RITANSERIN POTENTIATES THE STIMULATORY EFFECTS OF RACLOPRIDE ON NEURONAL-ACTIVITY AND DOPAMINE RELEASE SELECTIVELY IN THE MESOLIMBIC DOPAMINERGIC SYSTEM

The atypical profile of clozapine and some other new atypical antipsyc hotic drugs has been attributed to a relatively selective effect on th e mesolimbic dopaminergic system, as well as to their potent serotonin 5-HT2 receptor antagonism and high ratio of 5-HT2 to dopamine D-2 rec eptor affinities. It is unclear, however, how concurrent 5-HT2 and D-2 receptor antagonism specifically affects the mesoaccumbens and the me socortical dopaminergic systems. The present study examined the effect of pretreat ment with the 5-HT2 receptor antagonist, ritanserin, on c hanges in midbrain dopamine neuronal activity as well as in forebrain, extracellular concentrations of dopamine, induced by relatively low d oses of the D-2 receptor antagonist raclopride, utilizing in vivo extr acellular single cell recording techniques and voltammetry in anesthet ized rats, as well as microdialysis in freely moving rats, Raclopride alone (10-2560 mu g/kg, i.v.) induced a dose-dependent increase in thr ee parameters of neuronal activity, i.e. burst firing, firing rate and variation coefficient, of midbrain DA neurons. This effect of raclopr ide was more pronounced in cells of the ventral tegmental area than in cells of the substantia nigra-zona compacta. Ritanserin alone (1.0 mg /kg, i.v.) also increased all three parameters of neuronal activity in dopamine cells of the ventral tegmental area, but only firing rate in the cells of the substantia nigra. Ritanserin pretreatment (30 min) s ignificantly enhanced the stimulatory effects of low doses of raclopri de (10-20 mu g/kg) on burst firing in dopamine neurons, preferentially in the ventral tegmental area. Raclopride alone (50 mu g/kg, s.c.) in creased extracellular concentrations of dopamine in the medial prefron tal cortex and the dorsolateral striatum by 75 and 110%, respectively, as measured by microdialysis. Ritanserin alone (1.5 mg/kg, s.c.) did not significantly affect cortical and striatal extracellular dopamine concentrations; however, pretreatment (40 min) with ritanserin elevate d the raclopride-induced increase of dopamine concentrations in the me dial prefrontal cortex to about 250%, but failed to affect the action of raclopride on striatal dopamine levels. Raclopride alone (10 and 32 0 mu g/kg, i.v.) dose-dependently increased extracellular concentratio ns of dopamine in the nucleus accumbens and the dorsolateral striatum to about 500%, as determined by voltammetry. Ritanserin alone (1.0 mg/ kg, i.v.) did not significantly affect the voltammetric dopamine signa l in the nucleus accumbens or the dorsolateral striatum; however, rita nserin pretreatment (30 min) enhanced the raclopride-induced increase in accumbal but not striatal dopamine concentrations to about 1600%. T he stimulatory effect of the combined ritanserin plus raclopride treat ment on neuronal activity and DA release was more pronounced in the me solimbic than the nigrostriatal dopaminergic system. The present data indicate that concurrent 5-HT2 and D-2 receptor antagonism selectively affects the activity of the mesolimbic dopaminergic system. These fin dings provide an experimental basis for the notion that combined 5-HT2 and D-2 receptor antagonism may underlie the limbic mode of action of at least some atypical antipsychotic drugs and consequently contribut e to their unique therapeutic effects.