Behavioral studies with anxiolytic drugs. VI. Effects on punished responding of drugs interacting with serotonin receptor subtypes.

The effects of drugs that bind selectively to different serotonin (5-HT) receptor subtypes were assessed in pigeons. Keypecking was maintained by a multiple fixed-ratio schedule of reinforcement in which responding also was punished during one component. The greatest increases in punished responding were produced by the buspirone analogs BMY 7378 and ipsapirone, which act at the 5-HT1A receptor. RU 24969, with high affinity for both 5-HT1A and 5-HT1B receptors, and 1-(2-methoxyphenyl)piperazine, a 5-HT1 compound, increased punished responding to a lesser extent, as did the 5-HT2 antagonists ketanserin and ritanserin. The 5-HT3 antagonists GR 38032F, ICS 205930 and MDL 72222 showed little systematic effect, and the mixed 5-HT1B/5-HT1C compound 1-(3-chlorophenyl)piperazine produced only decreases in punished responding. Levels of neurotransmitter metabolites in cerebrospinal fluid were assessed across a wide dose range of representative drugs used in the behavioral studies. Levels of the 5-HT metabolite 5-hydroxyindoleacetic acid were decreased significantly by BMY 7378 and ipsapirone, were not changed by ritanserin and were increased at one dose by MDL 72222. The results are consistent with suggestions that decreased 5-HT neurotransmission is involved in the effects of novel nonbenzodiazepine anxiolytics such as buspirone. Behavioral and neurochemical data also indicate that the effects of these drugs on other neurotransmitter systems do not play a significant role in their anxiolytic actions.