Grant Details: There is a critical need for pharmacological therapeutics to treat stimulant addiction, for which there are no approved drugs. While a common mechanism of action of addictive drugs is to increase dopamine transmission in the brain – for which stimulants such as cocaine and amphetamine are exceptionally effective – dopamine itself is a poor target for addiction treatment due to the numerous side effects, especially on movement and motivation. A growing body of basic and clinical evidence suggests that the GABA-A receptor is a promising target to indirectly regulate dopamine, although key pharmacological studies are lacking. For example, the benzodiazepine diazepam (Valium) can block amphetamine-induced dopamine release and associated behavior. However, benzodiazepines are also poor potential therapeutics to treat addiction, as chronic use can cause significant side effects and dependence. Neurosteroids represent an alternative way to modulate the GABA-A receptor and indirectly regulate dopamine release. Neurosteroids are naturally produced in the brain and have a good safety profile. Thus, the goal of this pilot study is to determine the ability of allopregnanolone, a neurosteroid and GABA-A modulator, to reverse the pharmacological effect of cocaine on dopamine release. Specifically, we will first expose rats to repeated cocaine, inducing typical neuroadaptations associated with stimulant use disorder. Then, we will test whether allopregnanolone can prevent or reduce the cocaine-induced increases in dopamine release in the nucleus accumbens, a brain region important in addiction and reward. We hypothesize that allopregnanolone will dampen or block the effect of cocaine to enhance naturally-occurring dopamine release in rats.
This Foundation of Hope Advanced/Non-Seed Grant will provide key data for a future NIH grant proposal, with the hypothesis that allopregnanolone counteracts the pharmacological effects of cocaine on dopamine release, thereby reducing or preventing the rewarding and reinforcing effects of cocaine. The R01 will test this hypothesis with behavioral studies (cocaine self-administration, “relapse,” reward conditioning) and with mechanistic studies on dopamine release. Specific preliminary data provided by this pilot:
- Whether allopregnanolone reduces spontaneous dopamine transients in awake rats
- Whether allopregnanolone blocks cocaine-induced increases in dopamine transients
- Whether this effect is different in rats with a history of cocaine exposure (pretreatment).