Tolerance to the behavioural effects of the selective 5-HT(1A) agent, ipsapirone

Effects of ipsaprione on rats were studied in procedures in which tolerance was assessed with operant responding and in feeding tests. Initially, the suppressant effect of ipsapirone on Fixed Ratio 20 behaviour was studied. During 33 days treatment (7.5mg/kg daily) no tolerance developed. Subsequently, the same rats received ipsapirone (7.5mg/kg) three times daily, at intervals of 2.5h, the first injection preceding operant sessions. Over 10 further days of treatment, there was still no evidence of tolerance. In a second study, ipsapirone was again administered at 7.5mg/kg before operant sessions, followed by 2 daily injections of 20mg/kg, at at 2.5h intervals after operant sessions. Under these conditions, some tolerance developed although it was incomplete and rapidly lost. The effects of ipsapirone on operant responding were found to be short-lasting. The suppressant action of 7.5mg/kg of ipsapirone (to 50% of baseline) was abolished if the drug was injected 4h before sessions. In other studies, we confirmed that tolerance develops very rapidly to hyperphagic actions of ipsapirone (see Kennett et al., 1987). We conclude that: 1) tolerance develops at differing rates to various effects of ipsapirone; 2) only those effects of ipsapirone (and related agents) which involve activation of presynaptic autoreceptors show rapid tolerance; 3) tolerance develops to effects on operant responding only if high doses are administered frequently. Since ipsapirone is short-acting, tolerance to such effects develops only when drug is continuously present in body tissue. The tolerance observed (to effects on operant behaviour) was probably of a pharmacodynamic nature and did not involve learning processes.