VoL 243, No.3 Printedin U.S.A. 1027 0022.3565/87/2433-1027$02.00/0 THE JOURNAL OP PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS CopyrightO 1987 by The American Society for Pharmacology and Experimental Therapeutics Behavioral and Neurochemical Responses to Haloperidol and SCH-23390 in Rats Treated Neonatally or as Adults with 6- Hydroxydopamine1 GARY E. DUNCAN, HUGH E. CRISWELL, THOMAS J. McCOWN, IAN A. PAUL, ROBERT A. MUELLER AND GEORGE R. BREESE BlologicalSciences Research Center and Mental Health Clinical Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina Accepted forpublicationSeptember 14, 1987 ABSTRACT Behavioral and neurochemical effects of haloperidol (D2-dopa- mine antagonist) and SCH-23390(D1-dopamine antagonist) were examined in unlesioned rats and in rats lesioned with 6-hydroxy- dopamine (6-OHDA) as adults or as neonates. In unlesioned rats, chronic haloperidol treatment (1 5 days) resulted in an increase in D-dopamine receptor density, as measured with HJspipe- rone, in the nucleus accumbens and in the caudate-putamen. Rats treated as adults with 6-OHDA responded to chronic halo- peridol similarly to controls. However, adult rats treated with 6- OHDA as neonates did not exhibit an increase in [3H]spiperone binding in response to chronic halopendol treatment. Control and adult 6-OHDA-treated rats given haloperidol exhibited a profound akinesia. In contrast, rats that received 6-OHDA as neonates and were tested as adults did not display a significant behavioral response to haloperidol at doses as high as 2 mg/kg. Results similar to those for halopendol were also found for SCH-23390. Chronic treatment (1 5 days) with this D1-dopamine antagonist increased [3H]SCH-23390 binding in the nucleus accumbens and caudate-putamen in unlesioned rats as well as in adult 6-OHDA- treated rats. However, after neonatal 6-OHDA treatment, an elevation in [3HJSCH-23390 binding did not occur after chronic SCH-23390 treatment. SCH-23390 produced akinesia similar to that produced by haloperidol in unlesioned and in adult 6-OHDA- treated rats. In contrast, rats lesioned with 6-OHDA as neonates and tested as adufts did not exhibit a significant behavioral response to SCH-23390 under our test conditions. The results indicate that destruction of dopamine-containing neurons in neo- nates, but not in adults, is accompanied by neural adaptation that makes rats refractory to acute and chronic effects of D1- and D-dopamine receptor blockade, providing further documen- tation for the hypothesis that the age at which dopamine-con- taming neurons are destroyed results in different adaptive re- sponses. The sensitivity of neurotransmitter receptors may be modu- lated by variations in the degree to which they are activated. Functional supersensitivity of dopamine receptors has been demonstrated to occur by reducing dopamine innervation via lesions and after chronic treatment with dopamine antagonists. After unilateral 6-OHDA lesions of the substantia nigra, the caudate-putamen ipsilateral to the lesion becomes supersensi- tive to effects of dopamine agonists and exhibits an increased density of D2-dopamine antagonist binding sites relative to the intact side (Creese et at., 1977; Staunton et at., 1981). Rats given 6-OHDA intracisternally, thereby destroying dopamine neurons bilaterally, also display a behavioral supersensitivity to dopamine agonists (Breese et at., 1984, 1985a,b, 1987). How- ever, the functional supersensitivity that results from such bilateral destruction of dopaminergic neurons is not accom- Received for publication June 14, 1987. 1This work was supported in part by U.S. Public Health Service Grants HD- 03110, MH-33127 and NS-21345. panied by an increased density of D1- or D2-dopamine antago- nist binding in the caudate-putamen or nucleus accumbens (Breese et al., 1987). In the present study, we examined the effects of intracisternal injections of 6-OHDA, alone or in combination with chronic haloperidol (a D2-dopamine antagonist), or chronic SCH-23390 (a D1 antagonist), on D1- and D2-dopamine receptor binding in the nucleus accumbens and caudate-putamen. The purpose of this investigation was to determine whether destruction of dopaminergic neurons would alter the adaptive increase in dopamine receptor density that results from chronic pharma- cologic antagonism of these receptors. Previous work (Breese et at., 1984, 1985a,b, 1987) has demonstrated differential effects of 6-OHDA lesions on the functional sensitivity to D1- and D2- receptor agonists, depending on the age at which the neurotoxin is administered. Therefore, the present studies were performed in adult and neonatally 6-OHDA-lesioned rats to determine whether 6-OHDA administration at different developmental ABBREVIATiON: 6-OHDA, 6-hydroxydopamine. at Univ of Mississippi Med Ctr Rowland Med Lib on April 30, 2013 jpet.aspetjournals.org Downloaded from