Adolescent cannabinoid exposure modulates the vulnerability to cocaine-induced conditioned place preference and DNMT3a expression in the prefrontal cortex in Swiss mice.

RATIONALE: Cannabis sativa is the most widely used drug by adolescents globally. The recreational use of synthetic cannabinoids by teenagers has also grown in recent years. Despite the wrong perception that exposure to these drugs does not cause harm, repeated exposure to cannabinoids at early stages of life compromises important maturation processes and brain development. Chronic early cannabinoid use has been related to a higher risk of psychiatric outcomes, including cocaine addiction. Evidence suggests that exposure to natural and synthetic cannabinoids during adolescence modifies molecular and behavioral effects of cocaine in adulthood. Responses to cocaine are regulated by epigenetic mechanisms, such as DNA methylation, in the brain's reward regions. However, the involvement of these processes in modulation of the vulnerability to the effects of cocaine induced by prior exposure to cannabinoids remains poorly understood. OBJECTIVES: Investigate whether exposure to the synthetic cannabinoid WIN55,212-2 during adolescence modulates anxiety- and depression-like behavior, memory, and cocaine reward in adult mice. We also evaluated whether exposure to cannabinoids during adolescence modulates the expression of enzymes that are involved in DNA methylation. RESULTS: Exposure to WIN55,212-2 during adolescence did not alter anxiety- or depressive-like behavior. However, prior exposure to cannabinoids inhibited cocaine-induced conditioned place preference without modulating cocaine-induced hyperlocomotion, accompanied by an increase in expression of the enzyme DNA methyltransferase 3a (DNMT3a) in the prefrontal cortex. CONCLUSIONS: Our findings suggest that exposure to WIN55,212-2 during adolescence leads to changes in DNMT3a expression, and this pathway appears to be relevant to modulating the rewarding effects of cocaine.

Galanin microinjection into the dorsal periaqueductal gray matter produces paradigm-dependent anxiolytic effects.

Galanin is a peptide that is present in the central nervous system in mammals, including rodents and humans. The actions of galanin are mediated by three types of metabotropic receptors: GAL1, GAL2, and GAL3. GAL1 and GAL3 increase K(+) efflux, and GAL2 increases intracellular Ca(2+) levels. The distribution of galanin and its receptors suggests its involvement in fear and/or anxiety. The periaqueductal gray matter (PAG) is a key mediator of defensive behaviors that is both targeted by galaninergic projections and supplied with GAL1 receptors and, less markedly, GAL2 receptors. We examined the effects of galanin microinjections in the dorsal PAG (dPAG) on the performance of rats in different models of anxiety. Male Wistar rats (n=7-12) were implanted with guide cannulae in the dPAG. They received microinjections of either galanin (0.3, 1.0, and 3.0 nmol) or vehicle and were tested in the Vogel conflict test (VCT), elevated plus maze (EPM), and elevated T-maze (ETM). Rats that were tested in the ETM were further evaluated for exploratory activity in the open field test (OFT). Galanin microinjections had no effects on anxiety-like behavior in the EPM or VCT or exploratory activity in the EPM or OFT. In the ETM, however, microinjections of 3 nmol galanin impaired learned anxiety (i.e., avoidance of the open arms) without changing unconditioned fear (i.e., escape from the open arms). The present data suggest that galanin transmission in the dPAG inhibits the acquisition of anxiety-like responses in the ETM.