The intersection of metyrapone, inhibitory neurosteroids and cocaine addiction

Although systematic research into cocaine addiction has continued for more than 30 years, there is still no FDA-approved pharmacological treatment. Several compounds which potentiate GABA-induced inhibitory currents can also decrease stress, anxiety and addiction-related behaviors. Because of the well-established connection between stress and addiction, compounds which reduce stress-induced responses could be efficacious in treating addiction. Endogenous neurosteroids such as allopregnanolone may function similarly to benzodiazepines to reduce HPA axis activation and anxiety following stressful stimuli. These neurosteroids have the potential to modulate GABAA receptors and have been implicated in ethanol dependence, although their role in cocaine addiction is largely unknown. We hypothesized that exogenously applied neurosteroids would be able to reduce cocaine-seeking and -taking behaviors as measured by a cue-induced reinstatement model and a self-administration model, respectively. Both allopregnanolone and R6305-7 reduced cocaine-seeking behavior; however neither steroid selectively affected cocaine self-administration. These data suggest that neurosteroids may show efficacy in reducing relapse to cocaine use. Research in our lab has focused on decreasing cocaine self-administration using metyrapone, an 11 beta-hydroxylase inhibitor, which blocks the production of corticosterone. Other researchers have found that metyrapone can increase the biosynthesis of neurosteroids such as THDOC and allopregnanolone. Recent data in our laboratory suggested that metyrapone's effects on cocaine self-administration are not dependent on plasma corticosterone. By using bicuculline (GABA A receptor antagonist) and finasteride (neurosteroid biosynthesis inhibitor), these experiments demonstrate that GABAA-active neurosteroids contribute to metyrapone's effects on cocaine-related behaviors. A newly characterized peptide transmitter, Neuropeptide S, is also known to modulate HPA axis activation. Recent publications suggest that blockade of the Neuropeptide S receptor could decrease cocaine-motivated behaviors. These experiments demonstrate that an antagonist of the Neuropeptide S receptor decreases cocaine self-administration and reinstatement. Overall, the experiments presented in this dissertation support the role of novel neuromodulators like neurosteroids and Neuropeptide S in cocaine-related behaviors in rat.