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.

Effects of acute and chronic fluoxetine treatments on restraint stress-induced Fos expression.

Chronic treatment with antidepressants has been shown to attenuate behavioral changes induced by uncontrollable stress. The mechanisms and brain sites of this effect, however, remain controversial. The objective of the present work was to investigate the effects of chronic and acute treatment with fluoxetine (FLX), a selective serotonin reuptake blocker, on Fos expression in animals submitted to restraint stress. Male Wistar rats (n = 3-9/group) received, during 1 or 21 days, intraperitoneal. Injections of vehicle (saline + 0.2% Tween-80, 1 ml/kg) or FLX (10 mg/kg). One hour after the last injection they were forced restrained for 2 h and sacrificed immediately after. Non-stressed animals were sacrificed 2 h after the last injection. The brains were removed and processed for immunohistochemistry. Fos-like immunoreactivity (FLI) was quantified by a computer system. In acutely treated animals FLX decreased stress-induced FLI in the medial amygdala (MeA), bed nucleus of the stria terminalis (BNST), ventrolateral part, and dorsolateral periaqueductal gray (PAG). After chronic treatment, however, the drug induced a significant increase in FLI in the BNST (ventrolateral and medial parts), lateral septal nucleus (LSN, dorsal part), dorsal raphe nucleus (DRN), and locus coeruleus in restrained group. In non-restrained animals chronic treatment with FLX increased FLI in the MeA, BNST (ventrolateral and dorsolateral parts), LSN (dorsal and intermediate parts), dorsolateral and dorsomedial PAG and in the DRN. The results suggest that chronic fluoxetine treatment induce plastic changes that result in a different regional pattern of Fos expression.