Augmentation of Regional Cerebral Blood Flow Response by Repeated Administration of Methamphetamine in Rats

The purpose of this study was to observe the regional cerebral blood flow (rCBF) response to the methamphe-tamine challenge test in rats subjected to repeated administration of methamphetamine, and to investigate the mechanism (s) underlying the changes in rCBF response in relation to the dopaminergic receptors and cyclic AMP. Male Sprague-Dawley rats received daily injections of methamphetamine (0.3 mg/kg, i.p.) for 10 days and were then allowed a 4-day drugfree period. Naive and methamphetamine-pretreated rats were challenged with topical application of methamphetamine on the surface of the parietal cortex through a cranial window. The changes in rCBF were measured by laser-Doppler flowmetry. Acute topical application of methamphetamine concentration-dependently increased rCBF with little effect on mean arterial blood pressure. The methamphetamine-induced increases in rCBF were significantly blocked by SCH23390, a D1-like receptor antagonist, but not by sulpiride, a D2-like receptor antagonist. Repeated administration of methamphetamine induced progressive augmentation of the rCBF in response to the methamphetamine challenge. Repeated administration of methamphetamine in combination with SKF38393, a D1-like receptor agonist, as well as with SCH23390 significantly attenuated the augmentation of the rCBF response to methamphetamine. The augmentation of the rCBF response was markedly inhibited by pretreatment with both 2’,3’-dideoxyadenosine, a specific adenylyl cyclase inhibitor, and by Rp-cAMPS, a protein kinase A inhibitor. These results suggest that repeated methamphetamine administration induces an augmentation of the rCBF in response to methamphetamine challenge, and D1-like receptor-mediated cyclic AMP plays a critical role in the development of methamphetamine-induced rCBF response augmentation.