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Abstract

To analyze motivation, food self-administration and decision-making was evaluated in adolescent, adult and aged rats. Subjects were trained to press a lever (fixed ratio, FR1 and FR5) in an operant chamber, to obtain chocolate flavor pellets. We assessed the progressive ratio (PR), extinction and reinstatement of the behavior. To estimate decision-making for food, rats were trained in the conditioned place preference (CPP) paradigm: a) associating one compartment with lab chow (LCh) one day and the other compartment with rice krisspies (RK), the next day. b) Training similar to a) but on the day RK was the reinforcer, it was delivered with a progressive delay. In addition, CB1 and CB2 receptor expression in the nucleus accumbens (NAcc) and prefrontal cortex (PFC) was estimated by means of Western blot. Adolescent rats consumed higher amounts of RK/body weight than adult and aged rats during FR1, FR5 and PR. Extinction was more prolonged for adolescent rats than for adult and aged rats. First CPP condition, all three groups of rats preferred the RK-associated compartment. Second CPP condition, adolescent rats developed equal preference to both compartments, while adult and aged rats preferred the RK-associated compartment. Rats per group ate a similar amount of either reinforcer. Adolescent rats exhibited low expression of CB1R in the NAcc and low expression of both CB1R and CB2R in the PFC compared to adult and aged rats. Adolescent rats display higher motivation for palatable food and an indiscriminate seeking behavior suggesting involvement of both homeostatic and hedonic systems in their decision-making processes. This article is protected by copyright. All rights reserved.

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... La sensación placentera que experimenta el humano al comer, beber o tener sexo es regulada por diversas estructuras del sistema límbico y por neuronas dopaminérgicas, organizadas en un área llamada área tegmental ventral (ATV). Estas neuronas dopaminérgicas proyectan a diferentes núcleos cerebrales, constituyendo dos de las principales vías dopaminérgicas: la vía mesolímbica, que va del ATV al núcleo accumbens (NAc) y a la amígdala (AMI), y la vía mesocortical, que parte del ATV y proyecta a la CPF (Figura 1) (Méndez-Díaz et al., 2017). ...
... La CPF recibe información de los sistemas sensoriales y motores, y los compara con eventos semejantes almacenados en la memoria de largo plazo (análisis) para generar la respuesta adaptativa en ese momento. Posee un sistema de neurotransmisión múltiple: dopaminérgico, serotoninérgico, colinérgico y endocanabinérgico (Amancio-Belmont et al., 2017;Tirapu-Ustárroz et al., 2008;Wȩdzony & Chocyk, 2009). ...
... De los sistemas neuroquímicos que regulan este sistema de motivación-recompensa-motor, aquí se ha descrito a el sECB, quien aparece como un actor tanto del autocontrol como del TCS. Si bien la expresión de los receptores para canabinoides en estas estructuras es amplia (Méndez-Diaz et al., 2008) y en modelos animales se ha demostrado que su manipulación farmacologica modifica la expresión de las conductas impulsivas (Lallemand, & De Witte, 2006;Méndez-Diaz et al., 2012;Amancio-Belmont et al., 2017), la muestra más evidente de su involucro la revelan los polimorfismos del sECB, presentes en las enfermedades psiquiátricas (TDAH, TLP, TB, ansiedad), por lo que deberían ser considerados como marcadores genéticos del TCS. ...
Article
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La proporción de usuarios de una sustancia de abuso que desarrolla problemas con su consumo (abuso o dependencia) representa solo una parte de esta población. En México, el 63.8 % de la población consume alcohol, y de ellos, el 15 % desarrolla algún trastorno por consumo de alcohol (TCA). Se ha observado una relación causal entre el trastorno por consumo de sustancias (TCS) y la falta de autocontrol. Es decir, satisfacer necesidades de manera impulsiva, v. gr., consumir una droga sin evaluar las consecuencias. La corteza prefrontal (CPF) es el principal sustrato neuroanatómico del autocontrol y característicamente la CPF alcanza la madurez alrededor de los 30 años, sugiriendo que el autocontrol se alcanza despues de esta edad. Se ha propuesto que todos los grupos etarios que no han consolidado el uso del autocontrol son vulnerables al TCS. Similarmente ocurre con aquellos sujetos que por algún trastorno psiquiátrico tienen como característica una limitada función prefrontal. La CPF coordina una red subcortical cuya interacción depende de distintos sistemas de neurotransmisión, entre ellos, endocanabinoides. En este trabajo se revisó la función de la CPF y del sistema de endocanabinoides (sECB) y su relación con la vulnerabilidad a la adicción y otros trastornos psiquiátricos. Palabras clave: Impulsividad, autocontrol, transtorno por uso de sustancias, enfermedades psiquiátricas.
... Rats reached their breakpoint when they spent more than 20 min inactive (not pressing the active lever) or the session ended (session duration = 1 h). The protocol was performed according previous descriptions (Amancio-Belmont et al., 2017). ...
... Brains were rapidly removed and PFC and NAcc were dissected according to Paxinos and Watson's stereotaxic atlas (2007). The protocol used has been widely described and published elsewhere (Amancio-Belmont et al., 2017). In short, PVDF membranes were incubated overnight with rabbit polyclonal antibodies against CB1R (1:1000, CST, MA, USA) diluted in TBS-T at 4°C. ...
Article
Abusive alcohol consumption is a health problem, worldwide. There is extensive literature indicating that cannabinoid 1 receptor (CB1R) plays a crucial role in mediating alcohol's reward effects. Maternal care deprivation (MCD) is a reliable rodent model of early life stress that leads to high levels of anxiety and alterations in motivation, which may increase vulnerability to alcohol consumption. The present study researched whether anxiety-like behaviors and the level of motivation for a natural reward, and CB1R expression in the prefrontal cortex (PFC) and nucleus accumbens (NAcc) can predict alcohol consumption in non-MCD and MCD male rats. Results indicate that MCD increases anxiety-like behaviors, i.e., reduces time in open arms in the elevated plus maze and increases alcohol intake. In turn, the motivation for a palatable reward, i.e., a chocolate flavored pellet, was not affected by MCD. MCD reduces CB1R expression in the PFC and increases it in the NAcc. Hence, both higher anxiety-like behaviors and higher CB1R expression in the NAcc and lower CB1R expression in the PFC are associated with higher alcohol intake. These results suggest that early life adverse experiences induce a reprogramming of the brain's endocannabinoid system that very likely contributes to making the brain vulnerable to develop alcohol abuse and dependence.
... sobre esta estructura potencia la percepción placentera frente al consumo de alimentos palatables, así como aumenta la sensibilidad a sus características organolépticas, resultando en un refuerzo positivo de su ingesta y modela las preferencias alimentarias [51][52][53][54][55] . ...
... Lo anterior coincide con los resultados hallados por diversos autores [53][54][55][56][57] , quienes plantean que la actividad del sistema endocannabinoide en el núcleo accumbens puede verse asociada al aumento de la percepción de las propiedades hedónicas de los alimentos y propiciar el consumo de alimentos palatables, los cuales a su vez aumentan los niveles plasmáticos de endocannabinoides como el 2-AG 31 . Si se tiene en cuenta que el núcleo accumbens hace parte del circuito de recompensa, se puede afirmar que los cambios en esta estructura derivados de la actividad del sistema están profundamente relacionados a la conducta alimentaria en respuesta al consumo de los alimentos palatables que a su vez aumenten los niveles plasmáticos de precursores de los endocannabinoides (anandamida y 2 araquidonoil glicerol) como el ácido araquidónico. ...
Article
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Introducción: la adicción a la comida es un trastorno en el que se alteran vías dopaminérgicas en el sistema nervioso central que conllevan a cambios en la conducta alimentaria que favorecen el desarrollo de sobrepeso u obesidad. Actualmente se desconoce el o los componentes que puedan dar lugar a los cambios neurobiológicos tras la adicción a la comida. Objetivo: analizar la relación entre los cambios en el sistema endocannabinoide y el desarrollo de la adicción a la comida, bajo el marco de los cambios neurobiológicos y conductuales evidenciados en las adicciones a sustancias psicoactivas. Material y métodos: se realizó una revisión exploratoria de la literatura disponible en bases de datos como Cochrane, Pubmed, Embase y Google Scholar, utilizando los términos DeCS adicción a la comida, endocannabinoides, nutrición, núcleo accumbens, hipotálamo, receptor cannabinoide tipo 1 y conducta alimentaria, tras la cual se incluyeron sesenta y nueve recursos bibliográficos. Resultados: la activación del sistema endocannabinoide puede modular la regulación neuroendocrina del apetito y saciedad a nivel hipotalámico estimulando el consumo de alimentos, asimismo, la acción de este sistema sobre el núcleo accumbens puede potenciar las propiedades sensoriales de los alimentos palatables (ricos en azúcares y/o grasas), además de aumentar la liberación de dopamina en las vías dopaminérgicas mesolímbica y mesocortical, las cuales se asocian a cambios conductuales como la impulsividad, deseo intenso por el consumo, abstinencia, tolerancia y otros, evidenciados en la adicción a la comida y diferentes trastornos asociados al consumo de drogas de abuso. Conclusiones: el consumo de compulsivo y crónico de alimentos palatables podría estar asociado al aumento de niveles plasmáticos de endocannabinoides agonistas de los receptores cannabinoides tipo 1, lo cual desencadenaría un círculo vicioso que reforzaría el consumo de alimentos palatables a nivel de la estimulación de estructuras involucradas en vías dopaminérgicas, producto de esto se mantendría una sobreactivación del sistema endocannabinoide y facilitaría la ganancia de peso.
... In the test phase, animals are given free access to both chambers; those that develop conditioned place preference will spend more time in the US-paired context. Rewarding outcomes, including sex [96], food [97][98][99][100], fluids [100], and numerous drugs of abuse [for a review, see 95], have been shown to reliably induce conditioned place preference, which can be reinstated after extinction [95,101], but can be abolished by devaluing the US [100,102]. In Pavlovian lever autoshaping, the insertion and retraction of a lever (CS) signals food (US) delivery, irrespective of behavior. ...
... Preclinical work suggests largely overlapping neural circuits are involved in Pavlovian learning processes, including OFC [132], dorsolateral PFC [97], nucleus accumbens (NAcc) [133], subthalamic nucleus [134], amygdala [135][136][137][138][139][140], hippocampus [139], and insula [138], which are widely preserved across species [141,142]. Recent work has shown the relevance of adrenergic, cannabinoid receptor, and NMDA signaling for Pavlovian conditioning [99,[143][144][145][146]. Still, the seminal work of Schultz et al. [147,148] demonstrated the critical role of dopamine by showing a shift in dopaminergic firing from the US to the CS over the course of conditioning. ...
Article
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Purpose of Review Current theories of alcohol use disorders (AUD) highlight the importance of Pavlovian and instrumental learning processes mainly based on preclinical animal studies. Here, we summarize available evidence for alterations of those processes in human participants with AUD with a focus on habitual versus goal-directed instrumental learning, Pavlovian conditioning, and Pavlovian-to-instrumental transfer (PIT) paradigms. Recent Findings The balance between habitual and goal-directed control in AUD participants has been studied using outcome devaluation or sequential decision-making procedures, which have found some evidence of reduced goal-directed/model-based control, but little evidence for stronger habitual responding. The employed Pavlovian learning and PIT paradigms have shown considerable differences regarding experimental procedures, e.g., alcohol-related or conventional reinforcers or stimuli. Summary While studies of basic learning processes in human participants with AUD support a role of Pavlovian and instrumental learning mechanisms in the development and maintenance of drug addiction, current studies are characterized by large variability regarding methodology, sample characteristics, and results, and translation from animal paradigms to human research remains challenging. Longitudinal approaches with reliable and ecologically valid paradigms of Pavlovian and instrumental processes, including alcohol-related cues and outcomes, are warranted and should be combined with state-of-the-art imaging techniques, computational approaches, and ecological momentary assessment methods.
... onset age, 17 years old on average, than in previous studies (14 years old on average); therefore, cannabis use onset was in a different phase of brain development (Gogtay & Thompson, 2010); in fact, it is well known that CB1R expression increases as a function of age, increasing after adolescence (Amancio-Belmont et al., 2017;Long et al., 2012). These changes have been observed in the prefrontal cortex, which plays a key role in attention (Jha et al., 2004;Paneri & Gregoriou, 2017). ...
Article
Attention allows us to select relevant information from the background. Although several studies have described that cannabis use induces deleterious effects on attention, it remains unclear if cannabis dependence affects the attention network systems differently. Objectives To evaluate whether customary consumption of cannabis or cannabis dependence impacts the alerting, orienting, and executive control systems in young adults; to find out whether it is related to tobacco or alcohol dependence and if cannabis use characteristics are associated with the attention network systems. Method One-hundred and fifty-four healthy adults and 102 cannabis users performed the Attention Network Test (ANT) to evaluate the alerting, orienting, and executive control systems. Results Cannabis use enhanced the alerting system but decreased the orienting system. Moreover, those effects seem to be associated with cannabis dependence. Out of all the cannabis-using variables, only the age of onset of cannabis use significantly predicted the efficiency of the orienting and executive control systems. Conclusion Cannabis dependence favors tonic alertness but reduces selective attention ability; earlier use of cannabis worsens the efficiency of selective attention and resolution of conflicts.
... SF-1 KO mice present a late-onset obese phenotype that is predominantly due to decreased locomotor activity, not increased food intake [128]. While the complications involved in breeding and maintaining SF-1 KO mice could have contributed to their phenotype, targeted silencing of ERα- signaling in the VMH was capable of replicating many aspects of me- tabolic syndrome [129,130]. Even seemingly mild disruptions can cause homeostatic problems, for example, knockout of cannabinoid receptor type 1 in SF-1 neurons causes decreased leptin efficacy and increased adiposity [131]. ...
Article
This review lays out the evidence for the role of E2 in homeostatic and hedonic feeding across several species. While significant effort has been expended on homeostatic feeding research, more studies for hedonic feeding need to be conducted (i.e. are there increases in meal size and enhanced motivation to natural food rewards). By identifying the underlying neural circuitry involved, one can better delineate the mechanisms by which E2 influences feeding behavior. By utilizing more selective neural targeting techniques, such as optogenetics, significant progress can be made toward this goal. Together, behavioral and physiological techniques will help us to better understand neural deficits that can increase the risk for obesity in the absence of E2 (menopause) and aid in developing therapeutic strategies.
... CB2R expression has been shown in the cerebral cortex, hippocampus, striatum, amygdala, thalamic nuclei, periaqueductal grey, cerebellum, on glial, and neurons ( Fig. 6.3). Recent studies support a role for these receptors in the CNS (Xi et al. 2011;Romano-López et al. 2012;Amancio-Belmont et al. 2017). CB2R is of considerable interest because all the psychoactive effects of THC in humans can be abolished by selective antagonism of the CB1R, implying that THC activation of CB2R does not produce psychoactive effects. ...
Chapter
The sleep-wake cycle is a complex process that includes wake (W), non-rapid-eye-movement (NREM) and rapid-eye-movement (REM) sleep. Each phase is regulated by specialized brain structures that, by means of different neurotransmitters, maintain the constant expression of the sleep-wake cycle. Molecules like orexin, serotonin, noradrenaline, histamine, for waking; GABA, adenosine, prostaglandins, for NREM sleep and acetylcholine and glutamate for REM sleep, among other molecules are responsible for the expression and maintenance of each phase. When the endocannabinoid system was being described for the first time, almost three decades ago, oleamide’s sleep promoting properties were highlighted. Nowadays, enough evidence has been cumulated to support the endocannabinoid system role in the sleep-wake cycle regulation. The endocannabinoids oleamide anandamide, and 2-arachidonylglycerol promote NREM and/or REM sleep via the CB1R, thereby making this system a target to treat sleep disorders, such as insomnia.
... Beginning on P36, half of MS animals and half of Con animals (9-12/sex/group) were placed on a food-restricted diet that aimed to reduce body weight to $80% free-fed weight. The paradigm was developed based on earlier experiments in our laboratory wherein we observed that free-fed males and females between P35 and P55 consume between 15 and 25 g or 12 and 23 g, respectively, increasing daily intake by approximately one gram every two days [unpublished observations, but similarly reported in (Amancio-Belmont, Romano-Lopez, Ruiz-Contreras, Mendez-Diaz, & Prospero-Garcia, 2017) and (Robison et al., 2017)]. We have observed that limiting food to 85-90% of free-fed intake reduced subject weight to $80% of free-fed weight. ...
Article
Microglia are resident immune cells of the brain that can regulate neural communication and excitability. Any environmental influence on microglial activity has the potential to alter subsequent neural physiology and behavior. Within the prefrontal cortex, several types of stressors have been shown to increase microglial expression of activation markers such as ionized calcium-binding adapter molecule-1 (Iba-1), which suggests altered microglial activity. Recent reports in rodents suggest that exposure to forms of early-life stress such as maternal separation can alter microglial responsivity to subsequent challenges. Several learning paradigms used in rodents require food restriction to provoke motivational states that facilitate approach behaviors. Here, we tested whether food restriction (increasing from 13 g/day–23 g/day in males and 10 g/day–20 g/day in females, which reduced body weight to 72–84% free-fed weight) in adolescent rats is a sufficient challenge to affect microglial Iba-1 expression, and whether previous exposure to postnatal maternal separation influenced microglial outcomes. We measured prefrontal cortex Iba-1 expression and microglial morphology after 20 days of ad libitum or restricted food availability in males and females with or without exposure to maternal separation. Food-restricted animals displayed higher levels of Iba-1 in the prefrontal cortex, with hyper-ramified microglial morphology in maternally separated males and control females, compared to those that were free-fed. Together, our data provide evidence that food restriction paradigms may have unintended effects in some behavioral protocols.
... Many neurotransmitter systems fluctuate significantly during this period of neurodevelopment (Meyer et al., 2018;Thorpe et al., 2020), and make the brain highly susceptible to social, nutritional and environmental influences, as well as insults by drugs of abuse . The ECS has been shown to play a crucial role in adolescent neuronal development, including modulating the ratio of excitatory and inhibitory signaling in the PFC (Meyer et al., 2018), and CB2R expression specifically increases in the PFC, NAc, and hippocampus during the rat equivalent of adolescence (Amancio-Belmont et al., 2017). The existence of adolescent-specific stressors such as family, academic, and peer pressures make this a unique period for environmental modulation of ECS activity, which has been extensively implicated in stress response (Tottenham and Galvan, 2016). ...
Article
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The endocannabinoid system is responsible for regulating a spectrum of physiological activities and plays a critical role in the developing brain. During adolescence, the endocannabinoid system is particularly sensitive to external insults that may change the brain’s developmental trajectory. Cannabinoid receptor type 2 (CB2R) was initially thought to predominantly function in the peripheral nervous system, but more recent studies have implicated its role in the mesolimbic pathway, a network largely attributed to reward circuitry and reward motivated behavior, which undergoes extensive changes during adolescence. It is therefore important to understand how CB2R modulation during adolescence can impact reward-related behaviors in adulthood. In this study, adolescent male rats (postnatal days 28–41) were exposed to a low or high dose of the CB2R antagonist/inverse agonist SR144528 and Pavlovian autoshaping and instrumental conditional behavioral outcomes were measured in adulthood. SR144528-treated rats had significantly slower acquisition of the autoshaping task, seen by less lever pressing behavior over time [ F (2, 19) = 5.964, p = 0.010]. Conversely, there was no effect of adolescent SR144528 exposure on instrumental conditioning. These results suggest that modulation of the CB2R in adolescence differentially impacts reward-learning behaviors in adulthood.
... Infant versus adult ages were not specified in the latter study, so it is possible that adults were aged (e.g., 65 years old). Some rat studies have demonstrated a decline in brain CB1R from young adults to older (1-2 years old) adults (e.g., in the nucleus accumbens: Amancio-Belmont, Romano-López, Ruiz-Contreras, Méndez-Díaz, & Prospéro- García, 2017; in the basal ganglia: Romero et al., 1998; in the cerebellum and hypothalamus: Berrendero et al., 1998), but we could find no studies that specifically compared CB1R in painrelated brain areas between young adults and middle-aged adults. Furthermore, because systemically administered cannabinoids produce antinociception by acting at multiple sites from the periphery to spinal cord to brain (Starowicz & Finn, 2017), considerably more research will be needed to pinpoint the full range of agerelated changes in the endocannabinoid system that may underlie age-related differences in antinociceptive sensitivity to cannabinoids. ...
Article
Given the use of cannabis as an analgesic by a broadening age range of patients, the aim of this study was to determine whether the antinociceptive effects of Δ9-tetrahydrocannabinol (THC) differ by age. The antinociceptive potency and efficacy of THC (1.0-18 mg/kg ip) was compared in male and female rats aged postnatal day 35-40 (adolescent), 60-70 (young adult), and 291-325 (middle-aged adult), using warm water tail withdrawal and paw pressure tests. Motoric effects of THC were assessed using a locomotor activity test. On the tail withdrawal test, THC was significantly more effective in middle-aged adult than in young adult rats and significantly less effective in adolescent than in young adult rats. Similar but smaller age-related differences were observed on the paw pressure test. Sex differences in THC's antinociceptive effects were consistent across the 3 ages examined, with greater THC effects observed in females than males of each age. Age-related differences in THC's locomotor-suppressing effect were also observed, with the greatest effect in young adult female rats. Serum THC levels were slightly higher in adolescent than in young adult rats, and levels of the active metabolites 11-OH-THC and cannabinol, as well as the inactive metabolite 11-nor-9-carboxy-THC, did not differ between adolescent and young adult rats. These results suggest that the pain-relieving effects of THC may be more limited in adolescents than in adults and that these age-related differences in THC effect are not attributable to differential absorption or metabolism of THC. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
Article
Adverse early life experiences, i.e. abusive parenting, during postnatal development, induce long-lasting effects on the stress response systems and behavior. Such changes persist throughout an individual’s life, making him/her vulnerable to suffer psychiatric disorders, including anxiety disorders and drug addiction. Rat pup maternal separation (MS) is a widely used rodent early-life stress model. MS induces changes in the dopamine and endocannabinoid systems in the nucleus accumbens (NAcc) that facilitate alcohol consumption. In this study, our endeavor was to determine if social isolation during adolescence (aSI) was as efficient as MS to facilitate alcohol intake; and moreover, if their combination (MS + aSI) induces even higher alcohol intake and exacerbates anxiety-like behaviors. Also, we evaluated dopamine and endocannabinoid receptors in the NAcc to describe potential changes caused by MS, aSI or both. Wistar rats were reared under 4 different conditions: non-MS + social housing (SH), MS + SH, non-MS + aSI and MS + aSI. Once these rats became adults they were submitted to a voluntary alcohol intake protocol for 10 days. Similar groups of rats with no exposure to alcohol whatsoever, were sacrificed to dissect out the NAcc to analyze the expression of cannabinoid (CB1R and CB2R) and dopamine (D2R and D3R) receptors. Results showed that MS, aSI and MS + aSI increase both CB1R, D2R and D3R expression in the NAcc and also increase alcohol intake and anxiety. These results suggest that early life adverse experiences induce a reprogramming of the brain’s dopamine and endocannabinoid systems which increases subject’s vulnerability to develop anxiety, alcohol abuse and dependence.
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Adolescence is the transitional period between childhood and adulthood, during which extensive brain development occurs. Since this period also overlaps with the initiation of drug use, it is important to consider how substance use during this time might produce long-term neurobiological alterations, especially against the backdrop of developmental changes in neurotransmission. Alcohol, cannabis, nicotine, and opioids all produce marked changes in the expression and function of the neurotransmitter and receptor systems with which they interact. These acute and chronic alterations also contribute to behavioral consequences ranging from increased addiction risk to cognitive or neuropsychiatric behavioral dysfunctions. The current review provides an in-depth overview and update of the developmental changes in neurotransmission during adolescence, as well as the impact of drug exposure during this neurodevelopmental window. While most of these factors have been studied in animal models, which are the focus of this review, future longitudinal studies in humans that assess neural function and behavior will help to confirm pre-clinical findings. Furthermore, the neural changes induced by each drug should also be considered in the context of other contributing factors, such as sex. Further understanding of these consequences can help in the identification of novel approaches for preventing and reversing the neurobiological effects of adolescent substance use.
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Adolescence is characterised by substantial changes in emotion regulation and in particular, impaired extinction consolidation and retention. In this study, we replicated the well-established finding that increasing the activation of cannabinoid receptor 1 (CB1R) via the agonist WIN55212-2 improves fear extinction in adult rodents before examining whether this adjunct would also rescue the extinction retention deficit seen in adolescent rodents. Contrary to the effects in adults, we found that WIN55212-2 impaired within-session acquisition of extinction in adolescent rats with no effect on extinction retention. The same effects of WIN55212-2 were observed for juvenile rats, and did not vary as a function of drug dose. Increased fear expression observed during extinction training was not a result of altered locomotor or anxiety-like behaviour in adolescent rats, as assessed by the open field test. Lastly, we observed a linear decrease in CB1R protein expression across age (i.e., from juveniles, to adolescents, and adults) in both the medial prefrontal cortex and amygdala, two regions implicated in fear expression and extinction, suggesting that there is continued refinement of the endocannabinoid system across development in two regions involved in extinction. Our findings suggest that the expression and extinction of fear in developing rats is differentially affected by CB1R agonism due to an immature endocannabinoid system.
Article
This study was designed to investigate the neuronal mechanism underlying the influence of early-life food restriction on the central nervous system and subsequent behaviors in adult rats. Several behavioral paradigms were tested in rats, including sucrose negative contrast test, forced swimming test (FST) and elevated plus maze test (EPM). In vivo intracellular electrophysiological recordings were conducted in the lateral nucleus of the amygdala (LAT). Finally, the levels of neuropeptide Y (NPY) were examined using immunohistochemistry. Food restriction during adolescence reduced sucrose preference in adult rats. Adolescent food restriction increased total immobile time in the FST and reduced the latency in rats to the first bout of immobility. In the EPM test, rats that experienced food restriction in adolescence and tested four weeks later spent less time than unrestricted controls in the open arm. In addition, chronic food restriction in adolescence increased in vivo LAT neuronal excitability in adulthood. Finally, NPY immunoreactivity in the LAT was reduced in rats that experienced chronic food restriction in adolescence compared to controls. Our results suggest that food restriction in adolescence increases emotional disorder-like behaviors in adult life, in which NPY production regulates the LAT-dependent behaviors and may underly the vulnerability to emotional disorders.
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Binge-like eating behavior (BLE) has been characterized as an eating disorder in which subjects have an enhanced intake of food, mainly fats. However, intake of fats and carbohydrates may have differential effects on motivation. Previously it was shown that BLE produces an increase in operant responding for vegetable shortening. Our aim was to determine if BLE behavior induced with a sucrose solution would produce an increment in performance for sucrose reinforcers. Male Wistar rats were trained under an exponential progressive ratio schedule of sucrose reinforcement; thereafter, the limited access model was used to induce BLE. Finally, subjects were tested for increments in break points (BPs) in the progressive ratio schedule. We were unable to observe an increase in BPs after BLE. No increments in BPs were observed when a distinctive flavor (vanilla-flavored sucrose) was correlated with BLE induction and reinforcement, or when different types of ratio progression in the operant schedules were employed. However, rats adjusted their BPs according to reinforcer concentration after BLE induction, demonstrating that valuation (cost/benefit decision) of reinforcers was intact. Extent of training, alterations of reward processing after extended exposure to sucrose, and different mechanisms for processing high fat and high carbohydrate reinforcers are variables worth exploring to gain a better understanding of BLE behavior in rodent models.
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Maternal overnutrition negatively impacts the offspring's health leading to an increased risk of developing chronic diseases or metabolic syndrome in adulthood. What we eat affects the endocannabinoid system (eCS) activity, which in turn modulates lipogenesis and fatty acids utilization in hepatic, muscle, and adipose tissues. This study aimed to evaluate the transgenerational effect of maternal obesity on cannabinoid receptor 1 knock-out (CB1 KO) animals in combination with a postnatal obesogenic diet on the development of metabolic disturbances on their offspring. CB1 KO mice were fed a control diet (CD) or a high-fat diet (HFD; 33% more energy from fat) for 3 months. Offspring born to control and obese mothers were also fed with CD or HFD. We observed that pups born to an HFD-fed mother presented higher postnatal weight, lower hepatic fatty acid amide hydrolase activity, and increased blood cholesterol levels when compared to the offspring born to CD-fed mothers. When female mice born to HFD-fed CB1 KO mothers were exposed to an HFD, they gained more weight, presented elevated blood cholesterol levels, and more abdominal adipose tissue accumulation than control-fed adult offspring. The eCS is involved in several reproductive physiological processes. Interestingly, we showed that CB1 KO mice in gestational day 15 presented resistance to LPS-induced deleterious effects on pregnancy outcome, which was overcome when these mice were obese. Our results suggest that an HFD in CB1 receptor-deficient mice contributes to a “nutritional programming” of the offspring resulting in increased susceptibility to metabolic challenges both perinatally and during adulthood.
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The female bias in eating disorder prevalence is the largest in all of psychiatry. Binge eating on palatable food (PF) is a core, maladaptive symptom that cuts across all major types of eating disorders and can be studied via animal models. Using an individual differences rat model of binge eating that identifies binge eating prone (BEP) and binge eating resistant (BER) phenotypes, we previously showed that, compared with males, females consume more PF and are more likely to be classified as BEP. One potential explanation for this sex difference is that PF is inherently more rewarding to females, leading to higher rates of binge eating. Here we tested the hypothesis that females have more robust behavioral and neural responses to PF reward than males. Adult male (N=18) and female (N=17) Sprague-Dawley rats were exposed to the Conditioned Place Preference paradigm using PF as the unconditioned stimulus. Select males (N=9) and females (N=9) were video-recorded during three of the PF-paired conditioning sessions to score feeding behavior. Following CPP, 13 male and 12 female rats were exposed to PF just prior to sacrifice to induce expression of the neural activation marker Fos, and Fos expression was quantified in mesocorticolimbic, hypothalamic, and amygdalar circuits. In the CPP paradigm, females displayed a more robust shift in preference for the chamber paired with PF compared with males, and behavioral analyses revealed that average duration of individual feeding bouts during pairing sessions was longer in females than in males. Fos expression was significantly higher in females vs. males in select regions of the mesocorticolimbic reward circuit, with no sex differences in hypothalamic or amygdalar regions. These results provide initial evidence that PF may be more rewarding to females than to males, possibly due to heightened responsiveness of neural substrates that mediate the hedonic and motivational responses to PF, which in part, may underlie sex differences in binge eating proneness.
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Impulsivity is a behavioral trait frequently seen in drug addicted individuals, but also in individuals who pathologically overeat. However, whether impulsivity predates the development of uncontrollable feeding is unknown. In this study we hypothesized that a high impulsivity trait precedes and confers vulnerability for food addiction-like behavior. For this purpose we trained ad libitum fed male Wistar rats in a differential reinforcement of low rates of responding (DRL) task to select high- and low-impulsive rats. Then, we allowed Low- and High-impulsive rats to self-administer a highly palatable diet (Palatable group) or a regular chow diet (Chow group) in 1 h daily sessions, under fixed ratio (FR) 1, FR3, FR5, and under a progressive ratio (PR) schedules of reinforcement. In addition, we tested the compulsiveness for food in Low- and High-impulsive rats by measuring the food eaten in the aversive, open compartment of a light/dark conflict test. Finally, we measured the expression of the transcription factor ΔFosB in the shell and the core of the nucleus accumbens which is a marker for neuroadaptive changes following addictive drug exposure. The data we obtained demonstrate that impulsivity is a trait which predicts the development of food addiction-like behaviors, including: i) excessive intake, ii) heightened motivation for food, and iii) compulsive-like eating, when rats are given access to highly palatable food. In addition, we show that the food addiction phenotype in high impulsive subjects is characterized by an increased expression of the transcription factor ΔFosB in the nucleus accumbens shell. These results prove that impulsivity confers an increased propensity to develop uncontrollable overeating of palatable food.Neuropsychopharmacology accepted article peview online, 29 April 2014. doi:10.1038/npp.2014.98.
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Characterization of the ontogeny of the cerebral dopaminergic system is crucial for gaining a greater understanding of normal brain development and its alterations in response to drugs of abuse or conditions such as attention-deficit hyperactivity disorder. Pharmacological MRI (phMRI) was used to determine the response to dopamine transporter (DAT) blockers cocaine and methylphenidate (MPH), the dopamine releaser D-amphetamine (AMPH), the selective D1 agonist dihydrexidine, and the D2/D3 agonist quinpirole in young (<30 days old) and adult (>60 days old) rats. In adult rats, cocaine (0.5 mg/kg i.v.) or MPH (2 mg/kg) induced primarily positive cerebral blood volume (rCBV) changes in the dopaminergic circuitry, but negative rCBV changes in the young animals. Microdialysis measurements in the striatum showed that young rats have a smaller increase in extracellular dopamine in response to cocaine than adults. The young rats showed little rCBV response to the selective D1 agonist dihydrexidine in contrast to robust rCBV increases observed in the adults, whereas there was a similar negative rCBV response in the young and adult rats to the D2 agonist quinpirole. We also performed a meta-analysis of literature data on the development of D1 and D2 receptors and the DAT. These data suggest a predominance of D2-like over D1-like function between 20 and 30 days of age. These combined results suggested that the dopamine D1 receptor is functionally inhibited at young age.
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Epidemiological studies indicate that experimentation with addictive drugs and onset of addictive disorders is primarily concentrated in adolescence and young adulthood. The authors describe basic and clinical data supporting adolescent neurodevelopment as a biologically critical period of greater vulnerability for experimentation with substances and acquisition of substance use disorders. The authors reviewed recent literature regarding neurocircuitry underlying motivation, impulsivity, and addiction, with a focus on studies investigating adolescent neurodevelopment. Adolescent neurodevelopment occurs in brain regions associated with motivation, impulsivity, and addiction. Adolescent impulsivity and/or novelty seeking as a transitional trait behavior can be explained in part by maturational changes in frontal cortical and subcortical monoaminergic systems. These developmental processes may advantageously promote learning drives for adaptation to adult roles but may also confer greater vulnerability to the addictive actions of drugs. An exploration of developmental changes in neurocircuitry involved in impulse control has significant implications for understanding adolescent behavior, addiction vulnerability, and the prevention of addiction in adolescence and adulthood.
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Modern science begins to understand pleasure as a potential component of salutogenesis. Thereby, pleasure is described as a state or feeling of happiness and satisfaction resulting from an experience that one enjoys. We examine the neurobiological factors underlying reward processes and pleasure phenomena. Further, health implications related to pleasurable activities are analyzed. With regard to possible negative effects of pleasure, we focus on addiction and motivational toxicity. Pleasure can serve cognition, productivity and health, but simultaneously promotes addiction and other negative behaviors, i.e., motivational toxicity. It is a complex neurobiological phenomenon, relying on reward circuitry or limbic activity. These processes involve dopaminergic signaling. Moreover, endorphin and endogenous morphinergic mechanisms may play a role. Natural rewarding activities are necessary for survival and appetitive motivation, usually governing beneficial biological behaviors like eating, sex and reproduction. Social contacts can further facilitate the positive effects exerted by pleasurable experiences. However, artificial stimulants can be detrimental, since flexibility and normal control of behavior are deteriorated. Additionally, addictive drugs are capable of directly acting on reward pathways. Thus, the concrete outcome of pleasant experiences may be a question of dose. Moderate pleasurable experiences are able to enhance biological flexibility and health. Hence, pleasure can be a resistance resource or may serve salutogenesis. Natural rewards are mediated by sensory organ stimulation, thereby exhibiting a potential association with complementary medical approaches. Trust and belief can be part of a self-healing potential connected with rewarding stimuli. Further, the placebo response physiologically resembles pleasure phenomena, since both involve brain's reward circuitry stimulation and subjective feelings of well-being. Pleasurable activities can stimulate personal growth and may help to induce healthy behavioral changes, including stress management. However, more research is needed to better understand the nature, neurobiology and maybe dangerous aspects of pleasure. Also, a possible involvement of endogenous morphinergic signaling has to be studied further.
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Drug self-administration studies have recently employed progressive ratio (PR) schedules to examine psychostimulant and opiate reinforcement. This review addresses the technical, statistical, and theoretical issues related to the use of the PR schedule in self-administration studies in rats. Session parameters adopted for use in our laboratory and the considerations relevant to them are described. The strengths and weaknesses of the PR schedule are also discussed.
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Animal models of memory have been considered as the subject of many scientific publications at least since the beginning of the twentieth century. In humans, memory is often accessed through spoken or written language, while in animals, cognitive functions must be accessed through different kind of behaviors in many specific, experimental models of memory and learning. Among them, the novel object recognition test can be evaluated by the differences in the exploration time of novel and familiar objects. Its application is not limited to a field of research and enables that various issues can be studied, such as the memory and learning, the preference for novelty, the influence of different brain regions in the process of recognition, and even the study of different drugs and their effects. This paper describes the novel object recognition paradigms in animals, as a valuable measure of cognition. The purpose of this work was to review the neurobiology and methodological modifications of the test commonly used in behavioral pharmacology.
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The endogenous cannabinoid system is an important regulatory system involved in physiological homeostasis. Endocannabinoid signaling is known to modulate neural development, immune function, metabolism, synaptic plasticity and emotional state. Accumulating evidence also implicates brain endocannabinoid signaling in the etiology of drug addiction which is characterized by compulsive drug seeking, loss of control in limiting drug intake, emergence of a negative emotional state in the absence of drug use and a persistent vulnerability toward relapse to drug use during protracted abstinence. In this review we discuss the effects of drug intake on brain endocannabinoid signaling, evidence implicating the endocannabinoid system in the motivation for drug consumption, and drug-induced alterations in endocannabinoid function that may contribute to various aspects of addiction including dysregulated synaptic plasticity, increased stress responsivity, negative affective states, drug craving and relapse to drug taking. Current knowledge of genetic variants in endocannabinoid signaling associated with addiction is also discussed.
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1,2-diacylglycerol lipase alpha (DAGLα) is responsible for the biosynthesis and release of 2-arachidonoyl-glycerol (2-AG), the most abundant endocannabinoid in the brain. Although its expression has been detected in discrete regions, we showed here an integrated description of the distribution of DAGLα mRNA and protein in the rat forebrain using in situ hybridization histochemistry and immunohistochemistry. As novelty, we described the distribution of DAGLα protein expression in the olfactory system, the rostral migratory stream, neocortex, septum, thalamus, and hypothalamus. Similar DAGLα immunostaining pattern was also found in the brain of wild-type, but not of DAGLα knockout mice. Immunohistochemical data were correlated by the identification of DAGLα mRNA expression, for instance, in the somata of specific cells in olfactory structures, rostral migratory stream and neocortex, cells in some septal-basal-amygdaloid areas and the medial habenula, and magnocellular cells of the paraventricular hypothalamic nucleus. This widespread neuronal distribution of DAGLα is consistent with multiple roles for endocannabinoids in synaptic plasticity, including presynaptic inhibition of neurotransmitter release. We discuss our comparative analysis of the forebrain expression patterns of DAGLα and other components of the endocannabinoid signaling system, including the CB(1) receptor, monoacylglyceride lipase (MAGL), and fatty acid amide hydrolase (FAAH), providing some insight into the potential physiological and behavioral roles of this system.
Article
The cannabinoid system appears to play a critical facilitative role in mediating the reinforcing effects of nicotine and relapse to nicotine-seeking behaviour in abstinent subjects based on the actions of cannabinoid (CB) receptor antagonists. However, the effects of CB receptor stimulation on nicotine self-administration and reinstatement have not been systematically studied. Here, we studied the effects of WIN 55,212-2, a CB1/2 agonist, on intravenous nicotine self-administration under fixed-ratio (FR) and progressive-ratio (PR) schedules of reinforcement in rats. The effects of WIN 55,212-2 on responding for food under similar schedules were also studied. In addition, the effects of WIN 55,212-2 on nicotine- and cue-induced reinstatement of nicotine seeking were also studied, as well as the effects of WIN 55,212-2 on nicotine discrimination. WIN 55,212-2 decreased nicotine self-administration under the FR schedule. However, co-administration of WIN 55,212-2 with nicotine decreased responding for food, which suggests that this effect was non-selective. In contrast, WIN 55,212-2 increased both nicotine self-administration and responding for food under the PR schedule, produced dose-dependent reinstatement of nicotine seeking, and enhanced the reinstatement effects of nicotine-associated cues. Some of these effects were reversed by the CB1 antagonist rimonabant, but not by the CB2 antagonist AM630. In the drug discrimination tests between saline and 0.4 mg/kg nicotine, WIN 55,212-2 produced no nicotine-like discriminative effects but significantly potentiated discriminative stimulus effects of nicotine at the low dose through a CB1-receptor-dependent mechanism. These findings indicate that cannabinoid CB1-receptor stimulation increases the reinforcing effects of nicotine and precipitates relapse to nicotine-seeking behaviour in abstinent subjects. Thus, modulating CB1-receptor signalling might have therapeutic value for treating nicotine dependence.
Article
Endocannabinoids (eCBs) are mediators of the homeostatic and hedonic systems that modulate food ingestion. Hence, eCBs, by regulating the hedonic system, may be modulating the valence of the emotion associated to food ingestion (positive: pleasant or negative: unpleasant). Our first goal was to demonstrate that palatable food induces conditioned place preference (CPP), hence a positive-valence emotion. Additionally, we analyzed if this CPP is blocked by AM251, inducing a negative valence emotion, meaning avoiding the otherwise pursued compartment. The second goal was to demonstrate that CPP induced by regular food would be strengthened by the simultaneous administration of anandamide or oleamide, and if such, CPP is blocked by AM251. Finally, we tested the capacity of eCBs (without food) to induce CPP. Our results indicate that rats readily developed CPP to palatable food, which was blocked by AM251. The CPP induced by regular food was strengthened by eCBs and blocked by AM251. Finally, oleamide, unlike anandamide, induced CPP. These results showed that eCBs mediate the positive valence (CPP) of the emotion associated to food ingestion. It was also observed that the blockade of the CB1 receptor causes a loss of correlation between food and CPP (negative valence: avoidance). These data further support the role of eCBs as regulators of the hedonic value of food.
Article
Associative learning depends on multiple cortical and subcortical structures, including striatum, hippocampus, and amygdala. Both glutamatergic and dopaminergic neurotransmitter systems have been implicated in learning and memory consolidation. While the role of glutamate is well established, the role of dopamine and its receptors in these processes is less clear. In this study, we used two models of dopamine D(1) receptor (D(1)R, Drd1a) loss, D(1)R knock-out mice (Drd1a(-/-)) and mice with intrahippocampal injections of Drd1a-siRNA (small interfering RNA), to study the role of D(1)R in different models of learning, hippocampal long-term potentiation (LTP) and associated gene expression. D(1)R loss markedly reduced spatial learning, fear learning, and classical conditioning of the eyelid response, as well as the associated activity-dependent synaptic plasticity in the hippocampal CA1-CA3 synapse. These results provide the first experimental demonstration that D(1)R is required for trace eyeblink conditioning and associated changes in synaptic strength in hippocampus of behaving mice. Drd1a-siRNA mice were indistinguishable from Drd1a(-/-) mice in all experiments, indicating that hippocampal knockdown was as effective as global inactivation and that the observed effects are caused by loss of D(1)R and not by indirect developmental effects of Drd1a(-/-). Finally, in vivo LTP and LTP-induced expression of Egr1 in the hippocampus were significantly reduced in Drd1a(-/-) and Drd1a-siRNA, indicating an important role for D(1)R in these processes. Our data reveal a functional relationship between acquisition of associative learning, increase in synaptic strength at the CA3-CA1 synapse, and Egr1 induction in the hippocampus by demonstrating that all three are dramatically impaired when D(1)R is eliminated or reduced.
Article
Cannabis use during adolescence is associated with an increased risk for schizophrenia and other disorders. The neuronal basis is unclear, but prefrontal cortical mechanisms have been implicated. Here, we investigated developmental changes in the endocannabinoid system by assessing expression and function of the CB1 cannabinoid receptor in prefrontal and other cortical areas in juvenile (postnatal day 25, P25), adolescent (P40), and adult (P70) rats. Overall, the expression of CB1 receptors in the cortex is highest in juveniles and drops thereafter toward adult levels. However, CB1 receptor expression follows distinct developmental trajectories in different cortical areas. The most pronounced and progressive decrease in CB1 expression was observed in medial prefrontal and other limbic/associative regions. In contrast, major changes in sensorimotor cortices occurred only after P40. We also assessed electrophysiological measures of CB1 receptor function and found that CB1-dependent inhibition of synaptic transmission in the prefrontal cortex follows the same developmental trajectory as observed for receptor expression. Together, these findings indicate that CB1 receptor-mediated signaling decreases during development but is differentially regulated in limbic/associative vs. sensorimotor systems. Therefore, cannabis use during adolescence likely differentially affects limbic/associative and sensorimotor cortical circuits.
Article
Major depression and addiction are mental health problems associated with stressful events in life with high relapse and recurrence even after treatment. Many laboratories were not able to detect the presence of CB2 cannabinoid receptors (CB2-Rs) in healthy brains, but CB2-R expression has been demonstrated in rat microglial cells and other brain-associated cells during inflammation. Thus, neuronal expression of CB2-Rs has been ambiguous and controversial, and its role in depression and substance abuse is unknown. In this study we tested the hypothesis that genetic variants of the CB2 gene might be associated with depression in a human population and that alteration in CB2 gene expression may be involved in the effects of abused substances, including opiates, cocaine, and ethanol, in rodents. Here we demonstrate that a high incidence of Q63R but not H316Y polymorphism in the CB2 gene was found in Japanese depressed subjects. CB2-Rs and their gene transcripts are expressed in the brains of naïve mice and are modulated after exposure to stressors and administration of abused drugs. Mice that developed an alcohol preference had reduced CB2 gene expression, and chronic treatment with JWH015 a putative CB2-R agonist, enhanced alcohol consumption in stressed but not in control mice. The direct intracerebroventricular microinjection of CB2 antisense oligonucleotide into the mouse brain reduced mouse aversions in the plus-maze test, indicating the functional presence of CB2-Rs in the brain that modifies behavior. Using electron microscopy we report the subcellular localization of CB2-Rs that are mainly on postsynaptic elements in rodent brain. Our data demonstrate the functional expression of CB2-Rs in the brain that may provide novel targets for the effects of cannabinoids in depression and substance abuse disorders beyond neuroimmunocannabinoid activity.
Article
The anatomical distribution and density of cannabinoid receptors in the human brain was studied in one fetal (33 weeks gestation), two neonatal (aged three to six months) and eight adult (aged 21-81 years) human cases using quantitative receptor autoradiography following in vitro labelling of sections with the synthetic cannabinoid agonist [3H]CP55,940. Cannabinoid receptors were distributed in a heterogeneous fashion throughout the adult human brain and spinal cord. The allocortex contained very high concentrations of cannabinoid receptor binding sites in the dentate gyrus, Ammons's horn and subiculum of the hippocampal formation; high concentrations of receptors were also present in the entorhinal cortex and amygdaloid complex. Cannabinoid receptor binding sites were also present throughout all regions of the neocortex, where they showed a marked variation in density between the primary, secondary and associational cortical regions: the greatest densities of receptors were present in the associational cortical regions of the frontal and limbic lobes, with moderate densities in the secondary sensory and motor cortical regions, and with the lowest densities of receptors in the primary sensory and motor cortical regions. Relatively high concentrations of cannabinoid receptors were consistently seen in cortical regions of the left (dominant) hemisphere, known to be associated with verbal language functions. In all of the cortical regions, the pattern and density of receptor labelling followed the neocortical laminar organization, with the greatest density of receptors localized in two discrete bands--a clearly delineated narrow superficial band which coincided with lamina I and a deeper broader, conspicuous band of labelling which corresponded to laminae V and VI. Labelling in the intervening cortical laminae (II-IV) showed lower densities, with a well delineated narrow band of label in the middle of laminae IV in the associational cortical regions. The thalamus showed a distinctive heterogeneous distribution of cannabinoid receptors, with the highest concentration of receptors localized in the mediodorsal nucleus, anterior nuclear complex, and in the midline and intralaminar complex of nuclei, i.e. in thalamic nuclei which have connectional affiliations with the associational cortical areas. The basal ganglia showed a distinctive heterogeneous pattern of receptor binding, with the very highest concentrations in the globus pallidus internus, moderate concentrations in the globus pallidus externus and ventral pallidum, and moderately low levels of binding throughout the striatal complex. In the midbrain, some of the highest levels of cannabinoid receptor binding sites in the human brain were present in the substantia nigra pars reticulata, with very low levels of labelling in all other midbrain areas. The highest densities of cannabinoid receptor binding in the hindbrain were localized in the molecular layer of the cerebellar cortex and the dorsal motor nucleus of the vagus, with moderate densities of receptors in the nucleus of the solitary tract. The spinal cord showed very low levels of receptor binding. Studies on the distribution of cannabinoid receptors in the fetal and neonatal human brain showed similar patterns of receptor distribution to that observed in the adult human brain, except that the density of receptor binding was generally markedly higher, especially in the basal ganglia and substantia nigra. The pattern of cannabinoid receptor labelling in the striatum showed a striking patchy pattern of organization which was especially conspicuous in the fetal brain. These results show that cannabinoid receptor binding sites in the human brain are localized mainly in: forebrain areas associated with higher cognitive functions; forebrain, midbrain and hindbrain areas associated with the control of movement; and in hindbrain areas associated with the control of motor and sensory functions of the autonomic nervous system. (AB
Article
Schultz, Wolfram. Predictive reward signal of dopamine neurons. is called rewards, which elicit and reinforce approach behav-J. Neurophysiol. 80: 1–27, 1998. The effects of lesions, receptor ior. The functions of rewards were developed further during blocking, electrical self-stimulation, and drugs of abuse suggest the evolution of higher mammals to support more sophistithat midbrain dopamine systems are involved in processing reward cated forms of individual and social behavior. Thus biologiinformation and learning approach behavior. Most dopamine neucal and cognitive needs define the nature of rewards, and rons show phasic activations after primary liquid and food rewards and conditioned, reward-predicting visual and auditory stimuli. the availability of rewards determines some of the basic They show biphasic, activation-depression responses after stimuli parameters of the subject’s life conditions. that resemble reward-predicting stimuli or are novel or particularly Rewards come in various physical forms, are highly variable salient. However, only few phasic activations follow aversive stim-in time and depend on the particular environment of the subject. uli. Thus dopamine neurons label environmental stimuli with appe- Despite their importance, rewards do not influence the brain titive value, predict and detect rewards and signal alerting and motivating events. By failing to discriminate between different
Article
A series of experiments examined the effects of the cannabinoid CB1 receptor agonist CP 55,940 ((-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hyd roxypropyl)cyclohexanol) on the motivation to consume beer, near-beer (a beer-like beverage containing <0.5% ethanol) and sucrose solutions in rats. The experiments employed a 'lick-based progressive ratio paradigm' in which an ever increasing number of licks had to be emitted at a tube for each successive fixed unit of beverage delivered. Break point, the lick requirement at which responding ceased, was used as an index of motivation. In the first experiment, CP 55,940 (10, 30 or 50 microg/kg) caused a dose-dependent increase in break points for beer (containing 4.5% ethanol v/v) and for near-beer. The highest (50 microg/kg) dose of CP 55,940 also significantly decreased locomotor activity. In the second experiment, CP 55,940 (10 or 30 microg/kg) dose-dependently increased break points in rats licking for 'light' beer (containing 2.7% ethanol v/v) or for a sucrose solution (8.6% w/v) containing the same number of calories as the beer. In the third experiment, the facilitatory effects of CP 55,940 (30 microg/kg) on responding for beer and near-beer were reversed by both the cannabinoid CB1 receptor antagonist SR 141716 (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1H-pyrazole-3-carboxamide hydrochloride) (1.5 mg/kg) and the opioid receptor antagonist naloxone (2.5 mg/kg). Naloxone had a proportionally greater effect on rats licking for beer compared to near-beer, consistent with previous reports of opioid receptor mediation of alcohol craving. These results show that cannabinoids modulate the motivation for beer via both cannabinoid CB1 receptors and opioid receptors. The similar effect of CP 55,940 on the motivation for beer, near-beer and sucrose suggests that the drug effect may reflect a general stimulatory effect on appetite for palatable beverages, although a more specific effect on the desire for alcohol cannot be ruled out.
Article
While it has previously been assumed that mesolimbic dopamine neurons carry a reward signal, recent data from single-unit, microdialysis and voltammetry studies suggest that these neurons respond to a large category of salient and arousing events, including appetitive, aversive, high intensity, and novel stimuli. Elevations in dopamine release within mesolimbic, mesocortical and nigrostriatal target sites coincide with arousal, and the increase in dopamine activity within target sites modulates a number of behavioral functions. However, because dopamine neurons respond to a category of salient events that extend beyond that of reward stimuli, dopamine levels are not likely to code for the reward value of encountered events. The paper (i) examines evidence showing that dopamine neurons respond to salient and arousing change in environmental conditions, regardless of the motivational valence of that change, and (ii) asks how this might shape our thinking about the role of dopamine systems in goal-directed behavior.
Article
Cannabis (marijuana) is not only a frequently abused drug but also has the potential for the development of useful agents for the treatment of emesis, anorexia and multiple sclerosis. In this article, the effects of modulation of transmitter release by cannabinoids in both the CNS and the PNS of various species, including humans, will be discussed. Cannabinoids inhibit neurotransmitter release via specific presynaptic cannabinoid CB1 receptors. Studies using either the CB1 receptor antagonist and inverse agonist SR141716 or CB1-receptor-deficient mice suggest that numerous presynaptic cannabinoid receptors are tonically activated by endogenous cannabinoids and/or are constitutively active. CB1-receptor-mediated inhibition of transmitter release might explain, for example, reinforcing properties and memory impairment caused by cannabinoids.
Article
The neural basis of decision making has been an elusive concept largely due to the many subprocesses associated with it. Recent efforts involving neuroimaging, neuropsychological studies, and animal work indicate that the prefrontal cortex plays a central role in several of these subprocesses. The frontal lobes are involved in tasks ranging from making binary choices to making multi-attribute decisions that require explicit deliberation and integration of diverse sources of information. In categorizing different aspects of decision making, a division of the prefrontal cortex into three primary regions is proposed. (1) The orbitofrontal and ventromedial areas are most relevant to deciding based on reward values and contribute affective information regarding decision attributes and options. (2) Dorsolateral prefrontal cortex is critical in making decisions that call for the consideration of multiple sources of information, and may recruit separable areas when making well defined versus poorly defined decisions. (3) The anterior and ventral cingulate cortex appear especially relevant in sorting among conflicting options, as well as signaling outcome-relevant information. This topic is broadly relevant to cognitive neuroscience as a discipline, as it generally comprises several aspects of cognition and may involve numerous brain regions depending on the situation. The review concludes with a summary of how these regions may interact in deciding and possible future research directions for the field.
Article
Epidemiological research has emphasized that adolescence is associated with some temperamental and behavioral traits that are typical of this age and that might substantially contribute to both psychological and psychobiological vulnerability. The contribution of the important developmental rearrangements in neurobiological and neuroendocrinological processes has received surprisingly little investigation. The present review summarizes recent work in animal models, indicating that adolescent rodents exhibit marked peculiarities in their spontaneous behavioral repertoire. When compared to adults, adolescents show an unbalanced and 'extremes-oriented' behavior, consisting of an increased novelty seeking, together with decreased novelty-induced stress and anxiety, an increased risk-taking behavior in the plus-maze, as well as elevated levels of impulsivity and restlessness. Age-related discontinuities in the function of monoaminergic systems, which are a main target of abused drugs, can perhaps account for such a profile. In particular, a peculiar function within reward-related dopaminergic brain pathways actually seems to underlie the search for novel and rewarding sensations, as well as changes in the magnitude of psychostimulant effects. The role played by early epigenetic factors in the shaping of novelty-seeking behavior of adolescent and adult rodents are also reviewed. Two examples are considered, namely, subtle variations in the hormonal milieu as a function of intrauterine position and precocious or delayed maturation of nutritional independence as a function of changes in time of weaning. As for spontaneous drug consumption, a prominent vulnerability to the oral intake of nicotine during early adolescence is reported. In conclusion, adolescence in rodents may represent a suitable animal model with enough face- and construct-validity. Actually, this model is able to show behavioral features that resemble those found in human adolescents, including vulnerability to the consumption of psychoactive drugs.
Article
In animal models, cannabinoid-1 receptor (CB1) blockade produces a lean phenotype, with resistance to diet-induced obesity and associated dyslipidaemia. We assessed the effect of rimonabant, a selective CB1 blocker, on bodyweight and cardiovascular risk factors in overweight or obese patients. patients with body-mass index 30 kg/m2 or greater, or body-mass index greater than 27 kg/m2 with treated or untreated dyslipidaemia, hypertension, or both, were randomised to receive double-blind treatment with placebo, 5 mg rimonabant, or 20 mg rimonabant once daily in addition to a mild hypocaloric diet (600 kcal/day deficit). The primary efficacy endpoint was weight change from baseline after 1 year of treatment in the intention-to-treat population. Weight loss at 1 year was significantly greater in patients treated with rimonabant 5 mg (mean -3.4 kg [SD 5.7]; p=0.002 vs placebo) and 20 mg (-6.6 kg [7.2]; p<0.001 vs placebo) compared with placebo (-1.8 kg [6.4]). Significantly more patients treated with rimonabant 20 mg than placebo achieved weight loss of 5% or greater (p<0.001) and 10% or greater (p<0.001). Rimonabant 20 mg produced significantly greater improvements than placebo in waist circumference, HDL-cholesterol, triglycerides, and insulin resistance, and prevalence of the metabolic syndrome. The effects of rimonabant 5 mg were of less clinical significance. Rimonabant was generally well tolerated with mild and transient side effects. CB1 blockade with rimonabant 20 mg, combined with a hypocaloric diet over 1 year, promoted significant decrease of bodyweight and waist circumference, and improvement in cardiovascular risk factors.
Article
Cannabinoids are postulated to play a role in modulating the reinforcing effects of abused drugs, including alcohol. Experiment 1 examined alcohol self-administration in cannabinoid CB1 receptor knockout (KO), heterozygous (HT) and wild type (WT) mice in a two-bottle choice paradigm. Mice were trained in a limited 8 h access/day to 10% (v/v) EtOH (EtOH) versus water. After baseline drinking levels (% EtOH preference and total EtOH intake (g/kg)), results indicated that the CB1 knockout mice displayed significantly lower baseline EtOH consumption compared to wild type mice. Subsequently, treatment with SR141716A (5mg/kg) significantly attenuated EtOH intake in the WT and HT mice but had little effect on the knockout mice. Experiment 2 examined the CB1 WT and CB1 KO strains in a conditioned place preference (CPP) procedure between saline and 2g/kg EtOH. The CB1 WT mice spent significantly more time in the EtOH-paired versus saline-paired chambers, whereas no significant preference was observed in the CB1 KO mice. Finally, we observed that CB1 KO mice were significantly lighter than WT and HT and that SR141716A did not significantly alter body weight. These results demonstrate that the cannabinoid CB1 receptor is an essential component of the molecular pathways underlying the reinforcing effects of alcohol. Thus, medications targeting the CB1 receptors may be beneficial for the treatment of alcoholism.
Article
The brain neuronal systems defined by the neurotransmitter dopamine (DA) have since long a recognized role in the regulation of motor functions. More recently, converging evidence from patient studies, animal research, pharmacological intervention, and molecular genetics indicates that DA is critically implicated also in higher-order cognitive functioning. Many cognitive functions and multiple markers of striatal and extrastriatal DA systems decline across adulthood and aging. Research examining the correlative triad among adult age, DA, and cognition has found strong support for the view that age-related DA losses are associated with age-related cognitive deficits. Future research strategies for examining the DA-cognitive aging link include assessing (a) the generality/specificity of the effects; (b) the relationship between neuromodulation and functional brain activation; and (c) the release of DA during actual task performance.