Chronic administration of a selective dopamine D-2 agonist: factors determining behavioral tolerance and sensitization

The locomotor stimulant effects of sustained administration of a potent and selective dopamine (DA) D-2 receptor agonist, [+]-4-propyl-9-hydroxynaphthoxazine (PHNO), in rats were assessed 24 h a day during 12 h light-dark cycles. PHNO was administered continuously with subcutaneous implants of Alzet osmotic minipumps (5 g/h), for 12 h a day with modified osmotic minipumps (5 g/h), or by daily injections (15 g, SC). Tolerance was observed to occur only with 24 h continuous infusions and only during the light period. The other treatment regimens produced sensitization of the locomotor response. Daytime tolerance to continuous infusions of PHNO was reversed following reversal of the light-dark cycle. A normally arousing stimulus also reversed (temporarily) daytime tolerance. The present results indicate that the temporal pattern of administration of DA agonists, the phase of the circadian cycle and environmental stimuli associated with arousal are important determinants of the behavioral consequences of long-term treatment.