Prazosin modulates the changes in firing pattern and transmitter release induced by raclopride in the mesolimbic, but not in the nigrostriatal dopaminergic system

Abstract

Most antipsychotic drugs are, in addition to being dopamine (DA) D2 receptor antagonists, also relatively potent alpha 1 adrenoceptor antagonists. Here, we have studied the effects of the selective DA D2 receptor antagonist raclopride, alone and in combination with the selective alpha 1 adrenoceptor antagonist, prazosin, on midbrain DA neurons utilizing extracellular single cell recording techniques. As a reference compound, haloperidol (0.05-1.6 mg/kg, i.v.), a potent antagonist at both DA D2 receptors and alpha 1 adrenoceptors, was included in the electrophysiological part of the study. In addition, in vivo voltammetry was used to measure extracellular DA concentrations in the nucleus accumbens (NAC) and the dorsolateral striatum (STR) in anesthetized, pargyline pretreated rats treated with the above drugs. Raclopride (10-5120 micrograms/kg, i.v.) induced a dose dependent increase in firing rate of DA neurons in the ventral tegmental area (VTA), that was significant already at 10 micrograms/kg, and in the substantia nigra-zone compacta (SN-ZC), that reached significance at 2560 micrograms/kg. Burst firing of DA neurons was also increased in the VTA at 40 micrograms/kg, as well as in the SN-ZC at 640 micrograms/kg. A low dose of raclopride (80 micrograms/kg, cumulated dose) induced a significant increase in extracellular DA concentrations in NAC to 490% and in STR to 220%. A high dose of raclopride (2560 micrograms/kg, cumulated dose) induced a 930% increase in extracellular DA concentrations in NAC, but only a 280% increase in STR. These data demonstrate that raclopride exerts a relatively selective action on mesolimbic DA neurons. Prazosin (0.3 mg/kg, i.v.) decreased burst firing of VTA, but not SN-ZC DA neurons.(ABSTRACT TRUNCATED AT 250 WORDS)