dizocilpine-maleate and 1-(3-trifluoromethylphenyl)piperazine

Three-choice discrimination procedures are used to characterize how similar the discriminative stimulus effects of two drugs are in relation to each other. This procedure has suggested similarities between ethanol and ligands that positively modulate the gamma-aminobutyric acid type A (GABAA) receptor complex. As an extension to these studies, male Long-Evans rats were trained to discriminate midazolam (3.0 mg/kg, i.p.) from ethanol (1.0 g/kg, i.g.) from water (2.3 ml, i.g.) in a three-lever, food reinforced task. Substitution tests were conducted following administration of GABAA-positive modulators, noncompetitive N-methyl-D-aspartate (NMDA) antagonists, 5-HT1B agonists and isopropanol. Among the GABAA-positive modulators, diazepam was the only drug that completely substituted for midazolam; both pentobarbital and the neurosteroid allopregnanolone showed partial midazolam substitution. The NMDA antagonist dizocilpine substituted for ethanol, while phencyclidine showed no substitution for either ethanol or midazolam. The serotonin agonists tested also showed no substitution for either ethanol or midazolam. Isopropanol was the only other drug that completely substituted for ethanol. These data extend previous findings from an ethanol-pentobarbital-water discrimination and further define training conditions that result in a conditional basis for the ethanol discrimination where only those drugs with pharmacological heterogeneous effects similar to ethanol produce a full ethanol-like effect.

Topics: Animals; Anti-Anxiety Agents; Central Nervous System Depressants; Discrimination Learning; Discrimination, Psychological; Dizocilpine Maleate; Dose-Response Relationship, Drug; Ethanol; Excitatory Amino Acid Antagonists; Hypnotics and Sedatives; Indoles; Midazolam; Pentobarbital; Phencyclidine; Piperazines; Pregnanolone; Quinoxalines; Rats; Rats, Long-Evans; Receptor, Serotonin, 5-HT1B; Serotonin Receptor Agonists

The present study used a drug discrimination paradigm to characterize the contribution of separate receptor systems to the stimulus effects of different training doses of ethanol. In a two-lever drug discrimination paradigm two groups of adult male Long-Evans rats (n = 8 per group) were trained to discriminate either 1.0 g/kg ethanol from water or 2.0 g/kg ethanol from water, administered intragastrically (i.g.), 30 min prior to the start of daily sessions in which responding was maintained under a fixed ratio 20 schedule of food presentation. Following training, cumulative dosing substitution tests were conducted with the GABAA positive modulator pentobarbital (1-17 mg/kg, i.p.), the uncompetitive NMDA antagonist dizocilpine (0.01-0.3 mg/kg, i.p.) and the 5-HT1B/2C agonist m-trifluoromethylphenylpiperazine (TFMPP 0.17-1.7 mg/kg, i.p.). Next, the rats initially trained at 1.0 g/kg ethanol were retrained to discriminate 2.0 g/kg ethanol from water, and the rats initially trained at 1.0 g/kg were retrained to discriminate 2.0 g/kg ethanol from water. Both groups were then re-tested with the same ligands. Regardless of training history, animals currently discriminating 1.0 g/kg were more sensitive to the ethanol-like effects of TFMPP and pentobarbital compared to rats discriminating 2.0 g/kg ethanol. However, no difference in sensitivity to the ethanol-like effects of dizocilpine based on ethanol training dose was detected. These results support the view that ethanol is a heterogeneous discriminative stimulus comprised of GABAA, NMDA and 5-HT1B/2C receptor-mediated activity. Furthermore, changes in sensitivity to GABAA and 5-HT ligands as a function of training dose could be indicative of overshadowing by other components of ethanol's heterogeneous cue. Finally, it appears that the current profile of ethanol's heterogeneous stimulus effects, rather than an interaction with ethanol training history, determines the substitution pattern of specific receptor ligands.

Topics: Animals; Attention; Brain; Discrimination Learning; Dizocilpine Maleate; Dose-Response Relationship, Drug; Ethanol; Male; Motivation; Pentobarbital; Piperazines; Rats; Rats, Long-Evans; Receptor, Serotonin, 5-HT1B; Receptors, GABA-A; Receptors, N-Methyl-D-Aspartate; Receptors, Serotonin

Ligands acting at separate receptor systems are independently recognizable as ethanol in drug discrimination procedures. These findings suggest that the internal stimulus effects of ethanol are composed of actions at more than one receptor system and that these mixed effects remain distinct and do not blend to form a single subjective state. Furthermore, the relative contributions of these receptor systems to the ethanol cue depend upon the ethanol training dose and are not uniformly amplified when the dose of ethanol is increased. The data gathered from these studies can be used to identify transmitter systems that may contribute to dose-specific behavioral effects of ethanol.

Topics: Animals; Discrimination, Psychological; Dizocilpine Maleate; Dose-Response Relationship, Drug; Ethanol; Male; Pentobarbital; Piperazines; Rats; Receptors, Drug; Receptors, GABA-A; Receptors, N-Methyl-D-Aspartate; Receptors, Serotonin; Serotonin Receptor Agonists