Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
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Neuropsychopharmacology · Jul 2010
Behavioral characteristics and neural mechanisms mediating performance in a rodent version of the Balloon Analog Risk Task.
The tendency for some individuals to partake in high-risk behaviors (eg, substance abuse, gambling, risky sexual activities) is a matter of great public health concern, yet the characteristics and neural bases of this vulnerability are largely unknown. Recent work shows that this susceptibility can be partially predicted by laboratory measures of reward seeking under risk, including the Balloon Analog Risk Task. Rats were trained to respond on two levers: one of which (the 'add lever') increased the size of a potential food reward and a second (the 'cash-out lever') that led to delivery of accrued reward. ⋯ Rats exhibited a pattern of responding characteristic of incentive motivation and risk aversion, with a subset of rats showing traits of high-risk taking and/or suboptimal responding. Neural inactivation studies suggest that the orbitofrontal cortex supports greater reward seeking in the presence or absence of risk, whereas the medial prefrontal cortex is required for optimization of patterns of responding. These findings provide new information about the neural circuitry of decision making under risk and reveal new insights into the biological determinants of risk-taking behaviors that may be useful in developing biomarkers of vulnerability.
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Neuropsychopharmacology · Jul 2010
FAAH-/- mice display differential tolerance, dependence, and cannabinoid receptor adaptation after delta 9-tetrahydrocannabinol and anandamide administration.
Repeated administration of Delta(9)-tetrahydrocannabinol (THC), the primary psychoactive constituent of Cannabis sativa, induces profound tolerance that correlates with desensitization and downregulation of CB(1) cannabinoid receptors in the CNS. However, the consequences of repeated administration of the endocannabinoid N-arachidonoyl ethanolamine (anandamide, AEA) on cannabinoid receptor regulation are unclear because of its rapid metabolism by fatty acid amide hydrolase (FAAH). FAAH(-/-) mice dosed subchronically with equi-active maximally effective doses of AEA or THC displayed greater rightward shifts in THC dose-effect curves for antinociception, catalepsy, and hypothermia than in AEA dose-effect curves. ⋯ Experiments examining tolerance and cross-tolerance indicated that the behavioral effects of THC, a low efficacy CB(1) receptor agonist, were more sensitive to receptor loss than those of AEA, a higher efficacy agonist, suggesting that the expression of tolerance was more affected by the intrinsic activity of the ligand at testing than during subchronic treatment. In addition, the CB(1) receptor antagonist, rimonabant, precipitated a markedly reduced magnitude of withdrawal in FAAH(-/-) mice treated subchronically with AEA compared with mice treated repeatedly with THC. The findings that repeated AEA administration produces lesser adaptive changes at the CB(1) receptor and has reduced dependence liability compared with THC suggest that pharmacotherapies targeting endocannabinoid catabolic enzymes are less likely to promote tolerance and dependence than direct acting CB(1) receptor agonists.