Alterations in the density of
dopamine receptor subtypes and behaviors mediated by the D1-selective agonist
SKF-38393 were examined in rats treated chronically with
reserpine,
SKF-38393 or the combination of these drugs. Animals received either vehicle or
reserpine (1 mg/kg s.c.) on days 1 to 28 and, in addition, half of each of these groups were treated with vehicle and half were treated with
SKF-38393 (5-10 mg/kg s.c.) on days 15 to 29. Quantitative autoradiographic measurement of D1 receptors labeled with [3H]
SCH-23390 and D2 receptors labeled with [3H]
spiroperidol revealed that chronic administration of
reserpine increased the density of both receptor subtypes in the nucleus accumbens and caudate-putamen, but not in the substantia nigra. Chronic administration of
SKF-38393 alone did not alter D1 receptor density in any of these regions. However, chronic administration of the agonist in reserpinized animals decreased D1 receptor density in the nucleus accumbens, but not in the caudate-putamen or substantia nigra, demonstrating that this partial agonist can selectively down-regulate D1 receptors when endogenous dopaminergic tone is removed. The chronic
drug treatments also altered behavioral responses. Chronic administration of
SKF-38393 alone produced sensitization of the
oral dyskinesia response elicited by a challenge injection of the agonist, but no significant change in the grooming response. Acute administration of
SKF-38393 in rats treated with
reserpine for 14 days produced stereotypy which was not altered after chronic administration of the agonist. Surprisingly, chronic administration of
reserpine alone produced a spontaneous
oral dyskinesia, which was blocked dose-dependently by the D2-selective antagonist
spiroperidol. These findings are discussed in terms of their relevance to
Parkinson's disease and
tardive dyskinesia.