Differential effects of anesthetics on cocaine's pharmacokinetic and pharmacodynamic effects in brain.

Most studies of the effect of cocaine on brain activity in laboratory animals are preformed under anesthesia, which could potentially affect the physiological responses to cocaine. Here we assessed the effects of two commonly used anesthetics [alpha-chloralose (alpha-CHLOR) and isofluorane (ISO)] on the effects of acute cocaine (1 mg/kg i.v.) on cerebral blood flow (CBF), cerebral blood volume (CBV), and tissue hemoglobin oxygenation (S(t)O(2)) using optical techniques and cocaine's pharmacokinetics (PK) and binding in the rat brain using (PET) and [(11)C]cocaine. We showed that acute cocaine at a dose abused by cocaine abusers decreased CBF, CBV and S(t)O(2) in rats anesthetized with ISO, whereas it increased these parameters in rats anesthetized with alpha-CHLOR. Importantly, in ISO-anesthetized animals cocaine-induced changes in CBF and S(t)O(2) were coupled, whereas for alpha-CHLOR these measures were uncoupled. Moreover, the clearance of [(11)C]cocaine from the brain was faster for ISO (peak half-clearance 15.8 +/- 2.8 min) than for alpha-CHLOR (27.5 +/- 0.6 min), and the ratio of specific to non-specific binding of [(11)C]cocaine in the brain was higher for ISO- (3.37 +/- 0.32) than for alpha-CHLOR-anesthetized rats (2.24 +/- 0.4). For both anesthetics, cocaine-induced changes in CBF followed the fast uptake of [(11)C]cocaine in the brain (peaking at approximately 2.5-4 min), but only for ISO did the duration of the CBV and S(t)O(2) changes correspond to the rate of [(11)C]cocaine's clearance from the brain. These results demonstrate that anesthetics influence cocaine's hemodynamic and metabolic changes in the brain, and its binding and PK, which highlights the need to better understand the interactions between anesthetics and pharmacological challenges in brain functional imaging studies.