Dopamine receptor ‘supersensitivity’ occurring without receptor up-regulation

Abstract

Unilateral 6-hydroxydopamine (6-OHDA)-induced lesions of the substantia nigra have been widely used to study various aspects of dopamine neurobiology, and to screen for antiparkinsonian drugs. This study examined the role of receptor alterations in pharmacological supersensitivity seen in response to lesioning of central dopamine pathways in rats by intracisternal (IC) administration of 6-OHDA (200 μg), as well as by bilateral (BIL) or unilateral (UNI) infusion of 6-OHDA into the substantia nigra (8 μg/side). Both IC and BIL lesions resulted in permanent decreases in dopamine concentration in the striatum, the major terminal projection from the substantia nigra. When challenged with apomorphine (0.3 mg/kg), IC-lesioned rats exhibited bursts of rapid locomotion interspersed by rearing, whereas BIL-lesioned rats displayed intense grooming or gnawing and nose poking of the cage floor; these behaviors were not seen in respective sham (i.e. vehicle)-lesioned rats injected with apomorphine. Scatchard analysis of saturation isotherms of both D 1 ([ 3H]SCH23390 binding sites) and D 2 ([ 3H]spiperone binding sites) dopamine receptors in the striatum revealed no difference in either the maximum number of binding sites (B max), or the dissociation constant (K d) of either receptor type when BIL and IC lesioned rats were compared to appropriate controls. Conversely, the UNI lesioned rats had, under identical conditions of analysis, the expected increase in the density of D 2 receptors on the lesioned side. There was no change in dopamine-sensitive adenylate cyclase activity in the striata of supersensitive IC-lesioned rats, but there was a shift to the left in the dose-response curve in striata from rats bilaterally-lesioned in the substantia nigra, similar to what occurs in UNI lesioned rats. Together, these data clearly demonstrate that although increases in receptor density and changes in cAMP systems are seen in the UNI model, neither mechanism is a requirement for functional supersensitivity in response to 6-OHDA lesions. These data suggest that other cellular events (e.g. alterations in receptor interactions) may play a role in the response to insult, and raise questions about the utility of the unilateral model as a screen for antiparkinsonian drugs.