Naunyn-Schmiedeberg's Arch Pharmacol (1995) 352:374-385 © Springer-Verlag 1995 J.L. Andersson - G.G. Nomikos - M. Marcus P. Hertel • J.M. Mathb • T.H. Svensson Ritanserin potentiates the stimulatory effects of raclopride on neuronal activity and dopamine release selectively in the mesolimbic dopaminergic system Received: 17 October 1994/Accepted: 1 June 1995 Abstract The atypical profile of clozapine and some other new atypical antipsychotic drugs has been at- tributed to a relatively selective effect on the mesoli- mbic dopaminergic system, as well as to their potent serotonin 5-HT2 receptor antagonism and high ratio of 5-HT2 to dopamine D2 receptor affinities. It is unclear, however, how concurrent 5-HT2 and D2 receptor an- tagonism specifically affects the mesoaccumbens and the mesocortical dopaminergic systems. The present study examined the effect of pretreat- ment with the 5-HT2 receptor antagonist, ritanserin, on changes in midbrain dopamine neuronal activity as well as in forebrain, extracellular concentrations of dopamine, induced by relatively low doses of the D2 receptor antagonist raclopride, utilizing in vivo extracellular single cell recording techniques and vol- tammetry in anesthetized rats, as well as microdialysis in freely moving rats. Raclopride alone (10-2560 gg/kg, i.v.) induced a dose-dependent increase in three para- meters of neuronal activity, i.e. burst firing, firing rate and variation coefficient, of midbrain DA neurons. This effect of raclopride 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 (30min) significantly en- hanced the stimulatory effects of low doses of raclopr- ide (10-20 gg/kg) on burst firing in dopamine neurons, preferentially in the ventral tegmental area. Raclopride alone (50 gg/kg, s.c.) increased extracellular concentra- tions of dopamine in the medial prefrontal cortex and the dorsolateral striatum by 75 and 110%, respectively, J.L. Andersson • G.G. Nomikos • M. Marcus. P. Hertel J.M. Math~ ' T.H. Svensson( ~ ) KarolinskaInstitute, Departmentof Physiology and Pharmacology, Division of Pharmacology,S-17177 Stockholm,Sweden as measured by microdialysis. Ritanserin alone (1.5 mg/kg, s.c.) did not significantly affect cortical and striatal extracellular dopamine concentrations; how- ever, pretreatment (40 min) with ritanserin elevated the raclopride-induced increase of dopamine concentra- tions in the medial prefrontal cortex to about 250%, but failed to affect the action of raclopride on striatal dopamine levels. Raclopride alone (10 and 320 gg/kg, i.v.) dose-dependently increased extracellular concen- trations 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 signal in the nucleus accumbens or the dorsolateral striatum; however, ritanserin pretreatment (30 min) enhanced the raclopride-induced increase in accumbal but not stri- atal dopamine concentrations to about 1600%. The stimulatory effect of the combined ritanserin plus rac- lopride treatment on neuronal activity and DA release was more pronounced in the mesolimbic than the nig- rostriatal dopaminergic system. The present data indicate that concurrent 5-HT2 and D2 receptor antagonism selectively affects the acti- vity of the mesolimbic dopaminergic system. These findings provide an experimental basis for the notion that combined 5-HT2 and D2 receptor antagonism may underlie the limbic mode of action of at least some atypical antipsychotic drugs and consequently contri- bute to their unique therapeutic effects. Key words Antipsychotics Mesolimbic • Medial prefrontal cortex - Dopamine • Serotonin • Electrophysiology - Microdialysis - Voltammetry Introduction The atypical antipsychotic drug clozapine has been reported to have superior efficacy in schizophrenia, decreasing both positive and negative symptoms while