Tolerance to cannabinoid-induced behaviors in mice treated chronically with ethanol.

RATIONALE

Chronic ethanol (EtOH) treatment decreases the motor-impairing effects of cannabinoids and downregulates the cannabinoid type 1 (CB1) receptor. However, these studies have been limited to measures of ataxia and analysis of CB1 expression from whole-brain or hippocampal preparations.

OBJECTIVE

To more fully assess the interactions between ethanol and cannabinoids, a tetrad of four well-characterized cannabinoid-induced behaviors (hypolocomotion, antinociception, hypothermia, and catalepsy) was measured in mice following EtOH treatment. Additionally, immunoblotting assessed CB1 protein in tissue from nine brain regions associated with these behaviors and the addiction neurocircuitry.

MATERIALS AND METHODS

Male C57Bl/6J mice were administered EtOH (0, 2, or 4 g/kg; intraperitoneally (i.p.)) twice daily for 10 days. Tetrad behaviors induced by the CB1 agonist WIN 55212-2 (3 mg/kg, i.p.) were measured in subjects 1 or 10 days following the last EtOH injection. In a separate group of animals, tissue was collected at the same time points for immunoblot analysis.

RESULTS

EtOH-treated mice were less sensitive to the hypothermic, hypolocomotive, and antinociceptive effects of WIN, and this effect reversed to control levels over a 10-day abstinence period. EtOH treatment did not affect WIN-induced catalepsy. CB1 protein expression was significantly altered in several brain areas including the hypothalamus, periaqueductal gray, ventral tegmental area, and cerebellum.

CONCLUSIONS

These results show that chronic EtOH treatment significantly affects the behavioral sensitivity to cannabinoid drugs and alters CB1 expression in several brain regions. Furthermore, these effects are selective as some behaviors and brain regions display an altered response while others do not.