Postsynaptic 5-HT sub(1A) receptors mediate an increase in locomotor activity in the monoamine-depleted rat

Rationale. In animal models of reduced dopamine transmission, such as haloperidol-induced catalepsy or monoamine-depleted animals, serotonin (5-hydroxytryptamine; 5-HT) 5-HT sub(1A) agonists appear to enhance motor activity. However, the exact mechanism remains unclear. Objective. The objective of the present study was to demonstrate that 5-HT sub(1A) agonists can increase locomotor activity by activation of postsynaptic 5-HT sub(1A) heteroreceptors without the involvement of somatodendritic 5-HT sub(1A) autoreceptors which are known to regulate 5-HT neuronal activity. Methods. The effects of the 5-HT sub(1A) full agonist R-(+)-8-hydroxy-2-(di-n-propylamino)tertralin (R-(+)-8-OHDPAT) on locomotor activity in reserpinized (i.e., monoamine-depleted) rats were studied. Results. The present data demonstrate that R-(+)-8-OHDPAT significantly increased locomotor activity in monoamine-depleted animals at a dose as low as 0.01 mg/kg. The partial 5-HT sub(1A) agonist/D2 antagonist buspirone (3 mg/kg) also elevated locomotor activity. The effects of these 5-HT sub(1A) compounds were found to be similar to the locomotor-stimulating effect of the dopamine precursor 3,4-dihydroxyphenylalanine (150 mg/kg, 15 min after 50 mg/kg benserazide). The 5-HT sub(1A) antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-cyclo hexanecar box maleate (WAY 100635; 0.2 mg/kg) blocked the R-(+)-8-OHDPAT (0.03 mg/kg)-mediated increase in locomotion. Blockade of 5-HT synthesis with DL-p-chlorophenylalanine (pCPA), a tryptophan hydroxylase inhibitor, prior to reserpinization did not affect R-(+)-8-OHDPAT-induced locomotion. Conclusions. The present data indicate that R-(+)-8-OHDPAT can increase motor activity in monoamine-depleted rats through postsynaptic 5-HT sub(1A) receptors and not necessarily through 5-HT sub(1A) autoreceptor-mediated alterations in 5-HT synthesis and release. A potential mechanism of 5-HT sub(1A)-mediated modulation of non-monoaminergic motor circuits in the brain is discussed. Taken together, the results suggest that 5-HT sub(1A) agonists would provide a novel approach to the amelioration of antipsychotic-induced side effects and the symptomatic treatment of Parkinson's disease