82 Neuroscience Letters, 96 (1989) 82 88 Elsevier Scientific Publishers Ireland Ltd. NSL 05808 Acute haloperidol administration induces depolarization block of nigral dopamine neurons in rats after partial dopamine lesions Jeffrey R. Hollerman and Anthony A. Grace Departments of Behavioral Neuroscienceand Psychiatry, Center for Neuroseience, University of Pittsburgh, Pittsburgh, PA (U.S.A.) (Received 16 June 1988; Revised version received 9 August 1988; Accepted 13 September 1988) Key words." Dopamine; Neuroleptic; Haloperidol; 6-Hydroxydopamine; Parkinson's disease; Substantia nigra; Electrophysiology; Dopamine neuron The effects of the antipsychotic drug haloperidol (HAL) on the electrophysiological activity of do- pamine (DA)-containing cells in the substantia nigra was assessed in rats 6 weeks after partial 6-hydroxy- dopamine (6-OHDA)-induced lesions of the nigrostriatal DA pathway. Depleting 75% or more of striatal DA altered the response of DA neurons to acute HAL administration. Whereas acute HAL administration generally accelerates DA neuron firing in control rats, similar HAL doses given to lesioned rats not only increased firing rate but induced depolarization block of DA neuron spike generation similar to that result- ing from chronic neuroleptic administration. In contrast, acute administration of doses of HAL up to le- thal levels typically could not induce depolarization block of DA neurons in non-lesioned rats. This prepa- ration thus could be an effective model for investigating the exacerbation of behavioral deficits produced by an increased demand placed upon a compromised DA system, as may occur in Parkinson's disease or with antipsychotic drug treatment. Dopamine is thought to play a major role in schizophrenia, in part due to the ob- servation that all neuroleptic drugs which show clinical efficacy in the treatment of schizophrenia also block DA receptors [cf. 25]. Although neuroleptics, such as HAL, block DA receptors shortly after administration, weeks of treatment typically are required for therapeutic efficacy to occur [2, 7, 22]. Recordings from DA neurons in rats have provided a possible insight into this phenomenon. Thus, whereas acute administration of HAL will increase the rate of DA neuron firing [4], 3 weeks of treatment instead produces an inactivation of the spontaneous activity of these neu- rons [3]. This inactivation may also be related to neuroleptic-induced extrapyramidal side effects, since chronic treatment with classic neuroleptics, which are effective in treating schizophrenia but often cause extrapyramidal side effects, inactivate DA Correspondence: A.A. Grace, Departments of Behavioral Neuroscience and Psychiatry, Center for Neu- roscience, University of Pittsburgh, Pittsburgh, PA 15260, U.S.A. 0304-3940/89/$ 03.50 O 1989 Elsevier Scientific Publishers Ireland Ltd.