Maternal separation plus social isolation during adolescence reprogram brain dopamine and endocannabinoid systems and facilitate alcohol intake in rats.

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.

Opposed cannabinoid 1 receptor (CB1R) expression in the prefrontal cortex vs. nucleus accumbens is associated with alcohol consumption in male rats.

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.

Endocannabinoids and sleep.

Sleep is regulated by several brain structures, neurotransmitters and neuromodulators. Endocannabinoids (eCBs) are a group of lipids with modulatory activity in the brain and bind mainly to cannabinoid receptors CB1R and CB2R, thereby modulating several brain functions, (memory, mood, food intake, pain perception). Oleoylethanolamide and palmitoylethanolamide belong to the N-acylethanolamides (NAEs) family, another type of active endogenous lipids. They bind to the peroxisome proliferator-activated receptor α but not to CB1R, thereby modulating food satiety, inflammation and pain. Both eCBs and NAEs seem to be regulating the sleep-wake cycle. Our objective is to analyze the experimental evidence published in the literature and to discuss if eCBs and NAEs are actually sleep modulators. Studies suggested 1. eCBs and NAEs are under circadian control. 2. NAEs promote wake. 3. eCBs promote non-rapid-eye movement. 4. eCBs also promote rapid-eye-movement sleep by interacting with melanin-concentrating hormone neurons in the lateral hypothalamus. 5. The pharmacological blockade of the CB1R reduces sleep while increasing wake. 6. eCBs restore sleep in a model of insomnia in rats.

mGluR1/5 activation in the lateral hypothalamus increases food intake via the endocannabinoid system.

Mounting evidence has shown that glutamatergic and endocannabinoid systems in the hypothalamus regulate mammalian food intake. Stimulation of hypothalamic mGluR1/5 and CB1 receptors induces hyperphagia suggesting a possible interaction between these systems to control food intake. In addition, synthesis of endocannabinoids has been reported after mGluR1/5 stimulation in the brain. The aim of this study was to examine the potential cannabinergic activity in the food intake induction by lateral hypothalamic stimulation of mGluR1/5. Wistar albino male rats received bilateral infusions in the lateral hypothalamus (LH) of: (i) vehicle; (ii) (RS)-2-Chloro-5-hidroxyphenylglycine (CHPG; mGluR1/5 agonist); (iii) 2-AG (CB1 endogenous agonist); (iv) AM251 (CB1 antagonist); (v) tetrahydrolipstatin (THL, 1.2µg; diacyl-glycerol lipase inhibitor); and (vi) combinations of CHPG + with the other aforementioned drugs. Food intake was evaluated the first two hours after drug administration. CHPG significantly increased food intake; whereas CHPG in combination with a dose of 2-AG (with no effects on food intake) greatly increased food ingestion compared to CHPG alone. The increase induced by CHPG in food intake was prevented with AM251 or THL. These results suggest that activation of mGluR1/5 in the lateral hypothalamus induces an orexigenic effect via activation of the endocannabinoid system.