Pharmacological Characteristics of Hyperambulation Induced by the Sigma Ligand (+)-3-PPP in Rats

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(+)-3-(3-Hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3-PPP), a sigma ligand, at doses above 3 mg/kg (s.c.) increased the ambulatory activity of rats, while the (-) isomer of 3-PPP with low affinity for sigma receptors, did not significantly modify the ambulatory activity at 10 and 30 mg/kg (s.c.). The ambulation-increasing effect of (+)-3-PPP was prevented by the sigma receptor antagonists BMY 14802 and rimcazole or the sigma/dopamine D2 antagonist haloperidol. The (+)-3-PPP effect was also attenuated by pretreatment with the monoamine depletor reserpine or the tyrosine hydroxylase inhibitor α-methyltyrosine, but was not affected by the tryptophan hydroxylase inhibitor p-chlorophenylalanine. Moreover, the (+)-3-PPP effect was antagonized by the dopamine D2 antagonist sulpiride, whereas pretreatment with the 5-HT1A agonist 8-OH-DPAT and the a-adrenoceptor antagonist phenoxybenzamine did not exert any significant effect. These results indicate that sigma receptors are involved in the neuronal mechanism(s) of hyperambulation induced by (+)-3-PPP, and the sigma system may exert both a presynaptic action and a dopamine D2 receptor-mediated action to increase the central dopaminergic function.