Characterization of the ethanol-like discriminative stimulus effects of 5-HT receptor agonists as a function of ethanol training dose

A drug discrimination procedure was used to characterize the ethanol-like effects of a variety of 5-HT₁ agonists. Previous studies found that the degree of substitution of the 5-HT(1B/2C) agonist TFMPP (m-trifluoromethylphenylpiperazine) depended on the training dose of ethanol. The present studies extend this initial finding to four additional 5-HT agonists with different selectivity for 5-HT(1A), 5-HT(1B), or 5-HT(2C) receptors: CGS 12066B (7-trifluoromethyl-4(4-methyl-1-piperazinyl)-pyrrolo[1,2-a]quinoxaline maleate), mCPP [1-(3-chlorophenyl)piperazine diHCl], RU 24969 [5-methoxy-3(1,2,3,4-tetrahydro-4-pyridinyl]-1H-indole succinate and 8-OH DPAT [±)-8-hydroxy-2-(di-n-propylamino)tetralin HBr]. Separate groups of rats were trained to discriminate 1.0 g/kg (n=7), 1.5 g/kg (n=6) or 2.0 g/kg (n=8) ethanol from water. Following training, three to five doses of each 5-HT agonists were tested twice in each rat. The most selective 5-HT(1B) agonist tested, CGS 12066B (3-17 mg/kg; IP), completely substituted for the 1.0 g/kg ethanol, but not for 1.5 or 2.0 g/kg ethanol. Likewise, the 5-HT(1B/2C) agonist mCPP (0.56-1.7 mg/kg; IP) completely substituted only in the 1.0 g/kg ethanol training group. The 5-HT(1A/1B) agonist RU 24969 (0.1-3.0 mg/kg; IP) substituted for all training doses of ethanol, although in a lower proportion of the rats tested in the 2.0 g/kg ethanol training group. Finally, the 5-HT(1A) agonist 8-OH DPAT (0.1-1.0 mg/kg; IP) did not substitute completely for any ethanol training dose. The results consistently show that agonists with 5-HT(1B) activity produce discriminative stimulus effects similar to low and intermediate, but not high, ethanol training doses.