Dose‐dependent effects of Δ 9 ‐tetrahydrocannabinol on rates of local cerebral glucose utilization in rat

Recent reports have demonstrated that Δ 9 ‐tetrahydrocannabinol (Δ 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 Δ 9 ‐THC on rates of local cerebral glucose utilization. The first series of experiments was designed to determine if Δ 9 ‐THC‐mediated changes in cerebral metabolism followed a clear dose–response relationship. Adult male Sprague‐Dawley rats were treated with either vehicle or Δ 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 Δ 9 ‐THC produced significant decreases in cerebral metabolism in most brain regions studied. In contrast, administration of 0.25 mg/kg Δ 9 ‐THC produced no significant alterations in any brain region studied, while 1.0 mg/kg of Δ 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 Δ 9 ‐THC‐induced changes in functional activity were measured. Pretreatment with SR141716A attenuated the majority of functional changes produced by Δ 9 ‐THC, suggesting that these effects are primarily mediated by central cannabinoid receptors. Moreover, these findings indicate that the effects of Δ 9 ‐THC on cerebral metabolism are dose‐dependent and that there are regional differences in the metabolic response to acute cannabinoid exposure. Synapse 45:134–142, 2002. © 2002 Wiley‐Liss, Inc.