Dose-dependent effects of Delta9-tetrahydrocannabinol on rates of local cerebral glucose utilization in rat.
Recent reports have demonstrated that Delta(9)-tetrahydrocannabinol (Delta(9)-THC) stimulates locomotor activity at low doses (<2.5 mg/kg), while higher doses (>2.5 mg/kg) produce decreases in spontaneous activity. Using quantitative 2-[(14)C]deoxyglucose (2-DG) autoradiography, we systematically studied the effects of acute Delta(9)-THC on rates of local cerebral glucose utilization. The first series of experiments was designed to determine if Delta(9)-THC-mediated changes in cerebral metabolism followed a clear dose-response relationship. Adult male Sprague-Dawley rats were treated with either vehicle or Delta(9)-THC (0.25-2.5 mg/kg) and the 2-DG procedure was initiated 15 min following exposure. Administration of 2.5 mg/kg Delta(9)-THC produced significant decreases in cerebral metabolism in most brain regions studied. In contrast, administration of 0.25 mg/kg Delta(9)-THC produced no significant alterations in any brain region studied, while 1.0 mg/kg of Delta(9)-THC produced a restricted pattern of metabolic decreases. Significant decreases in metabolism following 1.0 mg/kg were concentrated in structures subserving limbic and sensory functions. In a second series of experiments, the effects of pretreatment with the cannabinoid receptor antagonist SR141716A (1.0 mg/kg) on Delta(9)-THC-induced changes in functional activity were measured. Pretreatment with SR141716A attenuated the majority of functional changes produced by Delta(9)-THC, suggesting that these effects are primarily mediated by central cannabinoid receptors. Moreover, these findings indicate that the effects of Delta(9)-THC on cerebral metabolism are dose-dependent and that there are regional differences in the metabolic response to acute cannabinoid exposure.
Center for the Neurobiological Study of Drug Abuse, Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
Cory S
CS
Freedland
Christopher T
CT
Whitlow
Mack D
MD
Miller
Linda J
LJ
Porrino
D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D008297:Male; D010147:Pain Measurement; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism; D000077285:Rimonabant
D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D013759:Dronabinol; D005947:Glucose; D000077285:Rimonabant