Tolerance to acute anxiolysis but no withdrawal anxiogenesis in mice treated chronically with 5-HT1A receptor antagonist, WAY 100635.
Anxiolytic-like activity in the mouse elevated plus-maze has recently been demonstrated for a range of compounds varying in degree of selectivity as 5-HT1A receptor antagonists. As tolerance and dependence liability are among the major clinical disadvantages of benzodiazepine therapy, the present study examined the effects of acute drug challenge on the plus-maze profiles of mice following daily treatment for 20 days with saline, chlordiazepoxide (CDP; 10.0 mg/kg) or the selective 5-HT1A receptor antagonist, WAY 100635 (0.1-1.0 mg/kg). To assess the development of physical dependence (withdrawal anxiogenesis), the study incorporated independent groups of animals tested on the maze 24 h after the final dose. Challenge with CDP or WAY 100635 produced behavioural changes indicative of anxiety reduction in mice that had received daily handling/saline for 20 days, thereby demonstrating that the chronic injection regimen per se had not compromised the acute efficacy of either agent. The absence of a similar response to acute drug challenge in mice treated chronically with CDP or WAY 100635 suggested the development of tolerance to the acute anxiolytic effects of both compounds under present test conditions. Despite these observations, however, no signs of enhanced anxiety were evident 24 h following discontinuation of chronic treatment with either compound. In a further experiment, the absence of withdrawal anxiogenesis at 24 h was replicated and extended to discontinuation periods of 36 and 48 h for both drugs. Although present results show that tolerance develops to the acute anxiolytic effects of CDP and WAY 100635 in the murine plus-maze, they also suggest that enhanced anxiety is not an inevitable consequence of abrupt cessation of chronic treatment with either compound.
Cao
B J
BJ
Ethopharmacology Laboratory, School of Psychology, University of Leeds, UK.
Rodgers
R J
RJ
D000818:Animals; D014151:Anti-Anxiety Agents / Q000009:adverse effects* / Q000494:pharmacology*; D002707:Chlordiazepoxide / Q000494:pharmacology; D004361:Drug Tolerance; D005106:Exploratory Behavior / Q000187:drug effects; D008297:Male; D051379:Mice; D010879:Piperazines / Q000009:adverse effects* / Q000494:pharmacology*; D011187:Posture / Q000502:physiology; D011725:Pyridines / Q000009:adverse effects* / Q000494:pharmacology*; D011985:Receptors, Serotonin / Q000187:drug effects*; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000009:adverse effects* / Q000494:pharmacology*; D013375:Substance Withdrawal Syndrome / Q000523:psychology*
D014151:Anti-Anxiety Agents; D010879:Piperazines; D011725:Pyridines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D002707:Chlordiazepoxide; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide