PRAZOSIN MODULATES THE CHANGES IN FIRING PATTERN AND TRANSMITTER RELEASE INDUCED BY RACLOPRIDE IN THE MESOLIMBIC, BUT NOT IN THE NIGROSTRIATAL DOPAMINERGIC SYSTEM

Most antipsychotic drugs are, in addition to being dopamine (DA) D-2 r eceptor antagonists, also relatively potent alpha(1) adrenoceptor anta gonists. Here, we have studied the effects of the selective DA D-2 rec eptor antagonist raclopride, alone and in combination with the selecti ve alpha(1) adrenoceptor antagonist, prazosin, on midbrain DA neurons utilizing extracellular single cell recording techniques. As a referen ce compound, haloperidol (0.05-1.6 mg/kg, i.v.), a potent antagonist a t both DA D-2 receptors and alpha(1) adrenoceptors, was included in th e electrophysiological part of the study. In addition, in vivo voltamm etry was used to measure extracellular DA concentrations in the nucleu s accumbens (NAC) and the dorsolateral striatum (STR) in anesthetized, pargyline pretreated rats treated with the above drugs. Raclopride (1 0-5120 mu g/kg, i.v.) induced a dose dependent increase in firing rate of DA neurons in the ventral tegmental area (VTA), that was significa nt already at 10 mu g/kg, and in the substantia nigra-zone compacta (S N-ZC), that reached significance at 2560 mu g/kg. Burst firing of DA n eurons was also increased in the VTA at 40 mu g/kg, as well as in the SN-ZC at 640 mu g/kg. A low dose of raclopride (80 mu g/kg, cumulated dose) induced a significant increase in extracellular DA concentration s in NAC to 490% and in STR to 220%. A high dose of raclopride (2560 m u g/kg, cumulated dose) induced a 930% increase in extracellular DA co ncentrations in NAC, but only a 280% increase in STR. These data demon strate that raclopride exerts a relatively selective action on mesolim bic DA neurons. Prazosin (0.3 mg/kg, i.v.) decreased burst firing of V TA, but not SN-ZC DA neurons. Pretreatment with prazosin (15 min) sign ificantly enhanced the increase in firing rate of VTA-DA neurons cause d by raclopride within the 20-160 mu g/kg dose range. The effects of t he pretreatment on raclopride-induced burst firing, on the other hand, was a marked decrease in VTA-DA neurons, while it left the effect of raclopride on SN-ZC DA neurons unaffected. Pretreatment with prazosin also caused a reduction in the raclopride-induced elevation of extrace llular DA concentrations in the NAC, but not in the STR. This effect w as only seen with the high dose of raclopride (2560 mu g/kg). Although haloperidol increased both firing rate and burst firing of neurons in VTA and SN-ZC, the haloperidol-induced increase in burst firing appea red much smaller than that caused by raclopride. Thus, alpha(1) adreno ceptors seem to modulate the effects of DA D-2 receptor antagonism pre ferentially in the mesolimbic DA system.