Dissociation of serotonergic regulation of anxiety and ethanol self-administration: a study with mCPP

Alcohol dependence frequently co-exists with anxiety disorders, although it is unclear how these disorders functionally or neurochemically relate. Central serotonergic dysfunction may be one common factor. The aim of this study was to compare the effects of the mixed 5-HT agonist m-chlorophenylpiperazine (mCPP) on both anxiety-related (hole board/plus maze) and ethanol self-administration (limited access procedure) behaviours in male Wistar rats. mCPP was selected because it is known to be anxiogenic in both animals and humans, and to induce "craving" in abstinent alcoholics. For comparative purposes pentylenetetrazole (PTZ), a non-serotonergic anxiogenic agent, was also examined. mCPP (0.3 and 1.0mg/kg s.c.) decreased exploratory behaviour in both the hole board and plus maze, which is indicative of anxiogenesis. At comparable doses, mCPP reduced ethanol and water intake during a limited access procedure where rats were presented with both a 12% ethanol solution and water. mCPP-induced anxiogenesis was reversed by two antagonists, metergoline (5-HT(1/2) receptor antagonist) and ritanserin (5-HT(2A/2C) receptor antagonist). However, the effect of mCPP on ethanol was modified only by metergoline, which suggests that different 5-HT receptor subtypes are involved in regulating these behaviours. Furthermore, there was no evidence of tolerance to the anxiogenic effect of mCPP (0.3mg/kg) following chronic (8 days) treatment. However, tolerance developed to its effect on ethanol intake. Upon discontinuation ethanol intake increased (by 41%). In contrast, PTZ (15.0mg/kg i.p.) induced anxiogenesis in the plus maze and also increased ethanol intake on chronic administration. Since mCPP and PTZ had opposite effects on ethanol intake, the effect of mCPP may not be related to its anxiogenic properties but rather reflect its non-selective pharmacology. This non-selectivity of mCPP makes it an unsatisfactory pharmacological tool with which to investigate the functional relationship between anxiety and alcohol dependence.