Individual differences in the sensitivity to serotonergic drugs: a pharmacobehavioural approach using rats selected on the basis of their response to novelty.

The mechanisms underlying individual differences in the response to serotonergic drugs are poorly understood. Rat studies may contribute to our knowledge of the neuronal substrates that underlie these individual differences. A pharmacobehavioural study was performed to assess individual differences in the sensitivity to serotonergic drugs in rats that were selected based on their response to a novel environment. Low responders (LR) and high responders (HR) to novelty rats were tested on the elevated T-maze following systemic injections of increasing doses of various serotonergic agents. The duration of avoidance of the open arms was scored for five trials. The duration of avoidance behaviour was larger in saline-treated LR rats compared to saline-treated HR rats. The 5-HT1A agonist 8-OH-DPAT and the 5-HT2 agonists mCPP and DOI decreased the duration of avoidance behaviour in LR rats, but increased it in HR rats. The 5-HT3 agonist SR57227A and the 5-HT releaser/reuptake inhibitor d-fenfluramine increased the duration of avoidance behaviour in both types of rat. However, higher doses of SR57227A were required to alter avoidance behaviour in HR than in LR rats. The onset of the effects of SR57227A, d-fenfluramine and WAY100635 was faster in LR than in HR rats. The described effects were receptor specific. A model explaining the data is presented. These data demonstrate that LR and HR rats differ in their sensitivity to serotonergic drugs that act at 5-HT3, 5-HT2 and 5-HT1A receptors. The implications of these individual differences for individual-specific treatment of substance abuse are briefly discussed.