J. Neurochem. (2011) 116, 291–303. Abstract BTBR mice are potentially useful tools for autism research because their behavior parallels core social interaction impairments and restricted‐repetitive behaviors. Altered regulation of central serotonin (5‐HT) neurotransmission may underlie such behavioral deficits. To test this, we compared 5‐HT transporter (SERT), 5‐HT1A and 5‐HT2A receptor densities among BTBR and C57 strains. Autoradiographic [3H] cyanoimipramine (1nM) binding to SERT was 20–30% lower throughout the adult BTBR brain as compared to C57BL/10J mice. In hippocampal membrane homogenates, [3H] citalopram maximal binding (Bmax) to SERT was 95 ± 13 fmol/mg protein in BTBR and 171 ± 20 fmol/mg protein in C57BL/6J mice, and the BTBR dissociation constant (KD) was 2.0 ± 0.3 nM versus 1.1 ± 0.2 in C57BL/6J mice. Hippocampal 5‐HT1A and 5‐HT2A receptor binding was similar among strains. However, 8‐OH‐DPAT‐stimulated [35S] GTPγS binding in the BTBR hippocampal CA1 region was 28% higher, indicating elevated 5‐HT1A capacity to activate G‐proteins. In BTBR mice, the SERT blocker, fluoxetine (10 mg/kg) and the 5‐HT1A receptor partial‐agonist, buspirone (2 mg/kg) enhanced social interactions. The D2/5‐HT2 receptor antagonist, risperidone (0.1 mg/kg) reduced marble burying, but failed to improve sociability. Overall, altered SERT and/or 5‐HT1A functionality in hippocampus could contribute to the relatively low sociability of BTBR mice.

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Consumers of marijuana typically feel a strong compulsive desire to consume food. Although past research revealed that the CB1 cannabinoid receptor is a potent regulator of food intake, the functional presence of neuronal CB2 cannabinoid receptors in the brain had been controversial. The role of CB2 receptors in food and alcohol consumption and the behavioral effects of CB2 receptor ligands are not well characterized. This is because CB2 cannabinoid receptors were thought to be absent from the brain and expressed primarily in immune cells and in the periphery. We tested the effects of peripheral injections of CB2 antagonist AM 630, CB2 agonist PEA and CB1 antagonist AM 251 on male C57BL/6, Balb/c, and DBA/2 mice at the beginning of the night cycle and after overnight 12-hour fasts. We also investigated the effects of the putative CB2 agonist, JWH015, and CB2 antagonist SR144528 in mouse motor function tests and in the two compartment black and white box. Under standard conditions, the CB2 antagonist AM 630 inhibited food consumption in C57BL/6 mice and DBA/2 mice, but failed to block food intake of Balb/c mice. The CB2 agonist PEA had no significant effect on food consumption in Balb/c mice, and reduced food intake in C57BL/6 and DBA mice. The CB1 antagonist AM 251 inhibited food ingestion in the three mouse strains at variable times. After 12-hour food deprivation, the CB2 antagonist AM 630 increased food consumption in C57Bl/6 mice, but failed to produce significant changes in food intake for Balb/c and DBA/2 mice. The CB2 agonist PEA also reduced food consumption in all three mice strains at variable times. In comparison to the CB2 ligands, CB1 antagonist AM 251 inhibited food ingestion in the mouse strains. A general pattern of depression in locomotor activity was induced by JWH 015 in both males and females in the three mouse strains tested as the dose was increased. The development and enhancement of alcohol preference was observed following chronic treatment with CB2 agonist JWH 015 in stressed mice but not in controls. Using the DBA/2 strain the spontaneous locomotor activity and stereotype behavior was enhanced by acute administration of low doses of SR144528. There was a reduction in CNR2 gene expression in the ventral mid-brain region of mice that developed alcohol preference but not in those that did not develop alcohol preference. These effects of CB2 cannabinoid receptor ligands in in vivo behavioral tests are provided as functional evidence that CB2-Rs in the brain plays a role in food and alcohol consumption and in the modification of mouse behavior.

Marijuana use activates cannabinoid receptors (CB-Rs) producing several behavioral effects related to addiction, mood, and appetite. We investigated the association between CNR2 gene, which encodes cannabinoid CB2 receptor (CB2-R) and eating disorders in 204 subjects with eating disorders and 1876 healthy volunteers in Japanese population. The effect of treatment with CB2-R ligands on mouse food consumption was also determined. The CB2-R ligands used suppressed food intake in a time-and strain-dependent manner when food was available ad libitum and during the 12-h fast except, AM 630-the CB2-R antagonist that stimulated food consumption in food-deprived mice. There is an association between the R63Q polymorphism of the CNR2 gene and eating disorders (P 5 0.04; Odds ratio 1.24, 95% CI, (1.01-1.53). These results suggest that cannabinoid CB2-R is involved in the endocannabinoid signaling mechanisms associated with the regulation of food intake and in eating disorders. Synapse 64:92-96, 2010. V

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