title: Antipsychotic drug-induced increases in ventral tegmental area dopamine neuron population activity via activation of the nucleus accumbens-ventral pallidum pathway.
abstract: Acute administration of antipsychotic drugs increases dopamine (DA) neuron activity and DA release via D2 receptor blockade. However, it is unclear whether the DA neuron activation produced by antipsychotic drugs is due to feedback from post-synaptic blockade or is due to an action on DA neuron autoreceptors. This was evaluated using two drugs: the first-generation antipsychotic drug haloperidol that has potent D2 blocking properties, and the second-generation drug sertindole, which is unique in that it is reported to fail to reverse the apomorphine-induced decrease in firing rate typically associated with DA neuron autoreceptor stimulation. Using single-unit extracellular recordings from ventral tegmental area (VTA) DA neurons in anaesthetized rats, both drugs were found to significantly increase the number of spontaneously active DA neurons (population activity). Apomorphine administered within 10 min either before or after sertindole reversed the sertindole-induced increase in population activity, but had no effect when administered 1 h after sertindole. Moreover, both sertindole- and haloperidol-induced increase in population activity was prevented when nucleus accumbens feedback was interrupted by local infusion of the GABAA antagonist bicuculline into the ventral pallidum. Taken together, these data suggest that antipsychotics increase DA neuron population activity via a common action on the nucleus accumbens-ventral pallidum-VTA feedback pathway and thus provide further elucidation on the mechanism by which antipsychotic drugs affect DA neuron activity. This provides an important insight into the relationship between altered DA neuron activity and potential antipsychotic efficacy.
authors.affiliation: Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA. valenti@pitt.edu
authors.forename: Ornella
authors.initials: O
authors.lastname: Valenti
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Grace
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D001058:Apomorphine / Q000008:administration & dosage / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004347:Drug Interactions; D055724:Electrophysiological Phenomena; D007093:Imidazoles / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D007211:Indoles / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D009434:Neural Pathways / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000502:physiology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000502:physiology*; D011975:Receptors, Mitogen / Q000502:physiology*; D012559:Schizophrenia / Q000188:drug therapy / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000502:physiology / Q000601:surgery
chemical_list: D014150:Antipsychotic Agents; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D007093:Imidazoles; D007211:Indoles; D011954:Receptors, Dopamine; D011975:Receptors, Mitogen; C034433:pallidin receptor; C066304:sertindole; D001058:Apomorphine; D004298:Dopamine