Discriminative stimulus effects of ethanol: Effect of training dose on the substitution of N-methyl-D-aspartate antagonists

The ethanol-like discriminative stimulus effects of N-methyl-D-aspartate (NMDA) antagonists that act at the NMDA recognition site [(D)-4-(3- phosphonoprop-2-enyl)piperazine-2-carboxylic acid (CPPene) and cis-4- phosphonomethyl-2-piperidine carboxylic acid] or within the NMDA associated cation channel [phencyclidine (PCP) and dizocilpine] were evaluated in rats trained to discriminate ethanol or PCP from vehicle in a two-lever discrimination procedure. Three groups of rats were trained to discriminate 1.0, 1.5 or 2.0 g/kg of ethanol from water and one group was trained to discriminate 1.5 mg/kg of PCP from saline. In the ethanol-trained groups, both PCP (1.0-5.6 mg/kg; i.p.) and dizocilpine (0.03-0.3 mg/kg; i.p.) completely substituted for ethanol in every rat tested, although the dizocilpine resulted in only partial substitution in rats trained to discriminate 1.0 g/kg of ethanol. As the training dose of ethanol increased, the potency of PCP and dizocilpine to substitute for ethanol increased. In contrast, CPPene (1-17 mg/kg; i.p.) and cis-4-phosphonomethyl-2-piperidine carboxylic acid (5.6-17 mg/kg; i.p.) resulted in partial substitution for ethanol, with lower amounts of ethanol-appropriate responding as the training dose of ethanol increased. These data indicate that uncompetitive antagonism of NMDA neurotransmission at sites within the cation channel produce discriminative stimulus effects that are similar to those of ethanol, particularly to higher ethanol doses. Neither ethanol (0.5-1.5 g/kg; i.p.) nor CPPene (5.6 and 10 mg/kg) completely substituted for the discriminative effects of PCP. The asymmetrical generalizations between ethanol and PCP are discussed in terms of the mixed discriminative effects of ethanol.