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.
Freedland
Cory S
CS
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.
Whitlow
Christopher T
CT
Miller
Mack D
MD
Porrino
Linda J
LJ
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