alpha-androstanediol. These results suggest that 3alpha-androstanediol has powerful anticonvulsant activity that occurs largely through non-genomic mechanisms. Testosterone-derived 3alpha-androstanediol might be an endogenous protective neurosteroid in the brain.
Background: Studies have demonstrated that exogenous neurosteroid treatment prevents the development of morphine tolerance and dependence, and attenuates abstinence behavior in mice. However, there are few studies on whether the levels of endogenous neurosteroids can be changed by morphine dependence and withdrawal. Objective: To investigate the levels of various neurosteroids in rat brain following morphine dependence and withdrawal. To evaluate the expressions of steroidogenic enzyme mRNAs and proteins. To identify the relationship between neurosteroids and morphine dependence at the whole animal behavior, neural biochemistry, and molecular levels. Design, Time and Setting: A randomized, controlled study. Experiments were performed at the Department of Pharmacology of Hebei Medical University and Department of Pharmacology of Beathune International Peace Hospital, China, from June 2004 to October 2007. Materials: Morphine hydrochloride injection (Shenyang First Pharmaceutical Factory, China), naloxone hydrochloride (Hunan Yiqiao Pharmaceutical Co., China) and a gas chromatography-mass spectrometry system (Agilent, CA, USA) were used in this study. Methods: Healthy adult Sprague Dawley rats were randomly divided into three groups: a morphine dependence group, morphine withdrawal group and control group (n = 20). The rats in the morphine dependence and morphine withdrawal groups were given increasing doses of morphine (5, 10, 15, 20, 30, 40 and 50 mg/kg, intraperitoneal) to create morphine dependence. The rats in the morphine withdrawal group were injected with 2 mg/kg naloxone to precipitate withdrawal 1 hour after the last morphine injection. Rats in the control group were treated with an equal volume of saline. Main Outcome Measures: Following morphine dependence and withdrawal, brain levels of the neurosteroids pregnenolone, progesterone and allopregnanolone were analyzed using gas chromatography-mass spectrometry. The mRNA expression of two key steroidogenic enzymes, P450 side-chain cleavage enzyme (P450scc) and 3β-hydroxysteroid dehydrogenase (3β-HSD), were determined in rat brain regions using reverse transcription-polymerase chain reaction. The distribution and expression of P450scc protein were visualized in brain regions associated with addiction by immunohistochemistry. Results: In brain tissue from the morphine dependence group, the levels of pregnenolone and progesterone were decreased by 62% (P < 0.01) and 92% (P < 0.01) respectively, compared with the control group. In the morphine dependence group, the key steroidogenic enzyme P450scc mRNA was decreased in striatum (P < 0.05), while 3β-HSD mRNA was decreased in amygdala (P < 0.05), striatum (P < 0.05) and frontal cortex (P < 0.05) compared with the control group. Morphine withdrawal induced a significant increase in the neurosteroid levels compared with the control group (P < 0.01). However, there was no significant difference in the expressions of P450scc and 3β-HSD mRNAs between the morphine withdrawal and control groups (P > 0.05). Conclusion: The neurosteroid levels and expressions of steroidogenic enzymes changed similarly in morphine dependent rats, suggesting that the morphine dependence-induced decrease in neurosteroids might depend on local expression of steroidogenic enzymes in the central nervous system. However, the changes in neurosteroids in morphine withdrawal rats were not in accordance with the changes in the expression of steroidogenic enzymes, suggesting that the effects of morphine withdrawal on brain neurosteroid levels may not depend primarily on the local expression of steroidogenic enzymes in the central nervous system.
Estrogenic and androgenic steroids synthesized in the brain may rapidly modulate synaptic plasticity interacting with specific membrane receptors. We explored by electrophysiological recordings in hippocampal slices of male rat the influence of 17β-estradiol (E2) and 5α-dihydrotestosterone (DHT) neo-synthesis on the synaptic changes induced in the CA1 region. Induction of long-term depression (LTD) and depotentiation (DP) by low frequency stimulation (LFS, 15 min-1 Hz) and of long-term potentiation (LTP) by high frequency stimulation (HFS, 1 s-100 Hz), medium (MFS, 1 s-50 Hz), or weak (WFS, 1 s-25 Hz) frequency stimulation was assayed under inhibitors of enzymes converting testosterone (T) into DHT (5α-reductase) and T into E2 (P450-aromatase). We found that LFS-LTD depends on DHT synthesis, since it was fully prevented under finasteride, an inhibitor of DHT synthesis, and rescued by exogenous DHT, while the E2 synthesis was not involved. Conversely, the full development of HFS-LTP requires the synthesis of E2, as demonstrated by the LTP reduction observed under letrozole, an inhibitor of E2 synthesis, and its full rescue by exogenous E2. For intermediate stimulation protocols DHT, but not E2 synthesis, was involved in the production of a small LTP induced by WFS, while the E2 synthesis was required for the MFS-dependent LTP. Under the combined block of DHT and E2 synthesis all stimulation frequencies induced partial LTP. Overall, these results indicate that DHT is required for converting the partial LTP into LTD whereas E2 is needed for the full expression of LTP, evidencing a key role of the neo-synthesis of sex neurosteroids in determining the direction of synaptic long-term effects.
In addition to androgenic properties mediated via androgen receptors, dihydrotestosterone (DHT) also regulates estrogenic functions via an alternate pathway. These estrogenic functions of DHT are mediated by its metabolite 5α-androstane-3β, 17β-diol (3β-diol) binding to estrogen receptor β (ERβ). CYP7B1 enzyme converts 3β-diol to inactive 6α- or 7α-triols, and plays an important role as a regulator of estrogenic functions mediated by 3β-diol. Using a mutant mouse carrying a null mutation for the CYP7B1 gene (CYP7B1KO), we examined the contribution of CYP7B1 on physiology and behavior. Male, gonadectomized CYP7B1KO and their wild type (WT) littermates were assessed for their behavioral phenotype, anxiety-related behavioral measures and hypothalamic pituitary adrenal (HPA) axis reactivity. No significant effects of genotype were evident in anxiety-like behaviors in open field (OFA), light-dark (L/D) exploration, and elevated plus maze (EPM). Testosterone (T) significantly reduced open arm time on the EPM, while not affecting L/D exploratory and OFA behaviors in CYP7B1KO and WT littermates. T also attenuated the corticosterone response to EPM in both genotypes. In gonadectomized animals, T was able to reinstate male-specific reproductive behaviors (latencies and number of mounts, intromission, and ejaculations) in the WT, but not in the CYP7B1KO mice. The male reproductive behavior defect in CYP7B1KO appears to be due to their inability to distinguish olfactory cues from a behavioral estrous female. CYP7B1KO mice also showed a reduction in androgen receptor (AR) mRNA expression in the olfactory bulb. Our findings suggest a novel role for the CYP7B1 enzyme in the regulation of male reproductive behaviors.
In recent years there has been a growing recognition of the influence of sex on brain structure and function, and in relation, on the susceptibility, prevalence and response to treatment of psychiatric disorders. Most theories and descriptions of the effects of sex on the brain are dominated by an analogy to the current interpretation of the effects of sex on the reproductive system, according to which sex is a divergence system that exerts a unitary, overriding and serial effect on the form of other systems. We shortly summarize different lines of evidence that contradict aspects of this analogy. The new view that emerges from these data is of sex as a complex system whose different components interact with one another and with other systems to affect body and brain. The paradigm shift that this understanding calls for is from thinking of sex in terms of sexual dimorphism and sex differences, to thinking of sex in terms of its interactions with other factors and processes. Our review of data obtained from animal models of psychopathology clearly reveals the need for such a paradigmatic shift, because in the field of animal behaviour whether a sex difference exists and its direction depend on the interaction of many factors including, species, strain, age, specific test employed and a multitude of environmental factors. We conclude by explaining how the new conceptualization can account for sex differences in psychopathology.
Linked Articles
This article is part of a themed section on Animal Models in Psychiatry Research. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-20
CA1 region of hippocampus has an important role in learning and memory. Previous reports have shown that androgens like testosterone and its metabolites are present in high concentration in CA1 region of hippocampus. Androgen receptors have also high density in this region. Therefore, it is suggested that neurohormones in CA1 have an important role in learning and memory. It is likely that testosterone exerts its effect via its metabolites, especially dihydrotestosterone (DHT), a 5α-reduced androgen. In this research, we conducted an experiment to assess the path of testosterone›s effectiveness on spatial learning and memory. Adult male rats were randomly divided into 4 groups and, bilaterally, cannulated into CA1 region of hippocampus. One week after the surgery, animals received DMSO 0.5 μL as a control group and different doses of dihydrotestosterone (DHT) (0.25, 0.5 and 1 µg/0.5 μL/side) 25-30 min before the training in spatial version of Morris Water Maze task. Training session contained two blocks which animals had to learn the position of hidden platform in 4 trials. On the test session (next day), rats performed a one-trial probe test and then a visible platform one. The results showed that escape latency and traveled distance were decreased significantly in DHT-treated (0.5 µg/0.5 μL/side) rats. This finding suggested that DHT may have improved the effect on acquisition of spatial learning and memory.
This article describes the emerging evidence of hormonal influence on epileptogenesis, which is a process whereby a brain becomes progressively epileptic due to an initial precipitating event of diverse origin such as brain injury, stroke, infection, or prolonged seizures. The molecular mechanisms underlying the development of epilepsy are poorly understood. Neuroinflammation and neurodegeneration appear to trigger epileptogenesis. There is an intense search for drugs that truly prevent the development of epilepsy in people at risk. Hormones play an important role in children and adults with epilepsy. Corticosteroids, progesterone, estrogens, and neurosteroids have been shown to affect seizure activity in animal models and in clinical studies. However, the impact of hormones on epileptogenesis has not been investigated widely. There is emerging new evidence that progesterone, neurosteroids, and endogenous hormones may play a role in regulating the epileptogenesis. Corticosterone has excitatory effects and triggers epileptogenesis in animal models. Progesterone has disease-modifying activity in epileptogenic models. The antiepileptogenic effect of progesterone has been attributed to its conversion to neurosteroids, which binds to GABA-A receptors and enhances phasic and tonic inhibition in the brain. Neurosteroids are robust anticonvulsants. There is pilot evidence that neurosteroids may have antiepileptogenic properties. Future studies may generate new insight on the disease-modifying potential of hormonal agents and neurosteroids in epileptogenesis.
Androgens have dramatic effects on neuronal structure and function in hippocampus. However, androgen depletion does not always lead to hippocampal impairment. To address this apparent paradox, we evaluated the hippocampus of adult male rats after gonadectomy (Gdx) or sham surgery. Surprisingly, Gdx rats showed increased synaptic transmission and long-term potentiation of the mossy fiber (MF) pathway. Gdx rats also exhibited increased excitability and MF sprouting. We then addressed the possible underlying mechanisms and found that Gdx induced a long-lasting upregulation of MF BDNF immunoreactivity. Antagonism of Trk receptors, which bind neurotrophins, such as BDNF, reversed the increase in MF transmission, excitability, and long-term potentiation in Gdx rats, but there were no effects of Trk antagonism in sham controls. To determine which androgens were responsible, the effects of testosterone metabolites DHT and 5α-androstane-3α,17β-diol were examined. Exposure of slices to 50 nm DHT decreased the effects of Gdx on MF transmission, but 50 nm 5α-androstane-3α,17β-diol had no effect. Remarkably, there was no effect of DHT in control males. The data suggest that a Trk- and androgen receptor-sensitive form of MF transmission and synaptic plasticity emerges after Gdx. We suggest that androgens may normally be important in area CA3 to prevent hyperexcitability and aberrant axon outgrowth but limit MF synaptic transmission and some forms of plasticity. The results also suggest a potential explanation for the maintenance of hippocampal-dependent cognitive function after androgen depletion: a reduction in androgens may lead to compensatory upregulation of MF transmission and plasticity.
A decline in androgen and/or estrogen levels with aging can be associated with cognitive deficits in men. Androgen replacement to rodents with reduced androgen levels due to extirpation of the testes can reverse these deficits. However, there are multiple routes of metabolism and multiple substrates through which androgens may act to produce beneficial cognitive effects. Testosterone (T), which has a high affinity for androgen receptors (ARs), can be aromatized to 17-estradiol, which may have actions at estrogen receptor (ER) to produce beneficial cognitive effects. Alternatively, T can be 5-reduced to dihydrotesterone (DHT), which also has actions at ARs, or further reduced to 5--androstane,17-diol-3-diol (3-diol), which may have actions at GABA/benzodiazepine (GBRs) or ER. The present studies examined whether administration of estrogens and androgens that may have actions at ERs can enhance cognitive performance of male rats. Adult male rats were sham-surgerized and administered vehicle, or gonadectomized 3-6 weeks prior to testing. Gonadectomized rats were administered 3-diol, selective estrogen receptor modulators (SERMs) that had similar affinity for ER and ER (17-estradiol), greater affinity for ER than ER (3-diol, diarylpropionitrile (DPN), coumestrol), or greater affinity for ER than ER (17-estradiol, propyl pyrazole triol (PPT), or vehicle control. Compounds were administered via 1 mg/kg subcutaneous injections immediately following training in the object recognition task. Four hours later, rats were tested in the task. Rats administered 17-estradiol, 3-diol, 17estradiol, or DPN had enhanced performance in the object recognition task compared to vehicle-administered rats. Thus, actions at ERs may underlie some of estrogens' or androgens' cognitive-enhancing effects.
The neurosteroids, dehydroepiandrosterone sulfate (DHEAS) and androsterone, are implicated in drug addictions. We examined their influence on locomotor activity and reward in male Wistar rats, and on steroid and monoamine metabolism in the hippocampus and striatum. In the open field test, DHEAS injections (10, 40, 80 mg/kg, i.p.) 30 min prior the test had no significant effect on ambulation, but androsterone (10 mg/kg) increased general locomotion and at doses 1-10 mg/kg, increased central field activity, suggestive of an anxiolytic action. In the conditioned place preference test, both steroids had a biphasic effect: DHEAS was rewarding at doses of 10 and 40 mg/kg, but not at 80 mg/kg, while androsterone was rewarding at doses of 1 and 10 mg/kg, but aversive at 40 mg/kg. Monoamine and steroid concentrations were analyzed in homogenates from the hippocampus and striatum of DHEAS and androsterone injected rats. DHEAS reduced the hippocampal dopamine level, increased striatal homovanilic acid (HVA) and decreased the striatal serotonin concentrations. Androsterone did not affect dopamine levels or turnover, but increased noradrenaline concentration and serotonin turnover in the hippocampus. DHEAS administration augmented concentrations of DHEA, pregnenolone, androstendiol and androstentriol in both brain structures, while androsterone injections increased brain levels of androsterone, epiandrosterone, 5α-dihydrotestosterone, and androstandiol. Present data document that although psychobehavioral and neurochemical effects of DHEAS and androsterone differ in several aspects; both neurosteroids have rewarding properties at certain dose ranges, suggesting their likely involvement in addictions, which entail different mechanisms.
Alcohol (EtOH) can enhance aggression in people and animal models. These effects are more salient in males than in females. Androgens, such as testosterone (T), may promote aggressive responding to EtOH. Effects of EtOH on androgens and aggression were examined in a resident-intruder paradigm. Gonadally-intact, or castrated (GDX), male rats were socially-isolated for 3 weeks and administered an acute dose of EtOH (2.0 g/kg) or saline (Experiment 1) or administered a dose-response regimen of EtOH (0.0, 0.5, 1.0, and 2.0 g/kg; Experiment 2). Cortical tissues were assessed for androgen concentrations and/or muscimol binding after receiving saline or EtOH. Compared to saline, acute EtOH administration in Experiment 1, enhanced aggression among intact rats and concomitantly enhanced formation of the T metabolite and neurosteroid, 3-androstanediol, (3-diol) in frontal cortex. T was also enhanced in cortex and circulation of intact but not GDX rats. Repeat testing in Experiment 2 revealed dose-dependent effects of EtOH to enhance aggression and cortical 3-diol among both intact and GDX rats. EC50 for muscimol binding was lower for intact and EtOHadministered rats than for GDX or vehicle-administered rats, indicating that less GABA was needed to achieve halfmaximal binding. Together, these data suggest that 3-diol enhancement may partly underlie EtOH’s effects on aggression, possibly via actions at GABAA receptors.
The abuse of androgens may be related to their ability to produce positive, hedonic interoceptive effects. Conditioned Place Preference (CPP) has been used in many experiments to examine hedonic effects of drugs. This review is focused on studies from our laboratory that utilized CPP to examine potential positive hedonic effects of testosterone (T), and its androgenic metabolite dihydrotestosterone (DHT), and its metabolite 3α-androstanediol (3α-diol). We hypothesized that administration of a high concentration of 3α-diol would produce a CPP, pharmacological concentrations of plasma androgens, and alter androgen receptors (AR) and the function of GABAA/benzodiazepine receptor complexes (GBR). In our studies, we observed that systemic 3α-diol (1.0 mg/kg) prior to exposure to the non-preferred side of a CPP chamber significantly increased preference for the non-preferred side of the chamber compared to baseline preference and homecage controls. Furthermore, administration of T, DHT, or 3α-diol increased levels of these androgens, decreased ARs (decreased seminal vesicle weight and intrahypothalamic AR) and GBR function (decreased GABA-stimulated chloride influx in cortical synaptoneurosomes, and muscimol binding in the hippocampus compared to control groups). With systemic administration of 3α-diol that enhanced CPP, concentrations of 3α-diol were increased in the nucleus accumbens (NA). Central implants of T, DHT, or 3α-diol to the NA also produced a CPP compared to baseline preference and vehicle controls. These data indicate that systemic 3α-diol is more effective at enhancing CPP and increasing circulating 3α-diol levels than is T or DHT and that central administration of 3α-diol to the NA can condition a place preference. These findings indicate that 3α-diol produces positive hedonic effects and suggest that T’s variable effects on CPP may be due in part to T’s metabolism to 3α-diol.
Developments in behavioral assessment, autonomic and/or baseline reactivity, psychopharmacology, and genetics, have contributed significantly to the assessment of performance-enhancing drugs in animal models. Particular classes of steroid hormones: androgenic steroids are of interest. Anecdotally, the performance enhancing effects of androgens are attributed to anabolic events. However, there is a discrepancy between anecdotal evidence and investigative data. While some androgen steroids may promote muscle growth (myogenesis), effects of androgens on performance enhancement are not always seen. Indeed, some effects of androgens on performance may be attributable to their psychological and cardiovascular effects. As such, we consider androgen effects in terms of their behavioral, autonomic, and neuroendocrine components. Techniques are discussed in this chapter, some of which are well established, while others have been more recently developed to study androgen action. Androgens may be considered for their positive impact, negative consequence, or psychotropic properties. Thus, this review aims to elucidate some of the effects and/or mechanisms of androgens on behavioral, autonomic, and/or neuroendocrine assessment that may underlie their controversial performance enhancing effects.
Oestradiol exerts a profound influence upon multiple brain circuits. For the most part, these effects are mediated by oestrogen receptor (ER)α. We review here the roles of ERβ, the other ER isoform, in mediating rodent oestradiol-regulated anxiety, aggressive and sexual behaviours, the control of gonadotrophin secretion, and adult neurogenesis. Evidence exists for: (i) ERβ located in the paraventricular nucleus underpinning the suppressive influence of oestradiol on the stress axis and anxiety-like behaviour; (ii) ERβ expressed in gonadotrophin-releasing hormone neurones contributing to oestrogen negative-feedback control of gonadotrophin secretion; (iii) ERβ controlling the offset of lordosis behaviour; (iv) ERβ suppressing aggressive behaviour in males; (v) ERβ modulating responses to social stimuli; and (vi) ERβ in controlling adult neurogenesis. This review highlights two major themes; first, ERβ and ERα are usually tightly inter-related in the oestradiol-dependent control of a particular brain function. For example, even though oestradiol feedback to control reproduction occurs principally through ERα-dependent mechanisms, modulatory roles for ERβ also exist. Second, the roles of ERα and ERβ within a particular neural network may be synergistic or antagonistic. Examples of the latter include the role of ERα to enhance, and ERβ to suppress, anxiety-like and aggressive behaviours. Splice variants such as ERβ2, acting as dominant negative receptors, are of further particular interest because their expression levels may reflect preceeding oestradiol exposure of relevance to oestradiol replacement therapy. Together, this review highlights the predominant modulatory, but nonetheless important, roles of ERβ in mediating the many effects of oestradiol upon adult brain function.
Little is known about the role of steroidogenic enzymes in pain modulation. This study examined the effects of 5α-reductase and aromatase inhibition on formalin-induced tonic pain (FITP) in adult female rats. The animals received subcutaneous injection (5 mg/kg) of finasteride (an inhibitor of 5α-reductase) and letrozole (an inhibitor of aromatase), either separately or in combination, 15 min before formalin injection at a low (0.25%) and high (2.5%) concentration. Pretreatment with inhibitors increased FITP evoked by injection of 0.25% formalin, but they were not effective on 2.5% formalin pain. The enhancing effects of finasteride and letrozole on FITP induced by 2.5% formalin was demonstrated by inhibitory actions of these drugs on morphine (7 and 10 mg/kg, intraperitoneal) induced antinociception. The nervous system could be considered as the main target of the enzymes inhibition, since the pronociceptive effect was also observed after administration of inhibitors to ovariectomized rats. Altogether, these findings suggest that the biological activity of the enzymes 5α-reductase and aromatase modulates FITP and may help to develop effective therapeutic strategies to counteract pain.
The purpose of this study was to provide a quantitative assessment of female rat sexual behaviors after acute exposure to the A-ring reduced testosterone metabolite, androstanediol (3α-Diol), through the nucleus accumbens (NA) shell.
Quantitative analyses of female rat sexual behaviors and assessment of protein levels for the enzyme glutamic acid decarboxylase isoform 67 (GAD67) and gephyrin, a protein that participates in the clustering of GABA-A receptors in postsynaptic cells, were accomplished.
Female rats were ovariectomized and primed with estrogen and progesterone to induce sexual behaviors. Females received a 3α-Diol infusion via guided cannula that aimed to the NA shell five minutes prior to a sexual encounter with a stud male. The following parameters were videotaped and measured in a frame by frame analysis: lordosis quotient (LQ), Lordosis rating (LR), frequency and duration of proceptive behaviors (hopping/darting and ear wiggling). Levels of GAD67 and gephyrin were obtained by Western blot analysis two or twenty-four hours after the sexual encounter.
Acute exposure to 3α-Diol in the NA shell enhanced LR, ear wiggling, and hopping/darting but not LQ. Some of these behavioral effects were counteracted by co-infusion of 3α-Diol plus the GABAA-receptor antagonist GABAzine. A transient reduction of GAD67 levels in the NA shell was detected.
The testosterone metabolite 3α-Diol enhances sexual proceptivity, but not receptivity, when infused into the NA shell directly. The GABAergic system may participate in the androgen-mediated enhancement of female rat sexual motivation.
The purpose of this study was to assess the effect of long-term deprivation of gonadal hormone on brain aging in mice to develop a model of gonadectomy-accelerated brain aging.
Male and female mice at 2 months old were orchiectomized (ORX) or ovarectomized (OVX) bilaterally or sham operated, and then they were fed for 10 months. The spatial learning and memory ability was tested using Morris Water Maze. The biomarkers of brain neuropathology were examined by Western blotting and immunohistochemistry.
Ovarectomy mildly impaired spatial learning and memory of mice, while the impairment in ORX-mice was not significant. The amount of Nissl bodies decreased in the hippocampus and cortex of gonadectomied mice. The expression of beta-amyloid (Aβ), beta-site APP cleaving enzyme 1 and phosphorylated-Tau increased in gonadectomied mice. Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) decreased in the brain of OVX-mice, but neurotrophin-3 (NT-3) showed no change. We detected no decrease of NGF, BDNF or NT-3 in ORX-mice. TrkA expression decreased and p75(NTR) increased in the brain of gonadectomied mice. In all the above tests, there were no significant differences between young (2 months old) and sham operated (12 months old) mice. Alternations in the brain aging parameters were more obvious in OVX-mice than in ORX-mice.
Long-term gonadal hormone deprivation by young-age gonadectomy accelerated mouse brain aging, which could serve as a valuable mouse model to study brain aging and aging-related pathological changes.
Some hippocampally-influenced affective and/or cognitive processes decline with aging. The role of androgens in this process is of interest. Testosterone (T) is aromatized to estrogen, and reduced to dihydrotestosterone (DHT), which is converted to 5alpha-androstane, 3alpha, 17alpha-diol (3alpha-diol). To determine the extent to which some age-related decline in hippocampally-influenced behaviors may be due to androgens, we examined the effects of variation in androgen levels due to age, gonadectomy, and androgen replacement on cognitive (inhibitory avoidance, Morris water maze) and affective (defensive freezing, forced swim) behavior among young (4 months), middle-aged (13 months), and aged (24 months) male rats. Plasma and hippocampal levels of androgens were determined. In experiment 1, comparisons were made between 4-, 13-, and 24-month-old rats that were intact or gonadectomized (GDX) and administered a T-filled or empty silastic capsule. There was age-related decline in performance of the inhibitory avoidance, water maze, defensive freezing, and forced swim tasks, and hippocampal 3alpha-diol levels. Chronic, long-term (1-4 weeks) T-replacement reversed the effects of GDX in 4- and 13-month-old, but not 24-month-old, rats in the inhibitory avoidance task. Experiments 2 and 3 assessed whether acute subcutaneous T or 3alpha-diol, respectively, could reverse age-associated decline in performance. 3alpha-diol, but not T, compared to vehicle, improved performance in the inhibitory avoidance, water maze, forced swim, and defensive freezing tasks, irrespective of age. Thus, age is associated with a decrease in 3alpha-diol production and 3alpha-diol administration reinstates cognitive and affective performance of aged male rats.
There are different physiological processes that influence behavior. One of this processes that produces approach behavior to a stimuli that induces a positive affective (PA) state, commonly known as reward, plays an important role in modulating behavior. There is an extensive literature in which the rewarding effects of drugs have been investigated. Less research has been devoted to the study of naturally occurring behaviors that produce a PA or reward state. Hormones modulate different behaviors, including sex. However, little attention has been devoted to study the possible role of hormones in reward states. One of the methods most frequently used to study reward or PA states is the conditioned place preference (CPP) paradigm. Hopefully this review will encourage researchers to directly address the effects of hormones on reward, research that is much needed.
New neurons are generated in the granule cell layer of the dentate gyrus (GCL) throughout adulthood. This process is modulated by many environmental and neurochemical factors. We previously observed that castrated mice, compared to sham-operated mice, perform poorly in the delayed matching to place water-maze task (DMTP). In this study, we quantified the number of doublecortin expressing (DCX+) immature neurons and Ki-67 expressing (Ki-67+) proliferating progenitors in mice previously tested in a spatial DMTP task, a nonspatial DMTP, or that received equivalent amounts of handling only. Regardless of DMTP training experience, castration reduced immature neuron number in the GCL but had no effect on proliferating progenitors. Compared to handling only, visible DMTP training reduced the immature neuron number, but hidden DMTP training had no effect. Castration did not alter these environmental effects. Finally, performance on the spatial DMTP task did not correlate with immature neuron number. In addition, while the number of immature neurons was strongly reduced following cranial irradiation with (137)Cs, this treatment did not affect spatial DMTP performance. Thus, in mice, castration disrupts spatial memory and reduces immature neuron number, but there is no strong link between these effects.
Evidence from mammalian species, including humans, suggests that testosterone (T) enhances motivational aspects of sexual behavior, although the mechanism by which T exerts this effect is unknown. The hypothesis that increases in plasma T have rewarding affective properties was examined. Acute elevations of plasma T were induced in intact male rats by systemic administration of a recently developed testosterone-hydroxypropyl-β-cyclodextrin inclusion complex that mimics pulsatile release of the hormone. In a conditioned-place-preference paradigm, rats displayed a preference for an environment previously paired with T administration (800 μg/kg and 1,200 μg/kg) as opposed to an environment paired with saline administration, indicating that T has rewarding affective properties. The findings suggest that T may enhance motivational aspects of mammalian sexual behavior by facilitating acquisition or expression of learned associations between environmental stimuli and sexual activity.
Rats that had previously consumed a 6% ethanol (ETOH) solution daily for 26 days and rats without such a history served as subjects in a test for the ability of ETOH to establish a conditioned place preference. The time of putative conditioning was from 4 to 8 min after injections of ETOH, 1 g/kg. The combination of programming the period of putative conditioning to be shortly after injections and using rats habituated to drinking ETOH allowed a conditioned place preference to emerge after only a few conditioning trials. Such a result potentially reveals features of the way ETOH achieves its reinforcing capability and sets the stage for understanding the mechanism of that reinforcement.
Examined the notion of conditioned inhibition and suggests a definition in terms of the learned ability of a stimulus to control a response tendency opposed to excitation. 2 techniques of measuring inhibition are outlined: (1) the summation procedure in which an inhibitor reduces the response that would normally be elicited by another stimulus, and (2) the retardation of acquisition procedure in which an inhibitor is retarded in the acquisition of an excitatory CR. Examples of the use of these procedures are given for a variety of UCS modalities. Several possible operations for generating conditioned inhibitors are reviewed: extinction following excitatory conditioning, discriminative conditioning, arrangement of a negative correlation between CS and a UCS, use of an extended CS-UCS interval, and presentation of a stimulus in conjunction with UCS termination. These operations suggest that conditioned inhibitors are not generated either by simple extinction procedures or by pairing a stimulus with UCS termination. By contrast, for both salivary and fear conditioning the other procedures do appear to generate inhibitors. Most of the procedures generating conditioned inhibitors can be described as arranging a negatively correlated CS and UCS. (2 p. ref.) (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Forty-nine male weight lifters, all users of anabolic-androgenic steroids (AASs), completed an anonymous, self-administered questionnaire to investigate addictive patterns of use. At least one DSM-III-R symptom of dependence was reported by 94% of the sample. Three or more symptoms, consistent with a diagnosis of dependence, were reported by 57%. Dependent users (n = 28) could be distinguished from non-dependent users (n = 21) by their use of larger doses, more cycles of use, more dissatisfaction with body size, and more aggressive symptoms. Multiple regression analysis revealed that dosage and dissatisfaction with body size were the best predictors of dependent use. Patterns of other substances used, although not predictive of AAS dependence, revealed very low cigarette use and at the same time high alcohol consumption. These data support the notion that AASs are addicting, and suggest that dissatisfaction with body size may lead to dependent patterns of use. The implications for both prevention and treatment are discussed.
Recent research has suggested that anabolic-androgenic steroids (AAS) can have positive reinforcing effects in individuals taking chronic high doses in an attempt to improve muscular appearance or to enhance athletic performance. In the present studies, the positive reinforcing efficacy of AAS was investigated in Sprague-Dawley rats by assessing whether testosterone could produce a conditioned place preference (CPP). In Experiment 1, animals administered either 1 mg of testosterone or 8 mg/kg of morphine paired with a specific side of the conditioning chamber showed an increase in the amount of time spent on the putative conditioned side, suggestive of a CPP. Experiment 2 showed that this increase was not differential across groups receiving context-testosterone pairings and those receiving unpaired exposure to testosterone and the context. Animals that received morphine paired with the context, however, showed evidence of a CPP as compared with animals that received unpaired exposure to morphine and the context. Experiment 3 demonstrated that a CPP could not be established using two lower doses of testosterone (10 and 100 μg). It is concluded that it is unlikely that testosterone can produce positive subjective states that can be conditioned to environmental stimuli. Furthermore, the importance of employing drug-exposed nonassociative control groups in the CPP paradigm is emphasized.
Objective.
—To evaluate the acute effects of anabolic steroids on mood and behavior in male normal volunteers.Design.
—A 2-week, double-blind (subject and rater), fixed-order, placebo-controlled crossover trial of methyltestosterone.Setting.
—An inpatient research unit at the National Institutes of Health.Subjects.
—A volunteer sample of 20 men who were medication free, free of medical and psychiatric illness, not involved in athletic training, and had no prior history of anabolic steroid use.Intervention.
—A sequential trial for 3 days each of the following four drug conditions: placebo baseline, low-dose methyltestosterone (40 mg/d), high-dose methyltestosterone (240 mg/d), and placebo withdrawal.Main Outcome Measures.
—Mood and behavioral ratings were completed during each drug condition and included both subjective and objective measures.Results.
—Significant (P<.05) albeit subtle increases in symptom scores were observed during high-dose methyltestosterone administration compared with baseline in positive mood (euphoria, energy, and sexual arousal), negative mood (irritability, mood swings, violent feelings, and hostility), and cognitive impairment (distractibility, forgetfulness, and confusion). An acute manic episode was observed in one of the 20 subjects, representing a 5% incidence, even under these conservative conditions. An additional subject became hypomanic. Baseline characteristics including family psychiatric history or previous drug abuse did not predict symptom changes.Conclusion.
—This is the first placebo-controlled prospective study demonstrating the adverse and activating mood and behavioral effects of anabolic steroids.(JAMA. 1993;269:2760-2764)
Background:
We sought to expand on preliminary findings suggesting that anabolic-androgenic steroids produce psychiatric effects in some athletes who use them.Methods:
We compared 88 athletes who were using steroids with 68 nonusers, using the Structured Clinical Interview for DSM-III-R to diagnose psychiatric syndromes occurring in association with steroid use (if applicable) and in the absence of steroid use. Demographic, medical, and laboratory measures were also performed.Results:
Steroid users displayed more frequent gynecomastia, decreased mean testicular length, and higher cholesterol—high-density lipoprotein ratios than nonusers. Most strikingly, 23% of steroid users reported major mood syndromes—mania, hypomania, or major depression—in association with steroid use. Steroid users displayed mood disorders during steroid exposure significantly more frequently than in the absence of steroid exposure (P<.001) and significantly more frequently than nonusers (P<.01). Users rarely abused other drugs simultaneously with steroids.Conclusion:
Major mood disturbances associated with anabolic-androgenic steroids may represent an important public health problem for athletes using steroids and sometimes for the victims of their irritability and aggression.
Three hundred years ago people made most of what they used, or got it in trade from their neighbours. Now, no one seems to make anything, and we buy what we need from shops. "Gifts and Commodities" describes the cultural and historical process of these changes and looks at the rise of consumer society in Britain and the United States. It investigates the ways that people think about and relate to objects in 20th century culture, at how those relationships have developed, and the social meanings they have for relations with others. Using aspects of anthropology and sociology to describe the importance of shopping and gift-giving in our lives and in western economies, this work traces the development of shopping and retailing practices, and the emergence of modern notions of objects and the self. It brings together a wealth of information on the history of the retail trade and examines the reality of the distinctions we draw between the impersonal economic sphere and personal social sphere and is an interdisciplinary study of the links we forge between ourselves, our social groups and the commodities we buy and give.
The GABAA-receptor agonist neuroactive steroid 3α-hydroxy-5α-pregnan-20-one (3α,5α-P) has anxiolytic and locomotor stimulant effects and shares some subjective properties with benzodiazepines, barbiturates and ethanol, but there have been no studies of its reinforcing or rewarding effects. The present study examined the rewarding properties of 3α,5α-P using the conditioned place preference paradigm. Male DBA/2J mice received four pairings of a distinctive floor stimulus with 3α, 5α-P (3.2, 10 or 17 mg/kg, IP) in an unbiased conditioning procedure. On alternate days a different distinctive floor was paired with vehicle. At the lowest dose (3.2 mg/kg), there was no difference between conditioning subgroups in preference for the drug-paired floor type, indicating an absence of place conditioning. However, a dose-dependent conditioned preference was evident at the higher doses as shown by the greater amount of time spent on the floor paired with 3α,5α-P. In addition, 3α,5α-P produced a dose-dependent increase in locomotor activity, which was significant following the 17 mg/kg dose. A control study showed no effect of the β-cyclodextrin vehicle on place conditioning in the absence of neurosteroid. These results provide the first demonstration that 3α,5α-P, an endogenous modulator of GABAA receptor function, possesses rewarding properties using the conditioned place preference paradigm.
A series of experiments are described providing an assessment of the procedures of conditioned place preference (CPP) testing involving an automated system having 12 separate chambers. Experiment 1 provides data to demonstrate (a) that in these chambers no initial preferences for one side over the other exists among rats, (b) that this neutrality of sides is not affected by session lengths between 15 and 60 min, and (c) that the optimal session length for tests in these chambers is on the order of 30 min. Experiment 2 demonstrates the stability of control groups' scores across a number of conditioning and testing sessions. Experiments 3 and 4 provide data to demonstrate (a) that a positive CPP can be established in our chambers using injections of morphine, (b) that a regimen of dosing with unequal numbers of days of putative and alternate conditioning is a reliable and conservative test of the opioid's ability to establish a CPP, and (c) that although the activity of rats decreases across a session, the general activity of rats before and after conditioning procedures is the same. Experiment 5 replicates the procedures employed by Scoles and Siegel (25) and demonstrates that the tendency for rats to explore novel environments is strong, and care must be taken to provide an opportunity for rats to pair different experiences with each side of the chamber in order for a CPP to emerge.
Ovariectomized rats with cannula over the medial basal hypothalamus (MBH) received implants of 3α-diol conjugated to bovine serum albumin (BSA; 3α-diol:BSA), free 3α-diol diluted with BSA (3α-diol&BSA), progesterone (PRE) conjugated to BSA (PRE:BSA), free PRE diluted with BSA (PRE&BSA), or BSA alone. 3α-diol:BSA or 3α-diol&BSA facilitated receptivity within 90 min. Other estradiol-treated rats received steroid implants in the preoptic area (POA); those receiving PRE:BSA or PRE&BSA showed significant elevations in lordosis in 5 min. When systemic PRE was given, 3α-diol:BSA and 3α-diol&BSA applied to the MBH or POA inhibited receptivity. When 3α-diol was given systemically, 3α-diol:BSA implants to the MBH and POA produced facilitatory effects. These data suggest 3α-diol can act at the membrane and that these effects are influenced by circulating steroids; yet membrane-mediated actions do not account for all of PRE-facilitated sexual behavior in the MBH and POA. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Anabolic steroid use is widespread and has been associated with a variety of pathological conditions. The subject of this case is a 20-year-old amateur bodybuilder who died of sudden cardiopulmonary arrest. He had no previous medical complaints but had a history of anabolic steroid abuse and a hypertrophic heart (515 g) at autopsy. This case presentation will discuss the cardiovascular effects of these drugs and the possible impact of long-term abuse.Copyright © 1995 S. Karger AG, Basel
Forty-nine male weight lifters, all users of anabolic-androgenic steroids (AASs), completed an anonymous, self-administered questionnaire to investigate addictive patterns of use. At least one DSM-III-R symptom of dependence was reported by 94% of the sample. Three or more symptoms, consistent with a diagnosis of dependence, were reported by 57%. Dependent users (n=28) could be distinguished from non-dependent users (n=21) by their use of larger doses, more cycles of use, more dissatisfaction with body size, and more aggressive symptoms. Multiple regression analysis revealed that dosage and dissatisfaction with body size were the best predictors of dependent use. Patterns of other substances used, although not predictive of AAS dependence, revealed very low cigarette use and at the same time high alcohol consumption. These data support the notion that AASs are addicting, and suggest that dissatisfaction with body size may lead to dependent patterns of use. The implications for both prevention and treatment are discussed.
Progesterone (a Δ4-3 keto-pregnane) as well as a series of pregnanes enhanced [3H]muscimol binding to rat cerebral cortex membranes. This effect was increased by preincubation in the presence of the drugs, progesterone being effective only after a 30 min preincubation. The effect of progesterone was dose-dependent from 1 nM to 100 μM reaching a maximum of 140% over control. Its 20α and 20β reduced metabolites (20α- and 20β-OH-4-pregnen-3-one) had no effect. Ring A reduction in either the 5α or 5β position resulted in steroids (5α- and 5β-pregnane-3,20-di-one) producing moderate but consistent facilitation of binding (30–40% increase at 10 μM). The presence of a hydroxyl group in C3 had variable results in the potency of pregnanes to facilitate muscimol binding. Pregnanes with a 3β-OH group showed weaker activity than those having a 3α-OH group, 5α-pregnan-3α-ol-20-one being the most potent (100% stimulation). Pregnenolone, a Δ5-3β-OH-pregnane, was only effective at low concentrations (10 nM to 10 μM). Scatchard analysis of [3H]muscimol binding in the presence of progesterone and 5α-pregnan-3α-ol-20-one revealed that the observed effect was due to an increase in binding sites rather than to a change in affinity.
The necessary conditions to alter rats' initial preferences for two sides of a shuttlebox were investigated, using procedures that are often used in the study of drug reinforcement. In Experiment 1, pairings of morphine sulfate (15 mg/kg, intraperitoneally) and either the nonpreferred side or a holding box was factorially combined with alternate-day pairings of saline and either the preferred side or a holding box. Pairings of saline and the preferred side were necessary and sufficient to increase preferences for the initially nonpreferred side. In Experiment 2, pairings of saline and the nonpreferred side, but not the holding box, strengthened the initial preference, regardless of whether morphine or saline injections preceded alternate-day holding-box placements. In Experiment 3, injection and placement in the preferred side in an unpaired manner, or placement only, decreased preferences for that side more than saline injections alone or no treatment. Paired saline injections and placement produced a greater change in preference than no treatment.
On alternating days, adult male Long–Evans rats implanted with unilateral cannulae in the medial preoptic area (MPOA) received intracerebral injections of testosterone (0.05, 0.1 or 0.2 μg/0.5 μl), or saline immediately prior to confinement for 30 min to one of two compartments of a place preference apparatus. All rats received 8 days of pairings (4 hormone and 4 saline). On day 9, the rats were given a hormone-free 20-min test session during which they had access to all compartments of the apparatus. Intra-MPOA injections of testosterone (0.1 μg) produced a conditioned place preference, while injections of a higher dose (0.2 μg) produced a conditioned place aversion. The rewarding effects of intra-MPOA testosterone may in part mediate the facilatory effects of testosterone on motivational aspects of sexual behavior.
This paper presents a biopsychological theory of drug addiction, the ‘Incentive-Sensitization Theory’. The theory addresses three fundamental questions. The first is: why do addicts crave drugs? That is, what is the psychological and neurobiological basis of drug craving? The second is: why does drug craving persist even after long periods of abstinence? The third is whether ‘wanting’ drugs (drug craving) is attributable to ‘liking’ drugs (to the subjective pleasurable effects of drugs)? The theory posits the following.
Previous evidence indicates that peripheral and intranucleus accumbens injections of testosterone have rewarding effects in male rats as measured in a conditioned place preference (CPP) paradigm. The present study investigated the neurochemical bases of the rewarding properties of testosterone by examining the effect of peripheral and intranucleus accumbens injection of the dopamine receptor antagonist α-flupenthixol on expression of testosterone-induced CPP. On alternating days, adult male Long–Evans rats received peripheral injections of testosterone in a water-soluble hydroxypropyl-β-cyclodextrin (HBC) inclusion complex (0.8 mg/kg) or saline-HBC immediately prior to being confined for 30 min to one of two compartments of a place preference apparatus. All rats received 8 days of pairings (four hormone pairings, four saline pairings). On day 9 the rats were given a 20-min test session during which they had access to all compartments of the apparatus. No hormone was injected prior to the test session; however, rats received a peripheral (20 min prior; 0.2, 0.3 mg/kg) or intra-accumbens (2 min prior, 5.0 μg) injection of α-flupenthixol or saline. On the test day, rats receiving saline injections spent significantly more time in the compartment previously paired with injections of testosterone than in the compartment previously paired with vehicle injections. In contrast, rats receiving peripheral or intra-accumbens α-flupenthixol injections did not spend significantly more time in the compartment previously paired with testosterone. The blockade of testosterone CPP was not due to an effect of α-flupenthixol on motor behavior. The findings provide further evidence of the rewarding affective properties of testosterone and indicate that peripheral administration and intra-accumbens administration of α-flupenthixol block expression of testosterone CPP. The rewarding affective properties of testosterone are mediated, at least in part, via an interaction with the mesolimbic dopamine system.
The levels of β-endorphin and Met-enkephalin-Arg-Phe (MEAP) immunoreactivity in various brain regions (including amygdala, cortex, hippocampus, hypothalmus, nucleus accumbens, pituitary and ventral tegmental area) were studied in male rats subjected to daily intramuscular injections during 14 days of high doses (5 and 15 mg/kg) of the anabolic androgenic steroid (AAS), nandrolone decanoate. At the nandrolone dose of 15 mg/kg a significant (about 20-fold) increase in β-endorphin levels in the ventral tegmental area (VTA) was observed. The steroid did not significantly affect the concentration of the peptide at any dose in other brain areas examined. The levels of MEAP remained unaltered in all studied regions. A slight increase in serum concentrations of both peptides was also found but this elevation was not statistically significant. The observed increase in β-endorphin in VTA was suggested to be involved in a mechanism by which the steroid may influence the reward system in the brain. An opioid mediated stimulation of the reward system following injection of AAS supports a previous hypothesis that AAS may induce psychological dependence.
Synaptosomal membranes were prepared from bovine retinas to measure both high- and low-affinity binding of [(3)H]muscimol which is displaceable by ?-aminobutyric acid (GABA) under various buffering conditions using Tris-citrate (non-physiological) and Krebs-Ringer's bicarbonate (physiological) buffers. The maximum number of high- and low-affinity sites (B(max)) was found when the tissue was prepared and assayed in Tris-citrate; the lowest B(max) occurred when the tissue was prepared and assayed in Krebs. The apparent affinity (K(D)) for the high-affinity site showed a slight dependence on buffering conditions, whereas the K(D) for the low-affinity site did not. These data support the suggestion that physiological ions act to alter the GABA-benzodiazepine receptor complex in vivo. Thus, the correlation of biochemical and electrophysiological data ought to reflect these observations.
Ammonium sulfate precipitation has been used for the separation of bound and free steroids in rat prostate and mouse kidney cytosol equilibrated with tritiated androgens. A high affinity, low capacity binding protein has been identified in the 35% saturation precipitate. Biochemical and physiological data indicate that this protein is identical with the previously described 8-10 S androgen receptor. It has been demonstrated that this receptor protein binds 17 beta - hydroxy-5alpha-androstan-3-one (DHT) and testosterone in both tissues. The apparent dissociation constant (Kd) of the prostatic receptor for DHT and of the renal receptor for testosterone is 1-2 nM. The number of binding sites equals 57 and 23 fmoles/mg protein in prostate and kidney respectively. Dterminations of apparent inhibition constants (Ki) for 26 steroidal and non-steroidal compounds suggest that the binding sites in these tissues is similar or identical.
The binding of GABA to crude synaptic membrane fractions of the rat central nervous system in the absence of sodium appears to involve synaptic receptor sites for GABA. The sodium-independent GABA receptor binding differs in a number of features from sodium-dependent GABA binding. In fresh tissue sodium-dependent GABA binding is about 10 times greater than sodium-independent binding, while freezing and thawing the brain membranes virtually abolishes sodium-dependent binding but increases sodium-independent GABA receptor binding about 2-fold. Both sodium-dependent and -independent GABA binding are saturable processes with dissociation constants of 1.2 muM and 0.37 muM respectively. Sodium-dependent GABA binding is much more sensitive to extremes of temperature and pH than is sodium-dependent GABA binding. In addition, regional variations in synaptosomal uptake of GABA, sodium-dependent and sodium-independent GABA binding are markedly different. Also, amino acids and drugs differ in their potencies as inhibitors of sodium-dependent and sodium-independent GABA binding, with the relative affinity of several agents for sodium-independent GABA receptor sites closely paralleling their abilities to mimic neurophysiologic effects of GABA at postsynaptic receptors. Though there are some similarities between the influence of drugs and amino acid analogues on sodium-dependent binding and synaptosomal accumulation of GABA there are also marked differences such as a much greater affinity of beta-alanine for the sodium-dependent GABA binding sites than for synaptosomal GABA uptake. This suggests that the sodium-dependent GABA binding may involve uptake sites for the GABA accumulating system of glia rather than for neuronal GABA transport.
Two proteins in the rat, androgen binding protein (ABP) and the cytoplasmic receptor (CR), have high affinity and limited capacity for binding androgens. To determine the structural requirements for binding with high affinity, each protein was partially purified and the ability of over 100 steroids to compete with [3H]dihydrotestosterone (17 beta-hydroxy-5 alpha-androstan-3-one) for binding sites was assessed. The results indicate marked differences in the steroid specificities of the two proteins. Some alterations of dihydrotestosterone at C-2 or C-2 and C-3 increase binding to ABP two to four-fold. Similarly, the affinity of 17 beta-hydroxy-7 alpha-methyl-4-estren-3-one for ABP increases two-fold when a double bond is created at C-14. Addition of a methyl group in the alpha position at C-7 or C-17, or an ethinyl group at C-17 cause little change in affinity; however, modifications at C-11 and C-17 beta, and deletion of the methyl group at C-10 significantly impair binding to ABP. Binding to the CR is maintained or increased by deletion of the methyl group at C-10. Binding is lessened by modifications at C-3 and C-17 beta. Most alterations at C-2, C-7, C-11, and C-17 alpha have only minor effects on binding to the CR. These studies should provide a molecular basis for predicting the effects of specific structural modifications. When some modifications at C-2 or C-2 and C-3 are combined with changes at C-17 beta, the resulting steroids retain very high affinity for ABP and very limited binding to the CR. Such steroids may provide a means for assessing the function of ABP.
A protein determination method which involves the binding of Coomassie Brilliant Blue G-250 to protein is described. The binding of the dye to protein causes a shift in the absorption maximum of the dye from 465 to 595 nm, and it is the increase in absorption at 595 nm which is monitored. This assay is very reproducible and rapid with the dye binding process virtually complete in approximately 2 min with good color stability for 1 hr. There is little or no interference from cations such as sodium or potassium nor from carbohydrates such as sucrose. A small amount of color is developed in the presence of strongly alkaline buffering agents, but the assay may be run accurately by the use of proper buffer controls. The only components found to give excessive interfering color in the assay are relatively large amounts of detergents such as sodium dodecyl sulfate, Triton X-100, and commercial glassware detergents. Interference by small amounts of detergent may be eliminated by the use of proper controls.
Nuclear concentration of steroid hormones or their metabolites exists in neurons in selective areas of the mammalian brain. The distribution of estrogen target cells in different mammalian species appears to follow a similar pattern that involves selective nuclear groups in the forebrain, midbrain and lower brainstem. The distribution of androgen target cells in the rat brain largely corresponds to the distribution of estrogen target cells, with differences existing, however, in certain structures, such as lateral septum, ventromedial hypothalamus, hippocampus, cortex, epithalamus, lower brainstem and spinal cord. The distribution of progestin in the guinea-pig hypothalamus seems restricted to the preoptic and infundibular region, where it overlaps with estrogen localization. Corticosterone target cells are accumulated in extrahypothalamic regions, and not in the hypothalamus, in contrast to the sex steroid. The synthetic “glucocorticosteroid” dexamethasone, however, is found in neurons and glial cells throughout the rat brain, differing from the natural glucocorticosteroid corticosterone. Localization of different hormones in neurons of identical regions suggests that the same neuron may be addressed by different hormones. On the other hand, the differential distribution of the various types of hormones is likely to reflect differences in their action.Both estrogens and androgens appear to act on neural structures that are identical to or closely associated with (1) various sensory pathways and (2) ventricular recess organs, constituting the periventricular gland. Androgens, in addition, stimulate selectively neurons of the somatomotor system and circuits of aggression.In general, the wide existence of hormone target cells in the central nervous system reflects the multiple actions of the steroid hormones on endocrine regulation, autonomic functions and behavior.
Increasing illicit use of anabolic steroids in adolescent and young adult populations has been reported. To determine the scope of this problem and its relationship to psychoactive substance abuse, we evaluated the prevalence of anabolic steroid use among individuals seeking inpatient treatment for substance abuse.
A randomized mail survey of 175 inpatient substance abuse treatment directors elicited information regarding the prevalence of anabolic steroid use for inpatients treated in 1989 and the first half of 1990. Additionally, directors were surveyed for experience with DSM-III-R psychoactive substance dependence criteria for anabolic steroid use.
Only 19% of centers responding had treated at least one individual using anabolic steroids. Facilities encountering anabolic steroid users reported a prevalence of less than 1% among all admissions. Anabolic steroid users were seen more commonly in privately funded facilities. Directors reported a majority of anabolic steroid users had at least three DSM-III-R psychoactive substance dependence criteria for anabolic steroid use. Treatment directors rarely found anabolic steroid use acknowledged as a problem by users and rarely found anabolic steroid use a primary reason for treatment.
Users of illicit anabolic steroids may have significant clinical differences compared with users of other psychoactive substances of abuse and dependence.
Six experiments were carried out to determine whether dihydrotestosterone (5 alpha-androstan-17 beta-ol-3-one; DHT) acts to inhibit oestradiol (OE2)-induced lordosis behaviour after its metabolic conversion to 5 alpha-androstane-3 alpha,17 beta-diol (3 alpha-androstanediol, 3 alpha-Adiol). In experiments 1 and 2, ovariectomized rats were treated with several doses of DHT or 3 alpha-Adiol, injected with OE2 and progesterone, and tested for lordosis responsiveness. Significant inhibition of lordosis occurred after a dose of 3 alpha-Adiol which was approximately threefold less than the effective DHT dose. In experiments 3 and 4, plasma concentrations of DHT and 3 alpha-Adiol were measured after the injection of these steroids to ovariectomized rats at doses shown to be both sufficient or insufficient to inhibit lordosis. Behaviourally effective dosages of DHT and 3 alpha-Adiol produced circulating concentrations of 3 alpha-Adiol greater than those produced by behaviourally ineffective doses of DHT or 3 alpha-Adiol. At 30 min after injection of DHT (experiment 3), 78.8% of plasma androgens were in the form of 3 alpha-Adiol, while after injection of 3 alpha-Adiol, only 7.4% were DHT. When plasma DHT and 3 alpha-Adiol were measured at 3, 6, 9 and 12 h after steroid injection (experiment 4), plasma levels of 3 alpha-Adiol produced by the behaviourally subthreshold dose of DHT were significantly lower than levels produced by behaviourally sufficient dosages of DHT or 3 alpha-Adiol. In experiments 5 and 6, concentrations of DHT and 3 alpha-Adiol were measured in five brain regions 1 and 6 h after injection of behaviourally sufficient doses of these steroids to ovariectomized females. At 1 h after injection, similar levels of DHT and 3 alpha-Adiol were measured in DHT- and 3 alpha-Adiol-injected females, and DHT concentrations in the preoptic area were significantly higher in both groups than in any other brain area. At 6 h, animals injected with DHT had significantly higher levels of DHT in all brain areas combined than did 3 alpha-Adiol- or vehicle-injected animals. Brain concentrations of 3 alpha-Adiol were not different between groups injected with DHT, 3 alpha-Adiol or vehicle at this time. In brain, 34.6% of DHT had been converted to 3 alpha-Adiol after 1 h and 53.0% of 3 alpha-Adiol had been converted to DHT.(ABSTRACT TRUNCATED AT 400 WORDS)
Stimulus properties of subcutaneously injected testosterone were studied in male and female rats. In a conditioned place preference procedure, dose-dependent effects (doses: 0, 0.5, and 1 mg/kg) were observed in males. In females, no place preference could be established (doses: 0, 1, and 3 mg/kg). In addition, 1 mg/kg testosterone acquired discriminative stimulus control in male rats in a taste aversion procedure. Animals injected with this hormone prior to saccharin-LiCl pairings and with its vehicle prior to saccharin-NaCl pairings suppressed fluid intake following the administration of testosterone and not following the administration of the vehicle. Subsequent generalization tests revealed dose-dependent stimulus control of this hormone (range of substitution doses: 0.125-2 mg/kg). It is concluded from the results that at least pharmacological (supraphysiological) doses of testosterone may act as appetitive stimuli in male rats, but not in female rats. Furthermore, in male rats (pharmacological doses of) testosterone also possess discriminative stimulus properties.
To assess physiological and psychological states accompanying anabolic-androgenic steroid use, male weight lifters 1) were interviewed regarding their physical training and the patterns and effects of any drug use; 2) completed a written physical and medical history questionnaire, a Profile of Mood States questionnaire, and the Buss-Durkee Hostility Inventory; and 3) were physically examined, including a blood sample and urinalysis. Subjects were divided into current anabolic-androgenic steroid users (N = 12), previous users (N = 14), and nonusers (N = 24). Current and previous users reported the following changes associated with anabolic-androgenic steroid use: increases in enthusiasm, aggression, and irritability; changes in insomnia, muscle size, muscle strength and density; faster recovery from workouts and injuries; and changes in libido. We were unable to confirm these interview and physical and medical history questionnaire responses using standardized and well-accepted psychological inventories. There were no significant differences among groups for any Profile of Moods factor, total mood disturbance, total Buss-Durkee Hostility Inventory score, or any subscale. For current users, there were no significant correlations between either total weekly drug dose or length of time on the current cycle of anabolic-androgenic steroids and any individual scale of the Profile of Mood States, Buss-Durkee Hostility Inventory, Profile of Mood States total mood disturbance, or composite Buss-Durkee Hostility Inventory score. Furthermore, anabolic-androgenic steroid users did not differ in their responses on these inventories from nonusers or from general population norms.(ABSTRACT TRUNCATED AT 250 WORDS)
Anabolic-androgenic steroids (AAS) are synthetic derivatives of the sex hormone testosterone. Anabolic refers to the "growth-promoting" effect while androgenic refers to the "masculinizing" effect. It is becoming more evident that nonathletes as well as athletes are abusing AAS. Although the abuse of alcohol and other drugs contribute significantly to current chemical use problems in American society, AAS abuse is one of the fastest growing "new drug" problems facing secondary and higher education institutes of learning. The purpose of this discussion is to present working hypotheses regarding the psychological treatment of AAS dependent individuals. The treatment approach presented incorporates the approaches used with eating disorders, substance abuse/dependence, and narcissistic personality disorders. This paper considers some of the preliminary considerations for the first phase of treatment, some pitfalls to avoid, and therapist characteristics, as well as treatment modalities that might be helpful in the treatment of AAS-dependent individuals.
Anabolic-androgenic steroid use may have a wide range of adverse psychiatric and behavioural effects. The available data, however, are often inconsistent and inconclusive concerning possible effects of anabolic-androgenic steroids on libido in men, in women and also the way in which they affect libido differently in males and females. Anabolic-androgenic steroids may both relieve and cause depression. Cessation or diminished use of anabolic-androgenic steroids may also result in depression. More study is required to determine whether or not the disparate data on depression are consistent clinical observations. The level of testosterone appears to be positively associated with "aggression", particularly in response to provocation. Various psychotic symptoms and manic episodes may be associated with anabolic-androgenic steroids. The possibility of hypomania induced by synthetic androgens must also be considered.
The brain substrates involved in the effect of cocaine on brain stimulation reward, in the psychomotor activation associated with cocaine, and in cocaine self-administration appear to be focused on the medial forebrain bundle and its connections with the basal forebrain, notably the nucleus accumbens. Chronic access to cocaine produces a withdrawal state as reflected in increases in brain stimulation reward thresholds, and this change in reward threshold appears to be opposite to the actions of the drug administered acutely. These effects are thought to reflect a change in the activity of reward elements in the medial forebrain bundle and may be responsible for the negative reinforcing state associated with the anhedonia of cocaine withdrawal. Opiate receptors particularly sensitive to the reinforcing effects of heroin also appear to be located in the region of the nucleus accumbens and the ventral tegmental area. There is good evidence for both dopamine-dependent and dopamine-independent opioid interactions in the ventral tegmental-nucleus accumbens connection. In addition, the opiate receptors in the region of the nucleus accumbens may become sensitized during the course of opiate withdrawal and thus become responsible for the aversive stimulus effects of opiate dependence. Reliable measures of the acute reinforcing effects of ethanol have been established in rat models, and substantial evidence exists to show that non-deprived rats will orally self-administer pharmacologically relevant amounts of ethanol in lever-press choice situations. Neuropharmacological studies of ethanol reinforcement in non-dependent rats suggest important roles for serotonin, GABA and dopamine. A role for opioid peptides in ethanol reinforcement may reflect more general actions of opioid peptides in consummatory behavior. Studies of ethanol dependence have implicated brain GABAergic and CRF systems in the more motivational aspects of withdrawal. Future studies will need to focus on the common neurobiologic changes associated with all these drugs, particularly regarding their hedonic and motivational properties.
Anabolic steroids are synthetic derivatives of the hormone testosterone. Anabolic effects such as anticatabolism, increased skeletal muscle mass, and increased aggressiveness are usually desired; however, androgenic effects also result. Decreases in high-density lipoprotein, increases in low-density lipoprotein, changes in total serum cholesterol, hematocrit, and clotting factors, and the development of hypertensive diseases have all been implicated as resulting from anabolic steroid use. Research does not directly link anabolic steroids with cardiovascular diseases, but steroid use can significantly increase risk factors for atherosclerotic cardiovascular disease.
We characterized the temporal dynamics of brain and pituitary cell nuclear androgen receptor binding and serum androgen and gonadotropin levels associated with the implantation and removal of testosterone (T)-filled Silastic capsules into performed s.c. flank pouches of castrated, awake male rats. These capsules produced serum T levels in the physiologic range. The number of cell nuclear androgen + receptor complexes, as measured in an exchange assay using [3H]R1881, increased 15-fold at 0.5 h after capsule insertion in the HPAS (combined hypothalamus, preoptic area, amygdala and septum) and anterior pituitary gland, but then showed a second progressive rise within the next 8 h. This pattern suggests that T exerts an initial action in the tissues to alter the affinity and/or number of available androgen receptors. There was a lag time of 2-4 h to the first indication of negative feedback suppression of LH secretion. Serum LH levels declined only slightly at 4 h after capsule insertion but continued to fall thereafter, reaching undetectable values by 24 h. In contrast, serum FSH levels declined only slightly after 24 h of T exposure. After removal of the T capsules, serum T levels declined to castrate values within 2 h at which time the level of androgen + receptor complexes had fallen to 60% in the brain and pituitary. Serum LH and FSH concentrations were unchanged at 2 h after capsule removal, but rose significantly within the next 2 h. The data indicate that the occupation of androgen receptors rapidly changes in response to variations in circulating T in a fashion that implicates their involvement in the expression of this steroid's negative feedback actions on gonadotropin secretion.