Acetylcholine (ACh) is involved in brain reward and learning functions, and perturbations to this neurotransmitter system may contribute to substance abuse disorders. Animal studies have shown the importance of muscarinic ACh receptors in cocaine reinforced- and non-reinforced-responding, and acetylcholinesterase (AChE) inhibitors reduced methamphetamine-seeking behavior in rodents. Consistent with these findings, a recently completed double-blind placebo-controlled study from our group demonstrated that treatment with the AChE inhibitor rivastigmine reduced craving produced by administration of methamphetamine in the laboratory. In this application, we propose a human laboratory research to evaluate the effects of rivastigmine (3 or 6 mg, daily) or huperzine A (0.4 or 0.8 mg, daily) on craving and reinforcing effects produced by administration of cocaine in cocaine-dependent, non-treatment seeking participants. Rivastigmine is a carbamate derivative that inhibits both AChE and BuChE with equal potency and has selectivity for central activity. Huperzine A is an innovative drug choice for this revised application and is derived from the Chinese herb Huperzia serrata. Huperzine A is a potent cholinesterase inhibitor, and has several other effects in brain (via DA, NMDA and GABA, as well as antioxidant effects and neuroprotection) that may ultimately contribute to its efficacy. In the proposed studies, we will include only participants exhibiting cocaine-induced craving prior to randomization;a strategy predicted to increase statistical power to detect effects of medication treatment on this specific symptom. The public health significance of the proposed project is clear. No medications are currently available for prevention of relapse in patients who are addicted to cocaine, and AChE inhibitors are predicted to be useful for this indication.
No medications are currently available for prevention of relapse in patients who are addicted to cocaine, and acetylcholinesterase inhibitors are predicted to be useful for this indication. To this end, we propose a human laboratory research study to evaluate the effects of rivastigmine or huperzine A on craving and reinforcing effects produced by administration of cocaine.
|Patel, Marguerite M; Nielsen, David A; Kosten, Thomas R et al. (2018) FAAH variant Pro129Thr modulates subjective effects produced by cocaine administration. Am J Addict 27:567-573|
|Patriquin, Michelle A; Hamon, Sara C; Harding, Mark J et al. (2017) Genetic moderation of cocaine subjective effects by variation in the TPH1, TPH2, and SLC6A4 serotonin genes. Psychiatr Genet 27:178-186|
|Mahoney, James J; Kalechstein, Ari D; De Marco, Anthony P et al. (2017) The relationship between premorbid IQ and neurocognitive functioning in individuals with cocaine use disorders. Neuropsychology 31:311-318|
|Shorter, Daryl; Nielsen, David A; Hamon, Sara C et al. (2016) The ?-1 adrenoceptor (ADRA1A) genotype moderates the magnitude of acute cocaine-induced subjective effects in cocaine-dependent individuals. Pharmacogenet Genomics 26:428-35|
|De La Garza 2nd, Richard; Verrico, Christopher D; Newton, Thomas F et al. (2015) Safety and Preliminary Efficacy of the Acetylcholinesterase Inhibitor Huperzine A as a Treatment for Cocaine Use Disorder. Int J Neuropsychopharmacol 19:pyv098|
|Brewer 3rd, Alex J; Nielsen, David A; Spellicy, Catherine J et al. (2015) Genetic variation of the dopamine transporter (DAT1) influences the acute subjective responses to cocaine in volunteers with cocaine use disorders. Pharmacogenet Genomics 25:296-304|
|Mahoney 3rd, James J; Kalechstein, Ari D; Verrico, Christopher D et al. (2014) Preliminary findings of the effects of rivastigmine, an acetylcholinesterase inhibitor, on working memory in cocaine-dependent volunteers. Prog Neuropsychopharmacol Biol Psychiatry 50:137-42|
|Yoon, Jin H; Shah, Ravi S; Arnoudse, Nicholas M et al. (2014) Remote physiological monitoring of acute cocaine exposure. J Med Eng Technol 38:244-50|
|Brewer 3rd, Alex J; Mahoney 3rd, James J; Nerumalla, Chandra S et al. (2013) The influence of smoking cigarettes on the high and desire for cocaine among active cocaine users. Pharmacol Biochem Behav 106:132-6|
|Ross, Elizabeth L; Yoon, Jin H; Mahoney 3rd, James J et al. (2013) The impact of self-reported life stress on current impulsivity in cocaine dependent adults. Prog Neuropsychopharmacol Biol Psychiatry 46:113-9|
Showing the most recent 10 out of 11 publications