Patel_2019_Pharmacol.Biochem.Behav__172758

BACKGROUND: Acetylcholinergic (ACh) neurons interface with the mesolimbic dopamine pathway implicated in addiction, and acetylcholinesterase inhibitors (AChEis) have been shown to reduce the immediate effects of cocaine and amount used. Our study is the first to examine if the safe and low-interaction AChEi rivastigmine (riv) alters the subjective effects produced by cocaine administration. METHODS: Cocaine-dependent subjects were randomized to daily placebo, riv 3mg, or riv 6mg, administered inpatient for 10days. On day 1 (pre-dose) and day 9, subjects received both IV cocaine 40mg or placebo in a randomized order with subsequent serial assessments of visual analog scale (VAS) subjective effects and pharmacokinetic measurements. On day 10 all participants received one baseline dose of cocaine 20mg with assessment of subjective effects, and were then able to purchase additional doses at 15min intervals with study earnings. RESULTS: 40 subjects were randomized to placebo (n=16), riv 3mg (n=13), or riv 6mg (n=12). All subjects completed the study and there were no demographic differences between treatment groups. Pre- and post- treatment, there were no significant pharmacokinetic differences (blood levels of cocaine, BE, EME) following cocaine administration. In a two-way ANOVA, IV cocaine significantly increased positive VAS category ratings compared to placebo, but rivastigmine treatment at either dose had no significant effect on any VAS category ratings. Similarly, there was no significant rivastigmine effect on any category in the day 10 cocaine administration, and no effect on number of subsequent doses participants purchased. CONCLUSION: Rivastigmine 3 or 6mg had no significant effect on the subjective effects of cocaine after 9days of treatment. This is an important finding as other drugs in the AChEi class (donepezil, Huperzine A) have produced significant results, but differ in their receptor specificity and PK parameters.