CB1R chronic intermittent pharmacological activation facilitates amphetamine seeking and self-administration and changes in CB1R/CRFR1 expression in the amygdala and nucleus accumbens in rats.

Patterns of drug ingestion may have a dissimilar impact on the brain, and therefore also the development of drug addiction. One pattern is binge intoxication that refers to the ingestion of a high amount of drug on a single occasion followed by an abstinence period of variable duration. In this study, our goal was to contrast the effect of continuous low amounts with intermittent higher amounts of Arachidonyl-chloro-ethylamide (ACEA), a CB1R agonist, on amphetamine seeking and ingestion, and describe the effects on the expression of CB1R and CRFR1 in the central nucleus of the amygdala (CeA) and in the nucleus accumbens shell (NAcS). Adult male Wistar rats were treated with a daily administration of vehicle or 20 µg of ACEA, or four days of vehicle followed by 100 µg of ACEA on the fifth day, for a total of 30 days. Upon completion of this treatment, the CB1R and CRFR1 expression in the CeA and NAcS was evaluated by immunofluorescence. Additional groups of rats were evaluated for their anxiety levels (elevated plus maze, EPM), amphetamine (AMPH) self-administration (ASA) and breakpoint (A-BP), as well as AMPH-induced conditioned place preference (A-CPP). Results indicated that ACEA induced changes in the CB1R and CRFR1 expression in both the NAcS and CeA. An increase in anxiety-like behavior, ASA, A-BP and A-CPP was also observed. Since the intermittent administration of 100 µg of ACEA induced the most evident changes in most of the parameters studied, we concluded that binge-like ingestion of drugs induces changes in the brain that may make the subject more vulnerable to developing drug addiction.

Corrigendum: Intra-accumbens raclopride administration prevents behavioral changes induced by intermittent access to sucrose solution.

[This corrects the article DOI: 10.3389/fnins.2018.00074.].

SHELL Part of Nucleus Accumbens and Its Laterality Has Important Role in Response to Chronic Stress in Female Rats

Abstract The nucleus accumbens shell (NAcSh) plays a role in appetitive and negative motivation with sex differences in responses. NAcSh and its laterality in metabolic and hormonal responses to chronic stress in female rats is evaluated via transient inactivation of this nucleus during stress induction. Animals in the stress groups received consecutive stress for four days and transient inactivation of NAcSh was performed by administrating lidocaine (0.2%) unilaterally or bilaterally in the nucleus for five minutes before electric foot shock induction. After stress termination, food and water intake, latency to eat, plasma glucose, corticosterone, estradiol and progesterone were measured in all groups. Results showed that stress increased food intake and blood glucose level, but there were no change in the latency to eat and the amount of water intake. The right side, the left side, and both sides of NAcSh may be dominant in latency to eat, food intake, and both water intake and plasma glucose level, respectively. Although chronic stress included no changes for corticosterone and progesterone, it increased estradiol level in plasma. Also, bilateral and right sides of NAcSh may have modulatory effects on stress in corticosterone and progesterone, respectively, without affecting estradiol. It can be concluded that the NAc shell plays a pivotal role in metabolic and hormonal responses to chronic stress in a laterality manner in female rats.

CB1R mediates oleamide's reward while 5HT2cR mediates aversion in the nucleus accumbens shell of rats.

In this study, we have pursued to assess oleamide's potential role in reward and aversion mechanisms. To reach this goal we infused oleamide, either 1 µg into the nucleus accumbens shell (NAccS) and evaluated its effects on conditioned place preference (CCP) or 10 µg, to evaluate conditioned place aversion (CPA). Extinction and reinstatement were also evaluated in both cases. We sought to determine if CPP occurs via cannabinoid receptor 1 (CB1R) and CPA via serontoninergic 2c receptor (5HT2cR). Results revealed that 1 µg of oleamide administered bilaterally into the NAccS induced CPP, while 10 µg induced CPA. In both conditions CPP or CPA, reinstatement after extinction was induced. AM251 (CB1R inverse-agonist) prevented CPP induced with 1 µg; while SB242084 (5HT2cR antagonist) not only prevented CPA induced with 10 µg but caused a switch to CPP. These results suggest that oleamide at low doses promotes reward through CB1R, and aversion at high doses via 5HT2cR.

Intra-accumbens Raclopride Administration Prevents Behavioral Changes Induced by Intermittent Access to Sucrose Solution.

Overeating is one of the most relevant clinical features in Binge Eating Disorder and in some obesity patients. According to several studies, alterations in the mesolimbic dopaminergic transmission produced by non-homeostatic feeding behavior may be associated with changes in the reward system similar to those produced by drugs of abuse. Although it is known that binge-eating is related with changes in dopaminergic transmission mediated by D2 receptors in the nucleus accumbens shell (NAcS), it has not been determined whether these receptors may be a potential target for the treatment of eating pathology with binge-eating. Accordingly, the aim of the present study was to evaluate whether sugar binging induced by intermittent access to a sucrose solution produced changes in the structure of feeding behavior and whether blocking D2 receptors prevented these changes. We used the intermittent access model to a 10% sucrose solution (2 h/day for 4 weeks) to induce sugar binging in Sprague Dawley female rats. Experimental subjects consumed in a 2-h period more than 50% of the caloric intake consumed by the subjects with ad-lib access to the sweetened solution without any increase in body weight or fat accumulation. Furthermore, we evaluated whether sugar binging was associated to the estrous cycle and we did not find differences in caloric intake (estrous vs. diestrus). Subsequently, we characterized the structure of feeding behavior (microstructural analysis) and the motivation for palatable food (breakpoints) of the subjects with sugar binging and found that feeding episodes had short latencies, high frequencies, as well as short durations and inter-episode intervals. The intermittent access model did not increase breakpoints, as occurred in subjects with ad-lib access to the sucrose. Finally, we evaluated the effects of D2 receptor blockade in the NAcS, and found that raclopride (18 nM) prevented the observed changes in the frequency and duration of episodes induced by intermittent access to the sucrose solution. Our results suggest that alterations in behavioral patterns associated with binge-eating behavior depend in part on the dopaminergic transmission in the NAcS and that the antagonism of D2 receptors may be a therapeutic tool for feeding pathology with binge-eating.

Effects of CB1 cannabinoid receptor activation in the nucleus accumbens shell on feeding behavior / Efectos de la activación del receptor cannabinoide CB1 en el núcleo accumbens shell sobre la conducta alimentaria / Efeitos da ativação do receptor cannabinóide CB1 no núcleo accumbens shell sobre a conduta alimentar

Obesity and its related pathologies are well- known health hazards. Although obesity and overweight have multifactorial causes, overeating is common in both of these conditions. According to animal models, endocannabinoids and their receptors in the brain play a key role in the genesis and development of obesity. It has been proposed that the cannabinoid receptors CB1 (RCB1) expressed in the nucleus accumbens shell (NAC) are involved in the increase of the hedonic properties of food. To test this hypothesis, this study aimed to assess the effects of activating the NACs RCB1 on standard food intake during the light phase of the light-dark cycle. The effects of activating the RCB1 with CP 55,940 and WIN 55-212-2 (0.125, 0.25 and 0.5 nmol) in the NACS on feeding behavior and the behavioral satiety sequence of rats were assessed. It was found that both agonists increased food intake and delayed expression of satiety during the light phase. These results suggest that cannabinoid agonists encourage food intake when motivation is low and palatability is normal.

La obesidad y sus patologías relacionadas son riesgos de salud muy conocidos. Aunque la obesidad y el sobrepeso tienen causas multifactoriales, la sobreingesta de alimento es frecuente en estas condiciones. De acuerdo con modelos animales, los endocanabinoides y sus receptores en el cerebro juegan un papel clave en la génesis y desarrollo de la obesidad. Se ha propuesto que los receptores a canabinoides CB1 (RCB1) expresados en el núcleo accumbens shell (NAcS) están involucrados en el incremento de las propiedades hedónicas del alimento. Para probar esta hipótesis, este estudio tuvo como objetivo evaluar los efectos de la activación de los RCB1 en el NAcS sobre la ingesta de alimento estándar durante la fase de luz del ciclo luz-oscuridad. Se evaluaron los efectos de la activación de los RCB1 con WIN 55-212-2 y CP 55,940 (0.125, 0.25, y 0.5 nmol) en el NAcS sobre la conducta alimentaria y la secuencia de saciedad conductual en ratas. Se encontró que ambos agonistas aumentaron la ingesta de alimento y demoraron la expresión de la saciedad durante la fase de luz. Lo anterior sugiere que los agonistas canabinoides estimulan el consumo de alimento cuando la motivación por el mismo es baja y la palatabilidad es normal.

A obesidade e suas patologias relacionadas são riscos de saúde muito conhecidos. Ainda que a obesidade e o sobrepeso possuam causas multifatoriais, a sobre ingestão de alimento é frequente nestas condições. De acordo com modelos animais, os endocanabinóides e seus receptores no cérebro jogam um papel chave na gênese e desenvolvimento da obesidade. Foi proposto que os receptores a canabinóides CB1 (RCB1) expressos no núcleo accumbens shell (NAcS) estão envolvidos no aumento das propriedades hedônicas do alimento. Para testar esta hipótese, este estudo teve como objetivo avaliar os efeitos da ativação dos RCB1 nos NAcS sobre a ingestão de alimento padrão durante a fase de luz do ciclo luz-escuridão. Avaliaram-se os efeitos da ativação dos RCB1 com WIN 55-212-2 e CP 55,940 (0.125, 0.25, e 0.5 nmol) no NAcS sobre a conduta alimentar e a sequência de saciedade condutual em ratos. Encontrou-se que ambos agonistas aumentaram a ingestão de alimento e demoraram a expressão da saciedade durante a fase de luz. Isso sugere que os agonistas canabinóides estimulam o consumo de alimento quando a motivação pelo mesmo é baixa e a palatabilidade é normal.