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Neural Mechanisms of Reproduction in Females as a Predisposing Factor for Drug Addiction
Abstract
There is an increasing awareness that adolescent females differ from males in their response to drugs of abuse and consequently in their vulnerability to addiction. One possible component of this vulnerability to drug addiction is the neurobiological impact that reproductive physiology and behaviors have on the mesolimbic dopamine system, a key neural pathway mediating drug addiction. In this review, we examine animal models that address the impact of ovarian cyclicity, sexual affiliation, sexual behavior, and maternal care on the long-term plasticity of the mesolimbic dopamine system. The thesis is that this plasticity in synaptic neurotransmission stemming from an individual's normal life history contributes to the pathological impact of drugs of abuse on the neurobiology of this system. Hormones released during reproductive cycles have only transient effects on these dopamine systems, whereas reproductive behaviors produce a persistent sensitization of dopamine release and post-synaptic neuronal responsiveness. Puberty itself may not represent a neurobiological risk factor for drug abuse, but attendant behavioral experiences may have a negative impact on females engaging in drug use.
... Estrogens appear to increase serotonergic tone [82], to increase the release of acetylcholine [82], to increase norepinephrine turnover [83,84], to potentiate D1 receptors [84,85], to antagonize D2 receptors [85,84], to increase glutamatergic activity function [86] and to decrease GABA-ergic activity [87,88]. These effects of estrogens are thought to underlie, at least in part, their beneficial effects on mood, cognition (serotonin, acetylcholine) [82] and attention (norepinephrine) [83,84]. ...
... Estrogens appear to increase serotonergic tone [82], to increase the release of acetylcholine [82], to increase norepinephrine turnover [83,84], to potentiate D1 receptors [84,85], to antagonize D2 receptors [85,84], to increase glutamatergic activity function [86] and to decrease GABA-ergic activity [87,88]. These effects of estrogens are thought to underlie, at least in part, their beneficial effects on mood, cognition (serotonin, acetylcholine) [82] and attention (norepinephrine) [83,84]. ...
... These effects of estrogens are thought to underlie, at least in part, their beneficial effects on mood, cognition (serotonin, acetylcholine) [82] and attention (norepinephrine) [83,84]. In addition, estrogens may decrease the severity of psychotic symptoms through their antagonistic effects on D2 receptors) [85,84]. Converly, they may increase addictive behaviors due to their agonistic actions on D1 receptors [84,85] and increase seizure frequency (glutamate + /GABA -) [87,88]. ...
Sex steroids are thought to play a critical developmental role in shaping both cortical and subcortical structures in the human brain. Periods of profound changes in sex steroids invariably coincide with the onset of sex differences in mental health vulnerability, highlighting the importance of sex steroids in determining sexual differentiation of the brain. Yet, most of the evidence for the central effects of sex steroids relies on non-human studies, as several challenges have limited our understanding of these effects in humans: the lack of systematic assessment of the human sex steroid metabolome, the different developmental trajectories of specific sex steroids, the impact of genetic variation and epigenetic changes, and the plethora of interactions between sex steroids, sex chromosomes, neurotransmitters, and other hormonal systems. Here we review how multimodal strategies may be employed to bridge the gap between the basic and clinical understanding of sex steroid-related changes in the human brain.
... Estrogens also exhibit modulation action on dopaminergic signaling via their D1 receptors potentiation activity and D2 (Dopamine 2) receptor antagonizing activity (Soares et al. 2003;Hedges et al. 2010). Through their antagonistic effects on D2 receptors, estrogens can lessen the severe symptoms of psychotic disorders. ...
... Through their antagonistic effects on D2 receptors, estrogens can lessen the severe symptoms of psychotic disorders. On the other hand, they may intensify addictive behaviors through their agonistic actions on D1 receptors (Hedges et al. 2010). Estrogens have modulating activity on other signaling systems, which includes their stimulating effect on glutamatergic activity (Cyr et al. 2001), and their negative effect on GABAergic activity (Wójtowicz et al. 2008;Wójtowicz and Mozrzymas 2010). ...
Neurotransmitters are chemical messengers synthesized by neurons, which enable interconnection of nerve fibers within their vicinity. Neurotransmitters traditionally consist of amino acids and their derivatives, chains of amino acids, peptides or proteins. However, several studies report that steroids and hormones also exert an acute effect on the physiology of neuronal activity and the expression of behavior that can happen within minutes. Those steroids that can bind to the neurotransmitter receptors and modulate the neurotransmission signal are included together within the term neurosteroids or neuroactive steroids. The examples of neuroactive steroids include progesterone, estradiol, testosterone, DHEA, glucocorticoid, allotetrahydrodeoxycorticosterone (THDOC), androstanediol (AD), ganaloxone, androsterone, pregnenolone, allopregnanolone and their sulfate esters. Additionally, several synthetic steroids such as alphaxalone and 3ɑ-hydroxy-5β-pregnan-20-one hemisuccinate possess similar characteristics of modulating neuronal activities to the endogenous steroids. These hormonal steroids exert their neuronal excitability functions through various receptors and ion channels such as the estrogen receptor, progesterone receptor, androgen receptor, GABAA, AMPA and NMDA receptors. These neuroactive steroids are also involved in the pathology and physiology of various neurological disorders such as epilepsy, schizophrenia and traumatic brain injury. Additionally, these neuroactive steroids have agonistic or antagonistic effects toward the neurotransmission action of various other neurotransmitters some of which have undergone clinical trials for the treatment of various neurological disorders. Thus, these steroids and hormones can act as neurotransmitters, exert either agonistic or antagonistic effects on receptors and have potential benefits in the treatment of neurological disorders.
... Synaptic plasticity in the nucleus accumbens is a process through which the ongoing expression of motivated behaviors can be modified as a result of prior experience (Bradley et al., 2005;Goto and Grace, 2005;Kelley et al., 1997;Meisel and Mullins, 2006). We have developed a model of such experience based plasticity in which we discovered that repeated sexual experience produces augmented responsiveness, both pre-and postsynaptically, in the nucleus accumbens of female Syrian hamsters (Hedges et al., 2010;Meisel and Mullins, 2006). Besides female sexual behavior, other motivated behaviors such as male sexual behavior, aggression, and salt appetite induce similar patterns of plasticity in the nucleus accumbens (Pitchers et al., 2010a;Roitman et al., 2002;Staffend and Meisel, 2012), supporting a common neurobiological process across motivated behaviors. ...
... Drugs of abuse also produce changes in spine density within the nucleus accumbens (Dobi et al., 2011;Kim et al., 2011;Lee et al., 2006;Li et al., 2004;Shen et al., 2009), which are isolated to the dopamine D1 population of medium spiny neurons (Dobi et al., 2011;Kim et al., 2011;Lee et al., 2006). It is in this context that a guiding principle for our work is to test the proposition that high frequency sexual behavior experience impacts the nucleus accumbens creating a means through which certain life events can create a vulnerability for drug addiction (Hedges et al., 2010). Confocal images of dendritic segments of medium spiny neurons from the nucleus accumbens core from (A) sexually naïve or (B) sexually experienced females. ...
Female sexual behavior is an established model of a naturally motivated behavior which is regulated by activity within the mesolimbic dopamine system. Repeated activation of the mesolimbic circuit by female sexual behavior elevates dopamine release and produces persistent postsynaptic alterations to dopamine D1 receptor signaling within the nucleus accumbens. Here we demonstrate that sexual experience in female Syrian hamsters significantly increases spine density and alters morphology selectively in D1 receptor-expressing medium spiny neurons within the nucleus accumbens core, with no corresponding change in dopamine receptor binding or protein expression. Our findings demonstrate that previous life experience with a naturally motivated behavior has the capacity to induce persistent structural alterations to the mesolimbic circuit that can increase reproductive success and are analogous to the persistent structural changes following repeated exposure to many drugs of abuse.
... Our observations along with those of others [29,[32][33][34][35][36][37]40,53] highlight the impact of genetic factors on drug responsiveness in mice, findings that mirror the contribution of genetic polymorphisms to addiction vulnerability in people [24]. Even with identical genetic backgrounds (inbred mice or identical twins), experiential factors [54] can impact responsiveness to drugs [55,56]. Part of the basis for these individual differences stems from experiential regulation of the genome through epigenetic modification of individual genes [57][58][59], creating extensive variation in addiction liability [60]. ...
Introduction:
Preclinical literature, frequently utilizing rats, suggest females display a more rapid advancement of substance abuse and a greater risk of relapse following drug abstinence. In clinical populations, it is less clear as to what extent biological sex is a defining variable in the acquisition and maintenance of substance use. Even without considering environmental experiences, genetic factors are presumed to critically influence the vulnerability to addiction. Genetically diverse mouse models provide a robust tool to examine the interactions between genetic background and sex differences in substance abuse.
Methods:
We explored mouse strain variability in male vs. female behavioral sensitization to cocaine. Locomotor sensitization was observed following five consecutive days of subcutaneous cocaine across three genetically different mice strains: C57BL/6J, B6129SF2/J, and Diversity Outbred (DO/J).
Results:
Sex differences in cocaine locomotor sensitization was dependent on mouse strain. Specifically, we observed opposing sex differences in locomotor sensitization, with male C57BL/6J and female B6129SF2/J mice displaying heightened activity compared to their opposite sex counterparts. Conversely, no sex differences were observed in the DO/J mice. Acute cocaine administration resulted in locomotor differences across strains in male, but not female, mice. The magnitude of sensitization (or lack thereof) also varied by genetic background.
Conclusions:
While sex differences in drug addiction may be observed, these effects can be mitigated, or even reversed, dependent on genetic background. The clinical implications being that absent of understanding the genetic variables underlying vulnerability to addiction, sex provides little information regarding the predisposition of an individual to drug abuse.
... It is thought estradiol reduces anxiety and enhances positive effects. There is strong evidence that sex hormones influence reward center maturation and efficacy that are well observed in rodent and human studies [45,46]. However, about the application of testosterone in individuals with substance use disorder further studies are needed. ...
Drug addiction is a dangerous condition that is the concern of human societies. Nevertheless, several issues exist ahead of people with a drug use disorder during addiction. Accordingly, various types of studies have been conducted to understand better the problems that people with a drug use disorder encountered. People with a drug use disorder usually have a problem tolerating the withdrawal period and some relapse to drug abuse. Complementary studies further revealed that some hormones like oxytocin (OXT), vasopressin, hypothalamic-pituitary-adrenal axis (HPA) axis hormones, sex hormones, thyroid hormones, and nutritional hormones are probably involved in addiction processes. These hormones completely with different mechanisms can influence drug users' ultimate outcome. As we will see, these hormones influence tolerance, sensitization, and compulsive drug seeking and taking behavior. In this review, they have been further discussed.
... Long-term functional changes within this pathway result from chronic drug intake, i.e. from chronically enhanced activation of the mesolimbic dopamine transmission. Consequently, a sensitized increase in dopamine neurotransmission may cause morphological and functional changes in the mesolimbic reward circuitry (Hedges et al., 2010), which in turn leads to hypersensitivity to drug-associated stimuli (Di Chiara et al., 1999;Everitt and Wolf, 2002;Nestler, 2002a,b). These permanent neuroadaptations in the mesolimbic dopamine system contribute to the longterm behavioral and psychological changes observed in substance use disorder (for review see Guttman et al., 2018). ...
Women and men exhibit differences in behavior when making value-based decisions. Various hypotheses have been proposed to explain these findings, stressing differences in functional lateralization of the brain, functional activation, neurotransmitter involvement and more recently, sex hormones. While a significant interaction of neurotransmitter systems and sex hormones has been shown for both sexes, decision-making in women might be particularly affected by variations of ovarian hormones. In this review we have gathered information from animal and human studies on how ovarian hormones affect decision-making processes in females by interacting with neurotransmitter systems at functionally relevant brain locations and thus modify the computation of decision aspects. We also review previous findings on impaired decision-making in animals and clinical populations with substance use disorder and depression, emphasizing how little we know about the role of ovarian hormones in aberrant decision-making.
... Ovarian hormones have been shown to enhance drugaddiction related behaviors (acquisition, maintenance, and escalation) [76,99,100]. Estradiol has also been found to be a large contributor to female vulnerability to addictive behaviors [101] as well as mediation of cocaine-induced reinstatement after a period of abstinence [102]. Estradiol has also been shown to facilitate positive subjective effects of amphetamine and enhances the acquisition for cocaine [103][104][105]. ...
Exercise is known to have a myriad of health benefits. There is much to be learned from the effects of exercise and its potential for prevention, attenuation and treatment of multiple neuropsychiatric diseases and behavioral disorders. Furthermore, recent data and research on exercise benefits with respect to major health crises, such as, that of opioid and general substance use disorders, make it very important to better understand and review the mechanisms of exercise and how it could be utilized for effective treatments or adjunct treatments for these diseases. In addition, mechanisms, epigenetics and sex differences are examined and discussed in terms of future research implications.
... Cocaine produces short-lived, intense euphoric effects in human subjects along with an immediate profound craving for more (Breiter et al. 1997 ). Human neuroimaging and rodent neurobehavioral studies point to a shared neural substrate for sexual arousal and orgasm and cocaine's motivating and rewarding effects (Carboni et al. 1989 ;Childress et al. 2008 ;Frascella et al. 2010 ;Meisel et al. 1993 ;Pfaus et al. 1990 ). Further, the same molecular and morphological changes in brain reward circuitry that mediate transition from psychostimulant use to addiction are induced by certain patterns of "excessive" sexual behavior (Hedges et al. 2010 ;Meisel and Mullins 2006 ;Nestler 2008 ). It is therefore unsurprising that behavioral crosssensitization between repeated psychostimulant exposure and sexual behavior has been demonstrated in animal models (Levens and Akins 2004 ;Fiorino and Phillips 1999 ;Bradley and Meisel 2001 ). ...
Cocaine use and HIV infection in the United States are inextricably intertwined. Cocaine is a drug commonly injected by people who inject drugs (PWID) in the United States, and PWID are incontrovertibly at risk for HIV acquisition (Friedman et al. 1989). In addition, there are many other complex direct and indirect associations in different populations between cocaine use and HIV infection. Cocaine use is associated in various contexts with a greater number of recent and lifetime sexual partners, transactional sex (trading sex for drugs or money), poor adherence to protective measures and treatment programs, and concurrent use of other drugs. In addition, there is a neurobiological rationale for the connection between cocaine’s effects and sexual behavior that increases the risk of HIV acquisition, but sociological factors strongly shape drug use and health factors in humans (Friedman et al. 2009), highlighting the extreme complexity of the overlapping epidemiologic landscape of cocaine use and HIV infection in the United States. The recent availability of the first prototypes of HIV and cocaine vaccines raises the question of the impact of these biological/medicinal interventions on this complex landscape. Theoretically, a combination HIV and cocaine vaccine could profoundly synergize to reduce HIV spread in affected populations, but the reality of HIV and cocaine networks in these populations may predict a very different outcome. In this chapter, we review the status and potential of these medicinal interventions, discuss the concept of their use as a combination vaccine or immunotherapy, and engage the question of how they might impact specific US populations of cocaine users at various levels of risk for HIV infection.
... In immortalized hypothalamic NPY neurons, Arrb1 knockdown attenuated E2-induced mERαΔ4 internalization and phosphorylation of ERK1/2. EMS is part of E2-mediated events in the nervous system that include nociception, addiction and plasticity [70][71][72][73][74]. In terms of reproduction, perhaps the most studied E2 action in the CNS, EMS is important for both the regulation of the luteinizing hormone (LH) surge in estrogen positive feedback and the regulation of sexual receptivity [36,67]. ...
Estradiol (E2) action in the nervous system is the result of both direct nuclear and membrane-initiated signaling (EMS). E2 regulates membrane estrogen receptor-α (ERα) levels through opposing mechanisms of EMS-mediated trafficking and internalization. While ß-arrestin-mediated mERα internalization has been described in the cortex, a role of ß-arrestin in EMS, which underlies multiple physiological processes, remains undefined. In the arcuate nucleus of the hypothalamus (ARH), membrane-initiated E2 signaling modulates lordosis behavior, a measure of female sexually receptivity. To better understand EMS and regulation of ERα membrane levels, we examined the role of ß-arrestin, a molecule associated with internalization following agonist stimulation. In the present study, we used an immortalized neuronal cell line derived from embryonic hypothalamic neurons, the N-38 line, to examine whether ß-arrestins mediate internalization of mERα. β-arrestin-1 (Arrb1) was found in the ARH and in N-38 neurons. In vitro, E2 increased trafficking and internalization of full-length ERα and ERαΔ4, an alternatively spliced isoform of ERα, which predominates in the membrane. Treatment with E2 also increased phosphorylation of extracellular-signal regulated kinases 1/2 (ERK1/2) in N-38 neurons. Arrb1 siRNA knockdown prevented E2-induced ERαΔ4 internalization and ERK1/2 phosphorylation. In vivo, microinfusions of Arrb1 antisense oligodeoxynucleotides (ODN) into female rat ARH knocked down Arrb1 and prevented estradiol benzoate-induced lordosis behavior compared with nonsense scrambled ODN (lordosis quotient: 3 ± 2.1 vs. 85.0 ± 6.0; p < 0.0001). These results indicate a role for Arrb1 in both EMS and internalization of mERα, which are required for the E2-induction of female sexual receptivity.
... Consistent with this hypothesis, an investigation of healthy human subjects reported that drug-elicited DA release in the ventral striatum, caudate nucleus, and putamen was greater in male subjects compared with females (Munro et al., 2012). Additionally, a recent study showed that female smokers have significantly higher D2-like receptor availability than male smokers (Brown et al., 2012), further supporting the growing evidence of sex differences in dopaminergic system dynamics (Becker, 1999;Dreher et al., 2007;Festa et al., 2010;Hedges et al., 2010). On the other hand, the quinpirole-elicited yawning dose-response curve has been shown to be malleable to changes in food content and body weight (Baladi and France, 2009). ...
The dopamine (DA) D3 receptor (DRD3) has been associated with impulsivity, pathological gambling and drug addiction making it a potential target for pharmacotherapy development. Positron emission tomography (PET) studies using the DRD3-preferring radioligand [11C]-(+)-propyl-hexahydro-naphtho-oxazin ([11C]PHNO) have shown higher binding potentials in drug abusers compared to control subjects. Preclinical studies have examined DRD3 receptor activation using the DA agonist quinpirole and the unconditioned behavior of yawning. However, the relationship between quinpirole-elicited yawning and DRD3 receptor availability has not been determined. In Experiment 1, 10 drug-naive male rhesus monkeys were scanned with [11C]PHNO and the ability of quinpirole (0.01-0.3 mg/kg, i.m.) to elicit yawning was examined. Significant relationships between DRD3 receptor availability and quinpirole-induced yawns were noted in several brain regions. Experiment 2 replicated earlier findings that a history of cocaine self-administration did not affect quinpirole-induced yawning and extended this to examine monkeys with a history of methamphetamine (MA) self-administration and found that monkeys with experience self-administering MA showed greater potency and significantly higher quinpirole-elicited yawning compared to controls. Finally, quinpirole-elicited yawning was studied in drug-naive female monkeys and compared to drug-naive male. Sex differences were noted, with quinpirole being more potent and significantly eliciting more yawns in males compared to females. Taken together these findings support the use of quinpirole-elicited yawning as a behavioral tool for examining DRD3 activation in monkeys and that both drug history and sex may influence individual sensitivity to the behavioral effects of DRD3 compounds.
... Administration of drugs of abuse and/or exposure to drug conditioned stimuli results in activation of the mesolimbic DA pathway via stimulation of VTA DA release into the NAc ( Addiction: dysregulation of the dopamine system Normally, DAergic transmission within this circuit plays a critical role in modulating the flow of information through the limbic system to modulate naturally rewarding motivated behaviors such as feeding, drinking, sexual behavior, maternal and paternal behaviors, and social interactions (Gardner, 2011); however, chronic enhanced activation of mesolimbic DA transmission by drugs of abuse can result in long-term functional changes within this pathway. One consequence of repeated persistent increases in extracellular DA in the NAc is a sensitized increase in DA neurotransmission which is postulated to cause consequent morphological and functional changes in mesolimbic reward neurocircuitry (Hedges et al., 2010). For example, administration of psychostimulant drugs (cocaine and amphetamine) leads to increased dendritic branching of NAc medium spiny neurons Kolb, 1997, 1999a). ...
... We have used hamster sexual behavior to model the neurobiology of motivation. This model is valuable for elucidating the role of the mesolimbic DA pathway in naturally-occurring, non-pathological motivated behaviors, and also to provide insight into how reproductive physiology and behavior can impact vulnerability to addiction [20,32]. As such, identifying whether DA and GLU are co-expressed within the mesolimbic pathway of hamsters would contribute to a mechanistic understanding of the neurobiology of motivation this model system. ...
The nucleus accumbens (NAc) is an important brain region for motivation, reinforcement, and reward. Afferents to the NAc can be divided into two anatomically-segregated neurochemical phenotypes: dopaminergic inputs, primarily from the midbrain ventral tegmental area (VTA) and glutamatergic inputs from several cortical and sub-cortical structures. A population of glutamatergic neurons exists within the VTA and evidence from rats and mice suggests that these VTA axons may co-release dopamine and glutamate into the NAc. Our laboratory has used sexual experience in Syrian hamsters as a model of experience-dependent plasticity within the NAc. Given that both dopamine and glutamate are involved in this plasticity, it is important to determine whether these neurotransmitters are co-expressed within the mesolimbic pathway of hamsters. We therefore used immunofluorescent staining to investigate the possible co-localization of tyrosine hydroxylase (TH), a dopaminergic marker, and vesicular glutamate transporter 2 (VGLUT2), a glutamatergic marker, within the mesolimbic pathway. PCR analyses identified VGLUT2 gene expression in the VTA. No co-localization of TH and VGLUT2 protein was detected in NAc fibers, nor was there a difference in immunolabeling between males and females. Further studies are needed to resolve this absence of anatomical co-localization of TH and VGLUT2 in hamster striatal afferents with reports of functional co-release in other rodents.
... We have used female sexual behavior in Syrian hamsters as a model of experience-based plasticity in the brain (Hedges et al., 2010, Meisel & Mullins, 2006. This is a valuable model because repeated sexual experience reliably produces changes analogous to chronic exposure to drugs of abuse (Bradley et al., 2005a, Bradley & Meisel, 2001, Kohlert & Meisel, 1999, Meisel & Joppa, 1994, Meisel et al., 1996, Meisel & Mullins, 2006. ...
Motivated behaviors, including sexual experience, activate the mesolimbic dopamine system and produce long-lasting molecular and structural changes in the nucleus accumbens. The transcription factor ΔFosB is hypothesized to partly mediate this experience-dependent plasticity. Previous research in our laboratory has demonstrated that overexpressing ΔFosB in the nucleus accumbens of female Syrian hamsters augments the ability of sexual experience to cause the formation of a conditioned place preference. It is unknown, however, whether ΔFosB-mediated transcription in the nucleus accumbens is required for the behavioral consequences of sexual reward. We therefore used an adeno-associated virus to overexpress ΔJunD, a dominant negative binding partner of ΔFosB that decreases ΔFosB-mediated transcription by competitively heterodimerizing with ΔFosB before binding at promotor regions on target genes, in the nucleus accumbens. We found that overexpression of ΔJunD prevented the formation of a conditioned place preference following repeated sexual experiences. These data, when coupled with our previous findings, suggest that ∆FosB is both necessary and sufficient for behavioral plasticity following sexual experience. Furthermore, these results contribute to an important and growing body of literature demonstrating the necessity of endogenous ΔFosB expression in the nucleus accumbens for adaptive responding to naturally rewarding stimuli.
... Studies investigating the interaction between oxytocin and dopamine in relation to addiction have been limited, since the majority of experiments focused mainly on reproductive physiology (Clément et al. 2008;Frye and Walf 2010;Hedges et al. 2010) and maternal/social behaviour (Shahrokh et al. 2010;Robinson et al. 2011;Lenz and Sengelaub 2010). However there are reports implicating oxytocin in the reinforcing and long-term adverse effects of drug use (McGregor et al. 2008). ...
Methamphetamine is a highly addictive stimulant drug whose illicit use and resultant addiction has become an alarming global phenomenon. The mesolimbic dopaminergic pathway has been shown to be fundamental to the establishment of addictive behaviour. This pathway, as part of the reward system of the brain, has also been shown to be important in classical conditioning, which is a learnt response. Within the modulation of learning and memory, the neurohypophyseal hormones vasopressin and oxytocin have been reported to play a vital role, with vasopressin exerting a long- term facilitatory effect and oxytocin exerting an inhibitory effect. Therefore we adopted a conditioned place preference model to investigate whether vasopressin V1b receptor antagonist SSR 149415 or oxytocin treatment would cause a decrease in the seeking behaviour in a reinstatement paradigm. Behavioural findings indicated that methamphetamine induced a change in the place preference in the majority of our animals. This change in place preference was not seen when vasopressin was administered during the extinction phase. On the other hand the methamphetamine-induced change in place preference was enhanced during the reinstatement phase in the animals that were treated with oxytocin. Striatal dopamine levels were determined, as methamphetamine is known to increase dopamine transmission in this area. Significant changes in dopamine levels were observed in some of our animals. Rats that received both methamphetamine and oxytocin had significantly higher striatal dopamine than those that received oxytocin alone. Western blot analysis for hippocampal cyclic AMP response element binding protein (CREB) was also conducted as a possible indicator of glutamatergic NMDA receptor activity, a pathway that is important for learning and memory. The Western blot analysis showed no changes in hippocampal pCREB expression. Overall our data led us to conclude that methamphetamine treatment can change place preference behaviour in rats and that this change may be partially restored by vasopressin antagonism, but exaggerated by oxytocin.
... Recent studies have revealed substantial new information about the neurobiological mechanisms involved in hormonal modulation of synaptic plasticity, neuroprotection, and memory function, and these data can be exploited to guide the development of new therapeutics for menopausal women that mimic the beneficial effects of sex steroid hormones on cognition without the peripheral side effects associated with current treatments. Moreover, identifying the cellular and molecular mechanisms through which sex steroid hormones modulate cognitive processes could have broad implications beyond hormone therapy by providing important insights into the etiology of sex differences in cognition and the increased risks to women of such diseases as Alzheimer's, depression, drug abuse, psychotic disorders, and anxiety disorders (Carroll & Anker, 2010;Grigoriadis & Robinson, 2007;Hedges, Staffend, & Meisel, 2010;Huber, Borsutzky, Schneider, & Emrich, 2004;Weinstock, 1999;Yaffe et al., 2007;Yaffe et al., 1998;Zandi et al., 2002). As such, the insights to be gained from identifying the neurobiological mechanisms underlying hormone-induced cognitive alterations in adult females of various ages could open new avenues for drug development for the treatment of multiple disorders for which women are at increased risk. ...
A wealth of data collected in recent decades has demonstrated that ovarian sex-steroid hormones, particularly 17β-estradiol (E2), are important trophic factors that regulate the function of cognitive regions of the brain such as the hippocampus. The loss of hormone cycling at menopause is associated with cognitive decline and dementia in women, and the onset of memory decline in animal models. However, hormone therapy is not currently recommended to prevent or treat cognitive decline, in part because of its detrimental side effects. In this article, it is proposed that investigations of the rapid effects of E2 on hippocampal function be used to further the design of new drugs that mimic the beneficial effects of E2 on memory without the side effects of current therapies. A conceptual model is presented for elucidating the molecular and biochemical mechanisms through which sex-steroid hormones modulate memory, and a specific hypothesis is proposed to account for the rapid memory-enhancing effects of E2. Empirical support for this hypothesis is discussed as a means of stimulating the consideration of new directions for the development of hormone-based therapies to preserve memory function in menopausal women.
Citation: Hanna, C.; Yao, R.; Sajjad, M.; Gold, M.; Blum, K.; Thanos, P.K. Exercise Modifies the Brain Metabolic Response to Chronic Cocaine Exposure Inhibiting the Stria Terminalis. Brain Sci. 2023, 13, 1705. Abstract: It is well known that exercise promotes health and wellness, both mentally and physiologically. It has been shown to play a protective role in many diseases, including cardiovascular, neurological, and psychiatric diseases. The present study examined the effects of aerobic exercise on brain glucose metabolic activity in response to chronic cocaine exposure in female Lewis rats. Rats were divided into exercise and sedentary groups. Exercised rats underwent treadmill running for six weeks and were compared to the sedentary rats. Using positron emission tomography (PET) and [18F]-Fluorodeoxyglucose (FDG), metabolic changes in distinct brain regions were observed when comparing cocaine-exposed exercised rats to cocaine-exposed sedentary rats. This included activation of the secondary visual cortex and inhibition in the cerebellum, stria terminalis, thalamus, caudate putamen, and primary somatosensory cortex. The functional network of this brain circuit is involved in sensory processing, fear and stress responses, reward/addiction, and movement. These results show that chronic exercise can alter the brain metabolic response to cocaine treatment in regions associated with emotion, behavior, and the brain reward cascade. This supports previous findings of the potential for aerobic exercise to alter the brain's response to drugs of abuse, providing targets for future investigation. These results can provide insights into the fields of exercise neuroscience, psychiatry, and addiction research.
Introduction:
Exercise programs have been shown to be effective for both reducing risk for, and intervention following, substance abuse behaviors in both clinical and preclinical studies. Less is known, however, regarding the underlying neurobiological substrates involved in these changes in drug seeking behavior. In this study, we assessed cannabinoid receptor (CB1) levels throughout the brain which are key in endocannabinoid signaling following chronic aerobic exercise.
Methods:
Male and female Lewis young adult rats were grouped into exercise and sedentary groups at 8 weeks of age. Exercise rats ran on a treadmill at 10 m/min, 5 days/week, for 6 weeks, whereas sedentary rats remained in their home cage. Rats were euthanized after 6 weeks, and in vitro receptor autoradiography was performed using [3H] SR141716A to quantify CB1 receptors throughout the brain.
Results:
Exercise rats did not show significantly different [3H] SR141716A binding levels as compared to sedentary rats; however, an overall sex effect was found, where males had 29% higher [3H] SR141716A binding within the pyramidal layer of the hippocampus when compared to females. The chronic aerobic exercise regimen did not produce any changes in CB1 receptor levels.
Conclusions:
The present study found that chronic exercise during young adulthood did not alter cannabinoid CB1 receptor levels in the brain. Therefore, previously reported decreased cocaine preference in parallel treated cohorts did not involve exercise induced changes in CB1 levels which is key for endocannabinoid signaling.
Within the adult female, estrogen signaling is well-described as an integral component of the physiologically significant hypothalamic-pituitary-gonadal axis. In rodents, the timing of ovulation is intrinsically entwined with the display of sexual receptivity. For decades, the importance of estradiol activating intracellular estrogen receptors within the hypothalamus and midbrain/spinal cord lordosis circuits has been appreciated. These signaling pathways primarily account for the ability of the female to reproduce. Yet, often overlooked is that the desire to reproduce is also tightly regulated by estrogen receptor signaling. This lack of emphasis can be attributed to an absence of nuclear estrogen receptors in brain regions associated with reward, such as the nucleus accumbens, which are associated with motivated behaviors. This review outlines how membrane-localized estrogen receptors affect metabotropic glutamate receptor signaling within the rodent nucleus accumbens. In addition, we discuss how, as estrogens drive increased motivation for reproduction, they also produce the untoward side effect of heightening female vulnerability to drug addiction.
The ability to measure neurotransmitter release on a rapid time scale allows patterns of neurotransmission to be linked to specific behaviors or manipulations; a powerful tool in elucidating underlying mechanisms and circuitry. While the technique of microdialysis has been used for decades to measure nearly any analyte of interest in the brain, this technique is limited in temporal resolution. Alternatively, fast scan cyclic voltammetry is both temporally precise and extremely sensitive; however, because this technically difficult method relies on the electroactivity of the analyte of interest, the possibility to detect nonelectroactive substances (e.g., the neurotransmitter glutamate) is eliminated. This paper details the use of a turn-key system that combines fixed-potential amperometry and enzymatic biosensing to measure both electroactive and nonelectroactive neurotransmitters with temporal precision. The pairing of these two powerful techniques allows for the measurement of both tonic and phasic neurotransmission with relative ease, and permits recording of multiple neurotransmitters simultaneously. The aim of this manuscript is to demonstrate the process of measuring dopamine and glutamate neurotransmission in vivo using a naturally rewarding behavior (i.e., sexual behavior) in female hamsters, with the ultimate goal of displaying the technical feasibility of this assay for examining other behaviors and experimental paradigms.
In comparison to men, women initiate drug use at earlier ages and progress from initial use to addiction more rapidly. This heightened intake and vulnerability to drugs of abuse is regulated in part by estradiol, although the signaling mechanisms by which this occurs are not well understood. Recent findings indicate that within the nucleus accumbens core, estradiol induces structural plasticity via membrane-localized estrogen receptor α, functionally coupled to metabotropic glutamate receptor subtype 5 (mGluR5). Hence, we sought to determine whether mGluR5 activation was essential for estradiol-mediated enhancement of cocaine self-administration. Ovariectomized (OVX) female rats were allowed to freely self-administer cocaine under extended access conditions (6 h/d) for 10 consecutive days. The mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP) or vehicle was administered before estradiol (or oil), on a 2 d on/2 d off schedule throughout the extended access period. MPEP treatment prevented the estradiol-dependent enhancement of cocaine self-administration in OVX females. In a separate experiment, potentiation of mGluR5 function with the positive allosteric modulator 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (in the absence of estradiol treatment) failed to increase cocaine self-administration. These data suggest that mGluR5 activation is necessary for estradiol-mediated enhancement of responses to cocaine, but that direct mGluR5 activation is insufficient to mimic the female response to estradiol. Building on previous studies in male animals, these findings further highlight the therapeutic potential of mGluR5 antagonism in the treatment of addiction and suggest that there may be added therapeutic benefit in females.
The abuse of morphine has risen considerably in recent years, mainly due to the increase of its prescription in clinical medicine.Also, increased consumption of processed foods, rich in trans fatty acids (TFA), has caused concerns about human health. Thus, the aim of our study was to determine whether trans fat consumption in the perinatal period may affect preference for morphine in adolescent female and male rats. Dams were orally supplemented with water (C-control) or hydrogenated vegetable fat (HVF-rich in TFA) during gestation and lactation periods. On post-natal day 43, pups were exposed to morphine (4 mg/kg i.p., for 4 days) and assessed in the conditioned place preference paradigm. Anxiety-like symptoms were assessed, and oxidative status of the brain was estimated by reactive species (RS) generation. Female rats with HVF supplementation showed increased morphine preference and less anxiety-like symptoms. Additionally, both male and female rats from HVF-supplementation showed increased RS generation in the ventral tegmental area, whose level was similar in morphine-conditioned female rats. RS generation was increased in the hippocampus of morphine-conditioned female rats, regardless of the supplementation of their dams. We may infer that gender is a predictive factor to opioid preference, since adolescent female rats showed more susceptibility to addiction than males. Furthermore, trans fat consumption across the perinatal period is able to modify parameters of opioid preference in female rats, possibly due to TFA incorporation in phospholipid membranes, modifying the endogenous opioid system and the oxidative status in brain areas related to drug addiction.
Compared with men, women show enhanced responses to drugs of abuse, and consequently are thought to be more vulnerable to addiction. The ovarian hormone estradiol has emerged as a key facilitator in the heightened development of addiction in females. These actions of estradiol appear mediated by estrogen receptor (ER) activation of metabotropic glutamate receptor type 5 (mGluR5). However, the downstream effectors of this ER/mGluR5 signaling pathway are unknown. Here we investigate whether cannabinoid 1 receptor (CB1R) activation is a part of the mechanism whereby estradiol influences behavioral and synaptic correlates of addiction. Following repeated cocaine administration, estradiol-treated ovariectomized rats exhibited both sensitized locomotor responses and decreases in the dendritic spine density of nucleus accumbens core medium-spiny neurons in comparison to oil-treated controls. Both effects of estradiol were blocked by AM251, a CB1R inverse agonist. These results indicate that part of the signaling mechanism through which estradiol impacts behavioral and synaptic correlates of addiction in female rats requires activation of CB1Rs.
There is ample evidence of gender differences in neural processes and behavior. Differences in reward-related behaviors have been linked to either temporary or permanent organizational influences of gonadal hormones on the mesolimbic dopamine system and reward-related activation. Still, little is known about the association between biological gender and the neural underpinnings of the ability to resist reward-related impulses. Here we assessed with functional magnetic resonance imaging which neural processes enable men and women to successfully control their desire for immediate reward when this is required by a higher-order goal (i.e., during a 'desire-reason dilemma'; Diekhof and Gruber, 2010). Thirty-two participants (16 females) were closely matched for age, personality characteristics (e.g., novelty seeking) and behavioral performance in the 'desire-reason task'. On the neural level, men and women showed similarities in the general response of the nucleus accumbens and of the ventral tegmental area to predictors of immediate reward, but they differed in additional brain mechanisms that enabled self-controlled decisions against the preference for immediate reward. Firstly, men exhibited a stronger reduction of activation in the ventral pallidum, putamen, temporal pole and pregenual anterior cingulate cortex during the 'desire-reason dilemma'. Secondly, connectivity analyses revealed a significant change in the direction of the connectivity between anteroventral prefrontal cortex and nucleus accumbens during decisions counteracting the reward-related impulse when comparing men and women. Together, these findings support the view of a sexual dimorphism that manifested in the recruitment of gender-specific neural resources during the successful deployment of self-control.
The experience of interacting with pups causes long-term changes in mothers' brains that mediate long-term changes in maternal behavior. As little as 1 hr of pup experience postpartum results in enhanced maternal responses to pups 10 days later. This experiment investigated the effects of lesions in multiple neural sites that have been implicated either in the actual expression of maternal behavior or in learning and memory within other behavioral contexts on the initiation and the long-term experience-based retention of maternal behavior. Electrolytic lesions were performed either before or after a 1-hr or 24-hr maternal experience. Rats sustaining lesions of the nucleus accumbens (NACC), whether administered before parturition and experience or immediately after a brief experience, failed to show a maternal experience effect. NACC lesions sustained 24 hr after a maternal experience did not disrupt long-term retention of the maternal behavior.
This study compared the effects of centrally administered oxytocin (OT) and arginine vasopressin (AVP) on partner preference formation and social contact in male and female prairie voles (Microtus ochrogaster). After 1 hr of cohabitation and pretreatment with either AVP or OT, both males and females exhibited increased social contact and significant preference for the familiar partner. After pretreatment with either an OT receptor antagonist (OTA) or an AVP (V1a) receptor antagonist (AVPA), neither OT nor AVP induced a partner preference. In addition, treatment with OT+OTA or AVP+AVPA was associated with low levels of social contact in both sexes. Either AVP or OT is sufficient to facilitate social contact if either the OT or AVP receptor is available. However, the formation of partner preferences may require access to both AVP and OT receptors.
The possibility that female-paced coital behavior induces a reward state of sufficient intensity and duration to induce conditioning was evaluated by the conditioned-place-preference paradigm. Ovariectomized female rats, treated with estradiol benzoate and progesterone, regulated (paced) their coital interactions with a stud male through a 2-compartment chamber in which only the female could freely move from one compartment to the other. The females that paced their coital interactions showed a clear place preference. In contrast, no change in preference was observed in the females that could not pace their coital contacts. The change in preference in the females that paced their coital interactions was similar to that produced by an injection of morphine (1 mg/kg). These results suggest that coital interactions in females can induce a reward state when the females can control the pace of the sexual interaction.
Previous studies have demonstrated that central administration of vasopressin but not oxytocin facilitates pair bonding in the monogamous male prairie vole. This study tested vasopressin and oxytocin in the formation of the female vole's preference for a particular male partner. Initial studies showed that in monogamous female prairie voles (but not in nonmonogamous congeners), mating was followed by a partner preference that endured for at least 2 weeks. Nonmating prairie vole females developed a partner preference following oxytocin infusions, but not after vasopressin or cerebrospinal fluid infusions. Females given a selective oxytocin antagonist showed normal mating behavior, yet failed to develop a partner preference. The vasopressin antagonist failed to block partner preference formation in mated females. These results suggest that oxytocin, released with mating, may be critical to formation of a partner preference in the female prairie vole; this contrasts to vasopressin, which appears to be more important for pair bonding in the male of this species.
What is known about adolescent sexual behavior is reviewed. First, the onset of sexual behavior in the teenage years is considered as a function of cohort, gender, and ethnic differences. Omissions in the research on sexual behavior other than intercourse are highlighted. Possible biological, social, and social cognitive processes underlying teenage sexual behavior are then considered. Next, demographic trends in the use of contraceptives and antecedents of regular birth control use are reviewed. Finally, some of the successful program initiatives directed toward altering sexual and contraceptive practices are discussed, keeping in mind the importance and relative lack of well-designed and carefully evaluated programs.
Prairie voles (Microtus ochrogaster) and montane voles (M. montanus) display marked differences in social organization in the field. Trios of 1 male and 2 females were studied in a large enclosure for a 10-day period. Prairie voles spent 59% of the observation time in side-by-side contact, whereas montane voles spent only 7% of the time in contact. Vaginal smears indicated female-female suppression of estrus in prairie voles; female montane voles appeared to cycle in the presence of males. Male prairie voles preferentially paired and nested with 1 of the females, and vaginal estrus generally followed pair formation by 2 days. Male montane voles did not spend time preferentially with either female, even after mating. These results suggest that the contrasting mating systems of these species result from differences in the propensity for affiliative behavior and social bonding rather than from mate availability or female receptivity.
Performed hysterectomies between the 10th and 19th day of pregnancy, and tested females with pups for the onset of maternal behavior starting 0, 24, 48, or 72 hr after surgery. Ss were 394 Charles River female rats. Pups remained with females overnight, and testing was repeated daily with fresh pups until females exhibited maternal behavior. Latencies for the onset of maternal behavior were shorter after hysterectomy on the 10th and 16th days of pregnancy than in intact pregnant Ss at the same stages of pregnancy; latencies become shorter, the later the termination of pregnancy. When the ovaries were removed along with hysterectomy during pregnancy, short-latency maternal behavior no longer was exhibited. Pregnant Ss were tested during the last 40 hr of pregnancy: nest building began at 34 and retrieving at 28 hr prepartum. The effect of hysterectomy during pregnancy on ovarian secretion of estrogen and progesterone is reviewed, and it is concluded that the rise in estrogen secretion, which follows hysterectomy during pregnancy, is most likely the cause of the rapid onset of maternal behavior after hysterectomy. A similar proposal is made for the prepartum onset of maternal behavior in intact pregnant females. (50 ref)
Breeding units (occupants of a nest including at least one reproductive female) within two free-living populations of the prairie vole, Microtus ochrogaster, were monitored by live-trapping at nest during two 28-h periods each week from October 1980 to March 1984. Data are presented for 281 breeding units from all seasons, at high and low population densities and during breeding and nonbreeding periods. Fifty percent of the breeding units were monogamous (single resident reproductive male and female), 27% consisted of a single reproductive female with no resident adult male and 23% included more than one resident adult male and/or female (complex units). Monogamous units were present in the same proportions during breeding and nonbreeding periods. The number of monogamous units was significantly greater at low population densities than at high densities. During winter there were relatively more complex units and fewer single female units than during the rest of the year. Monogamous pairs remained together for an average of 42 days. Seventy-eight percent of these pairs were disbanded by the death of one or both members. There were few overlaps of the home ranges of adjacent breeding units. Significantly more nests were visited by nonresident males than by females, and the intervals between visits by males were significantly shorter than those for visits by females. Males visited single female units significantly more often than units with one or more resident males. Survival of juveniles was generally very low; 38% and 34% of young males and females, respectively, that were trapped survived until 30 days of age. Of young females remaining at the natal nest at low population densities, only 17.6% were reproductively activated; 77.1% of such females became reproductively activated at high densities. All young females that dispersed from the natal nest became reproductive.
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Field and experimental evidence is provided for the existence of pair-bonding or monogamy in prairie voles (Microtus ochrogaster).
2.
Multiple-capture live-trap data indicated that male and female pairs of M. ochrogaster were repeatedly captured together. (A comparable analysis for data from M. pennsylvanicus revealed no indications of long-term male-female associations.)
3.
Male-female pair captures of M. ochrogaster were equally likely during either the breeding or nonbreeding seasons, further suggesting a relative stability of pairs.
4.
In laboratory dyadic encounters, both males and females from breeding pairs tended to show relatively high levels of aggression toward unfamiliar animals of the opposite sex. In contrast, aggression was rarely observed between members of established breeding pairs. Nonpaired animals of either sex infrequently initiated aggressive encounters.
5.
When pairs were separated for 8 days (during which time the females lived with a new male) the apparent pair-bond with the original male was broken. These females became aggressive toward the male with which they had previously bred, and rarely fought with their new mate. This suggests that the pair-bonding process is reversible.
6.
Females in postpartum estrus preferentially showed high levels of sexual receptivity and low levels of aggression toward familiar males and were less likely to mate with unfamiliar sexually experienced males. The presence of pups at the time of testing did not appear to influence female-initiated aggression.
Oxytocin (OT) knock-out mice fail to recognize familiar conspecifics after repeated social exposures, despite normal olfactory and spatial learning abilities. OT treatment fully restores social recognition. Here we demonstrate that OT acts in the medial amygdala during the initial exposure to facilitate social recognition. OT given before, but not after, the initial encounter restores social recognition in OT knock-out mice. Using c-Fos immunoreactivity (Fos-IR) as a marker of neuronal activation in this initial encounter, we found similar neuronal activation in the wild-type (WT) and OT knock-out mouse in olfactory bulbs, piriform cortex, cortical amygdala, and the lateral septum. Wild-type, but not OT knock-out mice exhibited an induction of Fos-IR in the medial amygdala. Projections sites of the medial amygdala also failed to show a Fos-IR induction in the OT knock-out mice. OT knock-out, but not WT, mice showed dramatic increases in Fos-IR in the somatosensory cortex and the hippocampus, suggesting alternative processing of social cues in these animals. With site-specific injections of OT and an OT antagonist, we demonstrate that OT receptor activation in the medial amygdala is both necessary and sufficient for social recognition in the mouse.
Concentrations of 17-hydroxyprogesterone (17-OHP) were measured in serum samples obtained daily through 9 menstrual cycles. These samples had previously been assayed for estradiol, progesterone, luteinizing hormone (LH), and follicle-stimulating hormone. The concentration of 17-OHP increased at mid-cycle and continued to be high throughout the luteal phase of the cycle. The first sustained rise in 17-OHP levels was associated with the initiation of the mid-cycle LH surge. The results of this study indicate that the mid-cycle rise of 17-OHP may well be one of the earliest indicators of luteinization of the follicle as this hormone appears to be initially secreted by luteintzed thecal cells and then by the corpus luteum. It is concluded that estradiol levels rather than 17-OHP levels provide a good index of follicular maturation, whereas rising concentrations of the latter hormone indicate luteinization of the follicle.
Nature Reviews Neuroscience 10, 647–658 (2009) On page 654 of the above article, the scale bar in parts a and f of figure 4 should represent 5 μm rather than 5 mm. This has been corrected in the online version.
To investigate sex and menstrual cycle effects in response to cocaine administration, data from existing studies were analyzed. First, responses to a single delivery of 0.4 mg/kg smoked cocaine were investigated. Women reported lower ratings for measures of paranoid/suspicious and heart racing/pounding than did men. In addition, women in the luteal phase reported diminished ratings for a measure of feel high than did both women in the follicular phase of the menstrual cycle and men. Second, responses to up to 6 deliveries of 0.4 mg/kg smoked cocaine were investigated. Women, compared with men, had lower ratings on feel high, heart racing/pounding, and feel stimulated. Results suggest that there are significant sex and menstrual phase differences in the subjective effects of cocaine.
This series of studies explored the operant response rates for pup-reinforcement of female Sprague Dawley rats that were either postpartum or cycling and sustained lesions of the medial preoptic area (mpoa), the lateral amygdala, the nucleus accumbens, or sham lesions. The last experiment tested the effects on operant responding of preventing direct access to pups in mpoa and sham-lesioned postpartum mothers. All animals were trained prior to mating on an FR-1 bar-press schedule to criterion (50 presses in 30 min) for a food (Froot Loops) reward in an operant chamber. At the end of pregnancy animals that were to be tested postpartum were provided in their home cages with six newborn foster pups; mother-litter interactions were observed on the last 3 days of pregnancy and throughout the postpartum period. On each of these same days after a period of separation from pups, females were tested in the operant box for delivery of rat pups. With each bar-press response, a rat pup rather than a Fruit Loop was delivered down a gentle shoot into the hopper. Non-postpartum, but maternal, multiparous animals who were showing estrous cycles were tested using the same procedures. The first and second studies showed that animals (both postpartum and as cycling multiparous animals) with mpoa lesions exhibited a significant reduction in bar-press rate for pup reinforcement in the operant box. In postpartum animals, amygdala lesions also produced a bar-press deficit, whereas nucleus accumbens lesions did not. All lesioned groups showed deficits in maternal responding in the home cage and deficits in retrieval in the operant box. These results indicate that systems associated with the mpoa mediate both the stereotypical maternal behaviors and pup-reinforcement. In contrast, the expression of home cage maternal behavior is dependent on the integrity of both the amygdala and nucleus accumbens, whereas operant responding need not be. These results indicate a dissociation of mechanisms mediating expression of the species-typical maternal behavior and pup-reinforcement.
This chapter discusses the hormonal, sensory, neural, and experiential mechanisms that regulate the onset of maternal behavior across a variety of placental mammals representing different behavioral strategies. Maternal behavior usually emerges at or close to parturition. Just after birth, the female shows a very rapid interest in the newborn. Cleaning of the neonate and the consumption of amniotic fluids and placenta are widespread behaviors among mammalian orders, except in fully aquatic mammals or semiaquatic mammals. Mothers of many mammals also emit characteristic vocalizations in response to their young and show retrieval, gathering, herding, or carrying behaviors that protect the young from predation and tend to keep the young in close proximity to the mother. As well, most new mothers protect their young from predators and conspecifics. However, the most important and common pattern of maternal behavior in mammals is nursing, which occurs shortly after the young are born. Moreover, like other primates, humans are able to discriminate their own infants and may show a preference for them, but, unlike the ungulates, they do not necessarily reject infants belonging to other mothers.
Repeated exposure to cocaine produces an enduring increase in dendritic spine density in adult rat nucleus accumbens. It has been shown previously that chronic cocaine administration increases the expression of cyclin-dependent kinase-5 in this brain region and that this neuronal protein kinase regulates cocaine-induced locomotor activity. Moreover, cyclin-dependent kinase-5 has been implicated in neuronal function and synaptic plasticity. Therefore, we studied the involvement of this enzyme in cocaine's effect on dendritic spine density. Adult male rats, receiving intra-accumbens infusion of the cyclin-dependent kinase-5 inhibitor roscovitine or saline, were administered a 28-day cocaine treatment regimen. Animals were killed 24-48 h after the final cocaine injection and their brains removed and processed for Golgi-Cox impregnation. Our findings demonstrate that roscovitine attenuates cocaine-induced dendritic spine outgrowth in nucleus accumbens core and shell and such inhibition reduces spine density in nucleus accumbens shell of control animals. These data indicate that cyclin-dependent kinase-5 is involved in regulation of, as well as cocaine-induced changes in, dendritic spine density.
Changes in women's social role over the past years likely influenced the gender gap in substance use and substance—related disorders, with potentially significant prevention and treatment implications. The authors reviewed the literature about gender differences in prevalence estimates and course of substance—related disorders. Male—to—female ratios of prevalence estimates of substance use are narrowing in different countries. The initiation of substance use is progressively taking place at younger ages, the trend being more dramatic among women as compared to men. Women's accelerated progression to dependence (so—called “telescoping effect”) is a robust finding among alcohol—dependent individuals, although the effect seems to be weaker among younger individuals. As for other drugs, the literature is weaker and further research is needed. It is concluded that women's earlier age of initiation of substance use, faster progression to dependence and under—representation in addiction treatments should be addressed in future health care planning.
This rodent forms social groups that appear to have evolved as an adaptation for living in a low-food habitat.
The copulatory behavior of both wild and domestic strains of Rattus norvegicus was observed via continuous video monitoring as it spontaneously occurred in the large seminatural environment and under standard laboratory conditions. A factorial design demonstrated that the female Norway rat has the major role determining the amount and timing of copulation once mating begins. Copulation between wild pairs was characterized by fewer ejaculatory series than domestic pairs. The first ejaculatory series of wild pairs contained more intromissions at longer intervals. Domestic pairs had the same total number of intromissions in a copulatory session, but spread over multiple ejaculatory series with few intromissions at short intervals in the first series. The characteristic differences between the copulatory patterns of wild and domestic pairs was determined by the female's strain condition and was either statistically independent or opposite to the male's strain condition. Specifically, the population pattern of a wild female was characterized by fewer ejaculatory series and more intromissions at longer intervals before the first ejaculation than the pattern of a domestic female. These differences between wild and domestic populations were produced by differences in the rate of active solicitations for an intromission by individual females : the solicitation occurred virtually in a one-to-one correspondence with an intromission. There were no gross anatomical differences between the vaginal size and placement of the two strains. The female solicitation is a distinct and quantifiable behavior not found in the standard testing cage: its occurrence depends on a larger and more complex environment. In addition, copulation in the larger seminatural environment is characterized by fewer intromissions in each ejaculatory series of a session at longer copulatory intervals. The role of the female is discussed both in terms of the individual interactions which underlie it and in terms of its physiological functions for successful reproduction in the rat. Copulation with a wild male is characterized by longer intervals between the intromissions of the first ejaculatory series than with a domestic male. The wild condition of both the pair and the female showed the opposite effect. This difference is evaluated in terms of the different mating strategies for the two sexes on a population level and in terms of the individual interactions that allow a compromise for successful reproduction of the pair.
The neuropeptide oxytocin has been implicated in the mediation of several forms of affiliative behavior including parental care, grooming, and sex behavior. Here we demonstrate that species from the genus Microtus (voles) selected for differences in social affiliation show contrasting patterns of oxytocin receptor expression in brain. By in vitro receptor autoradiography with an iodinated oxytocin analogue, specific binding to brain oxytocin receptors was observed in both the monogamous prairie vole (Microtus ochrogaster) and the polygamous montane vole (Microtus montanus). In the prairie vole, oxytocin receptor density was highest in the prelimbic cortex, bed nucleus of the stria terminalis, nucleus accumbens, midline nuclei of the thalamus, and the lateral aspects of the amygdala. These brain areas showed little binding in the montane vole, in which oxytocin receptors were localized to the lateral septum, ventromedial nucleus of the hypothalamus, and cortical nucleus of the amygdala. Similar differences in brain oxytocin receptor distribution were observed in two additional species, the monogamous pine vole (Microtus pinetorum) and the polygamous meadow vole (Microtus pennsylvanicus). Receptor distributions for two other neurotransmitter systems implicated in the mediation of social behavior, benzodiazepines, and mu-opioids did not show comparable species differences. Furthermore, in the montane vole, which shows little affiliative behavior except during the postpartum period, brain oxytocin receptor distribution changed within 24 hr of parturition, concurrent with the onset of maternal behavior. We suggest that variable expression of the oxytocin receptor in brain may be an important mechanism in evolution of species-typical differences in social bonding and affiliative behavior.
Progress has been made over the last 10 years in determining the neural mechanisms of sensitization induced by amphetamine-like psychostimulants, opioids and stressors. Changes in dopamine transmission in axon terminal fields such as the nucleus accumbens appear to underlie the expression of sensitization, but the actions of drugs and stressors in the somatodendritic regions of the A10/A9 dopamine neurons seem critical for the initiation of sensitization. Manipulations that increase somatodendritic dopamine release and permit the stimulation of D1 dopamine receptors in this region induce changes in the dopamine system that lead to the development of long-term sensitization. However, it is not known exactly how the changes in the A10/A9 region are encoded to permit augmented dopamine transmission in the terminal field. One possibility is that the dopamine neurons of sensitized animals have become increasingly sensitive to excitatory pharmacological and environmental stimuli or desensitized to inhibitory regulation. Alternatively, changes in cellular activity or protein synthesis may result in a change in the presynaptic regulation of axon terminal dopamine release.
The prairie vole ( Microtus ochrogaster ), a monogamous rodent that forms long-lasting pair bonds, has proven useful for the neurobiological study of social attachment. In the laboratory, pair bonds can be assessed by testing for a partner preference, a choice test in which pair-bonded voles regularly prefer their partner to a conspecific stranger. Studies reported here investigate the role of dopamine D2-like receptors (i.e., D2, D3, and D4 receptors) in the nucleus accumbens (NAcc) for the formation of a partner preference in female voles. Mating facilitated partner preference formation and associated with an approximately 50% increase in extracellular dopamine in the NAcc. Microinjection of the D2 antagonist eticlopride into the NAcc (but not the prelimbic cortex) blocked the formation of a partner preference in mating voles, whereas the D2 agonist quinpirole facilitated formation of a partner preference in the absence of mating. Taken together, these results suggest that D2-like receptors in the NAcc are important for the mediation of social attachments in female voles. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
This chapter discusses the control of the ovarian cycle of the rats by the brain and its interaction with the anterior pituitary gland and ovaries. The ovarian cycle of the rats is characterized by a brief luteal phase, and the events of the cycle are largely under photoperiodic control. That is, the lighting periodicity plays a dominant role in the incidence and duration of the stages of the ovarian cycle. During the estrous cycle of the rat, three or more generations of corpora lutea can be present on the ovary from the immediately preceding ovulatory cycles whereas the preovulatory period of the estrous cycle is characterized by a growth of ovarian follicles and a concomitant enhanced secretion of estrogen. The secretion rate of estradiol into ovarian venous plasma is low on estrus, begins to rise significantly by late on metestrus through the morning of diestrus, and reaches peak concentrations by the afternoon of proestrus.
Although oxytocin (OT) and dopamine (DA) have been implicated in pair bond formation in monogamous prairie voles (Microtus ochrogaster), the nature of potential interactions between these two neurochemical systems and the brain circuits important for such interactions in the regulation of pair bonding have not been explored. Here, we demonstrated that access to both OT and DA D2-type receptors is necessary for pair bond formation, as blockade of either type of receptor prevented partner preferences induced by OT or a D2-type agonist. We also demonstrated that the nucleus accumbens (NAcc) is a brain area important for such OT-DA interactions. In NAcc, blockade of OT receptors prevented partner preferences induced by a D2-type agonist whereas blockade of D2-type, but not D1-type, DA receptors blocked OT-induced partner preferences. Together, our data suggest that concurrent activation of OT and DA D2-type receptors in NAcc is essential for pair bond formation in female prairie voles.
Interactions between ovarian hormones and cocaine may underlie gender and estrous cycle differences in cocaine-induced behavioral and neurochemical alterations. The aim of this study was to further understand how ovarian hormones modulate cocaine-induced behavioral alterations. Ovariectomized rats received acute or chronic saline or cocaine (15 mg/kg i.p.) administration and were further subdivided into one of four hormone-treatment conditions: cholesterol (vehicle-control), estrogen, progesterone, or estrogen+progesterone. Overall, acute and chronic cocaine administration increased all locomotor measurements (total locomotor, ambulatory, and rearing counts). Estrogen administration augmented cocaine-induced increases in ambulatory and rearing activity. After chronic cocaine administration, rats in the vehicle-control group developed behavioral tolerance (exhibited by a decrease in activity) in rearing and ambulatory activity. Estrogen replacement not only prevented the development of tolerance in ambulatory and rearing activities, but also enhanced total locomotor activity (sensitization) in response to chronic cocaine. Progesterone treatment did not alter the behavioral responses to acute or chronic cocaine administration. Estrogen+progesterone-treated animals had higher counts of locomotor activity in response to chronic cocaine than did vehicle-control or progesterone-treated rats. In stereotypic behaviors, the different hormonal treatments did not affect activity in cocaine- or saline-treated rats after acute or chronic drug administration. Plasma levels of cocaine did not change after different hormonal treatments. Interestingly, animals' coadministered chronic cocaine and estrogen had higher levels of corticosterone than did nonestrogen cocaine-treated rats. Thus, it is likely that alterations in HPA activation may underlie the observed behavioral differences. In summary, these data suggest that there are interactions between ovarian hormones and cocaine-induced behavioral alterations in female rats, and they extend previous results by showing that estrogen and progesterone affect the development of sensitization.
ΔFosB is a Fos family transcription factor that is induced by chronic exposure to cocaine and other drugs of abuse in the nucleus accumbens and related striatal regions, brain regions that are important for the behavioral effects of these drugs. To better understand the mechanisms by which ΔFosB contributes to the effects of chronic drug treatment, we used DNA microarray analysis to identify genes that are regulated in the nucleus accumbens upon ΔFosB expression in inducible bitransgenic mice. One of the most highly regulated genes was that encoding a subunit of another transcription factor, nuclear factor-κB (NF-κB). Subsequent experiments confirmed the induction of NF-κB in the nucleus accumbens of mice overexpressing ΔFosB as well as in wild-type mice treated chronically, but not acutely, with cocaine. These results establish NF-κB as a putative target for ΔFosB and implicate NF-κB signaling pathways in the long-term adaptations of nucleus accumbens neurons to cocaine.
The acute effect of physiological doses of estradiol (E2) on the dopaminergic activity in the striatum was studied. In a first series of experiments, ovariectomized rats were injected with 17 alpha or 17 beta E2 (125, 250, or 500 ng/kg of body weight, s.c.), and in situ tyrosine hydroxylase (TH) activity (determined by DOPA accumulation in the striatum after intraperitoneal administration of NSD 1015) was quantified. A dose-dependent increase in striatal TH activity was observed within minutes after 17 beta (but not 17 alpha) E2 treatment. To examine whether E2 acts directly on the striatum, in a second series of experiments, anesthetized rats were implanted in the striatum with a push-pull cannula supplied with an artificial CSF containing [3H]tyrosine. The extracellular concentrations of total and tritiated dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were measured at 20-min intervals. Addition of 10(-9) M 17 beta (but not 17 alpha) E2 to the superfusing fluid immediately evoked an approximately 50% increase in [3H]DA and [3H]DOPAC extracellular concentrations, but total DA and DOPAC concentrations remained constant. This selective increase in the newly synthesized DA and DOPAC release suggested that E2 affects DA synthesis rather than DA release. Finally, to determine whether this rapid E2-induced stimulation of DA synthesis was a consequence of an increase in TH level of phosphorylation, the enzyme constant of inhibition by DA (Ki(DA)) was calculated. Incubation of striatal slices in the presence of 10(-9) M 17 beta (but not 17 alpha) E2 indeed evoked an approximate twofold increase in the Ki(DA) of one form of the enzyme.(ABSTRACT TRUNCATED AT 250 WORDS)
Prairie voles (Microtus ochrogaster) are monogamous mammals that form male-female pair bonds. Partner preference formation, one component of the pair bond in prairie voles, occurs following male-female cohabitation and is facilitated by mating. The peptide hormone oxytocin is released during physical contact and particularly following vaginal stimulation. Oxytocin has been implicated in mother-infant bond formation. The present study tested the hypothesis that oxytocin participates in the partner preference component of pair bond formation in adult prairie voles. Ovariectomized female prairie voles were implanted with osmotic mini-pumps releasing oxytocin (1–100 ng/h) or artificial cerebrospinal fluid (CSF). Pumps were implanted intracerebroventricularly or subcutaneously and females then were housed for 6 h with a male partner, followed by a preference test in which females could elect to spend time with either the partner or an unfamiliar male. Females in groups that received centrally-administered oxytocin (10 or 100 ng/h), but not CSF, exhibited a significant preference for the partner present during infusion. The induction of a partner preference after oxytocin administration appeared specific for central oxytocin pathways as peripheral oxytocin administration was ineffective. Moreover, central administration of a selective oxytocin receptor antagonist inhibited the behavioral effect of exogenous oxytocin. These results suggest that oxytocin may be one factor contributing to the development of partner preferences in this monogamous rodent.
The distribution of oxytocin binding sites in the brain is highly variable among mammals. Using two species of microtine rodents (voles) with strikingly different patterns of oxytocin binding sites in the brain, we demonstrate that these differences are due to differences in region specific gene expression and not post-translational processing. The distribution of oxytocin receptor mRNA closely resembles the distribution of oxytocin receptor binding sites in both species. Analysis of the 5′ flanking region of the oxytocin receptor gene from both species reveals few differences in potential regulatory elements which could explain the differences in gene expression. These data suggest that species differences in oxytocin receptor binding are due to species differences in: i) distant DNA sequences further upstream or downstream which may influence expression; ii) the distribution of regulatory proteins such as transcription factors in the brain or iii) epigenetic factors, such as prenatal and perinatal environment which may affect gene expression in the adult.
When ovariectomized female rats receive estrogen, the response to the psychomotor stimulants amphetamine or cocaine is enhanced. Estrous cycle-dependent differences in amphetamine-stimulated behaviors and striatal dopamine release are also noted. Intact female rats exhibit a greater behavioral response to amphetamine on estrus than they do on other days of the cycle. Ovariectomy results in attenuation of amphetamine-induced behavior and the striatal dopamine response to amphetamine. Physiological doses of estrogen given to ovariectomized rats reinstate both of these responses to a level comparable to that in estrous females. Furthermore, a sex difference is noted, in that females tend to exhibit a greater behavioral response to the psychomotor stimulants, and estrogen enhances this sex difference. Repeated treatment with amphetamine or cocaine produces a progressive increase in behavioral responsiveness with subsequent drug administration, a process known as sensitization. In rodents, behavioral sensitization results in increases in both frequency and duration of psychomotor behaviors such as rotational behavior, stereotyped grooming, headbobs, and forelimb movements. Interestingly, females display greater sensitization of behaviors in response to psychomotor stimulants than do males. Previous research results are summarized, and new results are presented, demonstrating that estrogen selectively enhances components of behavior that exhibit sensitization in female rats. Results also indicate gender differences in sensitization independent of gonadal hormones, suggesting that the neural systems that undergo sensitization are sexually dimorphic.
Social recognition of juveniles by adult male residents has been shown to be modulated by neurohypophyseal hormones. The decrease of social investigation behavior during a second encounter with the same juvenile serves as index for social recognition. In the present study it was found that low doses (0.09–6.0 ng kg–1) of oxytocin (OXT) given subcutaneously dose dependently facilitated social recognition. The effect of OXT appeared specific, since no change in social investigation was found when a novel juvenile was tested during the second encounter. No disturbances of social recognition by the low doses of OXT could be detected, in contrast to higher doses of this hormone. Other neurohypophyseal hormones, vasopressin and vasotocin, did not facilitate social recognition when tested in the same range of low doses.
The effects of parity on the dopaminergic function of rats were studied. Striatal and hypothalamic levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), norepinephrine (NE), serotonin (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) as well as serum prolactin (PRL) levels of 7-days primigravid and multigravid rats were compared. Brains and trunk blood were collected from 1200–1400 h on day 7 of pregnancy and assayed for monoamines and their metabolites, and prolactin, respectively. Multigravid rats showed a significant increase in striatal and hypothalamic dopamine levels. A tendency to increase in striatal DOPAC levels was also observed in multigravid rats. Levels of other neurotransmitters and metabolites were not statistically different. Haloperidol (1 mg/kg) treatment induced a significant increase in multigravid 5-HT striatal levels. There was no statistical difference among primigravid and multigravid serum PRL levels after either saline or haloperidol treatment. These data suggest that prior parity produces a shift in dopaminergic activity in multigravid rats.
The conditioning of cocaine's pharmacological actions with environmental stimuli is thought to be a critical factor in long-lasting relapse risk associated with cocaine addiction. To study the significance of environmental stimuli in enduring vulnerability to relapse, the resistance to extinction of drug-seeking behavior elicited by a cocaine-related stimulus was examined. Male Wistar rats were trained to associate discriminative stimuli (SD) with the availability of intravenous cocaine (S+) vs. the availability of non-rewarding (S−) saline solution, and then placed on extinction conditions during which intravenous solutions and SD were withheld. The rats were then presented with the S+ or S− alone in 60-min reinstatement sessions conducted at 3-day intervals. To examine the long-term persistence of the motivating effects of the cocaine S+, a subgroup of rats was re-tested following an additional three months of abstinence during which time the rats remained confined to their home cages. Re-exposure to the cocaine S+ selectively elicited robust responding at the previously active lever. The efficacy and selectivity of this stimulus to elicit responding remained unaltered throughout a 34-day phase of repeated testing as well as following the additional extended abstinence period. In pharmacological tests, conducted in a separate group of rats, the dopamine (DA) D1 antagonist SCH 39166 (10 μg/kg), the D2/3 antagonist nafadotride (1 mg/kg), and the D2/3 agonist PD 128907 (0.3 mg/kg) suppressed the cue-induced response reinstatement while the D1 agonist SKF 81297 (1.0 mg/kg) produced a variable behavioral profile attenuating cue-induced responding in some rats while exacerbating this behavior in others. The results suggest that the motivating effects of cocaine-related stimuli are highly resistant to extinction. The undiminished efficacy of the cocaine S+ to induce drug-seeking behavior both with repeated testing and following long-term abstinence parallels the long-lasting nature of conditioned cue reactivity and cue-induced cocaine craving in humans, and confirms a significant role of learning factors in long-lasting vulnerability to relapse associated with cocaine addiction. Finally, the results support a role of DA neurotransmission in cue-induced cocaine-seeking behavior.
Preclinical and clinical research investigating female sexual motivation has lagged behind research on male sexual function. The present review summarizes recent advances in our understanding of the specific roles of various brain areas, as well as our understanding of the role of dopaminergic neurotransmission in sexual motivation of the female rat. A number of behavioral paradigms that can be used to thoroughly evaluate sexual behavior in the female rat are first discussed. Although traditional assessment of the reflexive, lordosis posture has been useful in understanding the neuroanatomical and neurochemical systems that contribute to copulatory behavior, the additional behavioral paradigms described in this review have helped us expand our understanding of appetitive and consumatory behavioral patterns that better assess sexual motivation – the equivalent of “desire” in humans. A summary of numerous lesion studies indicates that different areas of the brain, including forebrain and midbrain structures, work together to produce the complex repertoire of female sexual behavior. In addition, by investigating the effects of commonly addictive drugs, we are beginning to elucidate the role of dopaminergic neurotransmission in female sexual motivation. Consequently, research in this area may contribute to meaningful advances in the treatment of human female sexual dysfunction.
Multinomial random variables are used across many disciplines to model categorical outcomes. Under this framework, investigators often use a likelihood ratio test to determine goodness-of-fit. If the permissible parameter space of such models is defined by inequality constraints, then the maximum likelihood estimator may lie on the boundary of the parameter space. Under this condition, the asymptotic distribution of the likelihood ratio test is no longer a simple χ2 distribution. This article summarizes recent developments in the constrained inference literature as they pertain to the testing of multinomial random variables, and extends existing results by considering the case of jointly independent mutinomial random variables of varying categorical size. This article provides an application of this methodology to axiomatic measurement theory as a means of evaluating properly operationalized measurement axioms. This article generalizes Iverson and Falmagne’s [Iverson, G. J. & Falmagne, J. C. (1985). Statistical issues in measurement. Mathematical Social Sciences, 10, 131–153] seminal work on the empirical evaluation of measurement axioms and provides a classical counterpart to Myung, Karabatsos, and Iverson’s [Myung, J. I., Karabatsos, G. & Iverson, G. J. (2005). A Bayesian approach to testing decision making axioms. Journal of Mathematical Psychology, 49, 205–225] Bayesian methodology on the same topic.
Extracellular concentrations of dopamine in the nucleus accumbens were monitored using microdialysis in ovariectomized female Syrian hamsters hormonally primed with estradiol and progesterone or with a similar regimen of oil injections. Some females in each of these groups had their vaginas occluded with tape, whereas the remaining females' vaginas stayed unoccluded. When exposed to a male, both groups of hormonally primed females showed high levels of lordosis. However, only in the hormone-primed, unoccluded females were there significant elevations of dialysate dopamine during the sexual interactions with the male. There were no significant elevations in dopamine levels in the oil-treated females during interactions with the male. These data suggest that nucleus accumbens dopamine is responsive to stimuli associated with the vaginocervical stimulation received by the female during intromissions by the male. Histological analyses were based on Fluoro-Gold efflux through the probes combined with immunocytochemistry for tyrosine hydroxylase. Probe placements in the rostral accumbens, caudal accumbens, or rostral bed nucleus of the stria terminalis were not distinguishable based on analyses of basal dopamine levels, volume of Fluoro-Gold injection sites, or Fluoro-Gold labeling of midbrain, tyrosine hydroxylase-stained neurons. The number of midbrain neurons containing Fluoro-Gold was positively related to basal dopamine levels, indicating that the amount of dopamine recovered from the nucleus accumbens in microdialysis studies is a function of the number of neurons contributing to the terminal field in the region of the probe.
We examined the effects of prior sexual experience on extracellular concentrations of dopamine in the nucleus accumbens of female hamsters. Nucleus accumbens dopamine was measured by in vivo microdialysis during mating in female Syrian hamsters that had previously been given six prior sexual encounters with a male, three prior encounters, or were sexually naive. High levels of sexual behavior were observed in all three groups, which were accompanied by increases in dialysate dopamine during periods when the male was present. However, females that received six prior sexual encounters had significantly elevated and prolonged increases in dialysate dopamine compared with those of the sexually naive females or females with only three prior sexual encounters with a male. The data indicate that the mesolimbic system can be sensitized by repeated experiences associated with a motivated behavior.
We assessed the effects of the dopamine D2 receptor antagonists, sulpiride and raclopride, on conditioned place preference produced by sexual behavior in female Syrian hamsters. Female hamsters treated with sulpiride or raclopride showed high levels of sexual behavior (lordosis) that were equivalent to control females receiving vehicle injections. The degree of place preference conditioning for sulpiride-treated females was marginally reduced, whereas females treated with raclopride showed no evidence of conditioning. These results indicate that conditioned place preference is a useful means for probing the appetitive components of female sexual behavior, and that dopamine D2 receptors are involved in this appetitive process.
The analysis of the behavioural and neural mechanisms of reinforcement and motivation has benefited from the recent application of learning theory and better anatomical knowledge of the connectivity of certain key neural structures, such as the nucleus accumbens. This progress has enabled the dissection of motivational processes into components that can begin to be related to the functioning of specific limbic cortical structures that project to different compartments of the ventral striatum.
Latency to retrieve and group rat pups was measured in nonlactating primiparous and nulliparous rats. Primiparous females that raised litters to weaning and were tested for responsiveness to donor's pups 25 days postweaning exhibited an immediate onset of maternal responsiveness. The 21 day lactation period was found not be essential for the establishment of this level of responsiveness, since animals that experienced pregnancy and parturition, and interacted with their young for 1– hr during parturition also retrieved and grouped pups immediately when tested 25 days postpartum. The establishment of this behavioral response in the newly parturient animal was found to be independent of lactogenesis and the presence of the ovaries during parturition. Virgin females with or without previous pup exposure, animals caesarean sectioned on Day 22 of pregnancy, and primiparous females whose pups were removed immediately at birth did not exhibit this level of maternal responsiveness immediately when tested later in adulthood. The data suggest that an organization of maternal behavioral responsiveness occurs during parturition in the rat.
The results of two separate experiments indicate that limited sexual stimulation (six intromissions) increases both the lateral extent of the region on the perineum from which pelvic adjustment responses can be elicited by tactile stimulation and the magnitude of the responses elicited. Response magnitude was affected by the intensity and pattern of stimulation and varied significantly among individuals. Possible mechanisms for these sex responses are discussed in relation to the results of neurophysiological investigations of potentially similar processes in the rat [10].
In female prairie voles (Microtus ochrogaster) bilateral olfactory bulbectomy reduced affiliative behavior, as measured by social contact, and prevented the formation of partner preferences. Unilateral olfactory bulb removal did not significantly influence affiliative behavior, but did inhibit partner preferences. Bilateral, but not unilateral, bulbectomy significantly reduced the proportion of females exhibiting behavioral estrus following male exposure. In contrast to affiliative and sexual behavior, parental behavior was not significantly affected by either bilateral or unilateral olfactory bulbectomy. These results suggest that divergent sensory-neural pathways underlie social, sexual, and parental behaviors in this species.
Regional changes in striatal D2 dopamine (DA) receptor binding in castrated (CAST) or ovariectomized (OVX) rats were investigated following administration of a low dose of estradiol benzoate (EB), repeated treatment with EB followed by progesterone, or vehicle. In two separate experiments, there was a significant decrease in striatal D2 DA receptor binding in caudal striatum from OVX, but not CAST rats 30 min after a single injection of EB. In CAST rats, there was a significant increase in striatal D2 DA receptor binding in rostral striatum 4 h after injection of EB. There was no effect of EB plus progesterone treatment in either OVX or CAST rats. In addition, CAST rats had significantly lower D2 DA receptor binding in the lateral region of the rostral striatum than did OVX rats. These results show sexually dimorphic and regionally specific effects of estrogen on striatal D2 DA receptor binding, and a significant sex difference in striatal D2 DA receptor binding in the absence of circulating gonadal hormones. The present findings are discussed in light of previous reports of sex differences in gonadal hormone influences on striatal DA mediated behaviors.
Experiments were conducted to examine sex differences in striatal dopamine function using in vivo microdialysis in freely moving rats. We report here a sex difference in basal extracellular striatal dopamine determined by quantitative microdialysis (the no net flux method) when castrated and ovariectomized rats were compared. There was no sex difference in dopamine uptake into synaptosomes. This indicates that the sex difference in extracellular dopamine is most likely due to sex differences in dopamine release, synthesis, and/or metabolism. Within 30 min after a single injection (s.c.) of either estradiol benzoate (2.0 μg/100 g) or 17β-estradiol (1.5 μg/100 g) the amphetamine-stimulated release of dopamine was enhanced in the striatum of ovariectomized rats, but there was no effect in castrated male rats. The enhanced amphetamine-induced striatal dopamine release in ovariectomized rats was associated with an enhanced frequency of stereotyped head and limb movements and an increased peak in extra 1/4 turns. There were also sex differences in stereotyped behavior and extra 1/4 turns whether or not animals received estrogen treatment. Thus, there are sex differences in striatal extracellular dopamine and in the effect of estrogen on the striatal dopamine neurochemical and behavioral responses to amphetamine.
Ovariectomy (OVX) of female rats results in a decreased behavioral response to stimulation of the mesostriatal dopamine (DA) system and decreased striatal DA release in vitro. Estrogen replacement restores both behavioral and neurochemical responsiveness. In this report, microdialysis in freely moving rats is used to simultaneously study the behavioral and neurochemical effects of systemic estradiol. OVX rats received a unilateral 6-hydroxy-dopamine lesion of the substantia nigra and then underwent microdialysis of the intact striatum. Thirty min after a single injection of 5 μg estradiol benzoate, amphetamine-induced rotational behavior and striatal DA release are both potentiated, relative to the response of oil-treated control animals.