Forebrain serotonin and avoidance learning: behavioural and biochemical studies on the acute effect of p-chloroamphetamine on one-way active avoidance learning in the male rat.

The acute effects of p-chloroamphetamine (PCA) on one-way active avoidance learning and on central monoamine concentrations were examined in the male rat. The 5-HT specificity of the acute behavioural effect of PCA was examined in several experiments. PCA (0.08-5 mg/kg IP) injected 30-60 min before testing produced a dose-related impairment of both avoidance acquisition and retention. Pretreatment with the selective serotonin (5-HT) uptake inhibitors fluoxetine and zimelidine, but not the noradrenaline (NA) uptake inhibitor desipramine, resulted in a blockade of the avoidance deficit. Degeneration of brain 5-HT neurons by a high neurotoxic dose of PCA (2 x 10 mg/kg IP) 7 days prior to the administration of PCA also blocked the avoidance deficit. There was also a complete blockade of the PCA-induced avoidance deficit by pretreatment with metergoline, a central 5-HT receptor blocking agent. A 2.,5 mg/kg dose of PCA examined 60 min after injection produced regional changes in the 5-HT-levels preferentially in the forebrain region with significant reductions in the cerebral cortex, hippocampus and striatum while marginal effects were observed in the hypothalamus, midbrain and spinal cord. PCA failed to reduce dopamine and noradrenaline concentrations in the time- and dose-range of the avoidance deficit. Thus, the avoidance learning impairment appears to be specifically related to the acute release of endogenous 5-HT from presynaptic nerve endings possibly in the forebrain resulting in stimulation of postsynaptic 5-HT receptors. These findings indicate that 5-HT neurons in the forebrain play a role in active avoidance learning possibly by an involvement in memorial and/or retrieval processes.