Effects of Co‐Use of Nicotine on Cocaine‐Food Choice in Socially Housed Female and Male Cynomolgus Monkeys

Abstract

Cocaine use disorder (CUD) continues to be a major public health problem worldwide with 2.0 million Americans reporting current cocaine use. At present there are no FDA‐approved pharmacotherapies for CUD. An important consideration in evaluating mechanisms of CUD and potential treatment strategies is the observation that most individuals suffering from CUD also use tobacco products. However, most preclinical studies investigating cocaine do not include co‐exposure with nicotine. For these studies, socially housed female and male monkeys (N= 5/sex) self‐administered cocaine (saline, 0.001‐0.1 mg/kg/inj) under a concurrent schedule with food (1.0‐g banana‐flavored food pellets) as the alternative reinforcer during daily 1‐hr sessions. Under these conditions, the frequency of cocaine choice increases in a dose‐dependent manner; there were individual‐subject differences in sensitivity, but when nicotine was added to the cocaine solution, we individually chose the highest cocaine dose which resulted in <20% cocaine choice for each monkey. When increasing doses of nicotine (0.01‐0.056 mg/kg/inj) were added to the cocaine solution, non‐reinforcing doses of cocaine were chosen (i.e., >80% drug choice) in 8 of the 10 monkeys; importantly, in no cases were these nicotine doses chosen over food. These data suggest that when a non‐reinforcing dose of nicotine is added to a non‐reinforcing dose of cocaine, drug choice increases to the point that the combination is chosen over the non‐drug alternative. Next, environmental manipulations were studied to determine whether the cocaine+nicotine combination was more resistant to changes than cocaine alone. For these studies, we used a delay discounting procedure similar to that described by Woolverton and colleagues (Huskinson et al., 2015, 2016). We compared the indifference point (IP; 50% choice between cocaine and food) when a preferred dose of cocaine was available vs. food and cocaine was delayed, to the IP value when a lower cocaine dose + nicotine was available vs. food. We found that in each case, the IP value was greater for the cocaine+nicotine combination compared with the cocaine alone choice. These findings suggest (1) that co‐abuse of nicotine and cocaine can potentiate the reinforcing effects of cocaine and (2) that manipulations designed to decrease cocaine choice are less effective under conditions in which co‐use of nicotine is studied. These preliminary studies did not reveal sex differences or effects of social rank. At present, it is not known how nicotine and cocaine interact. One hypothesis is that both drugs together produce entirely novel neurobiological effects compared with either one alone. The behavioral endpoints may look additive, as shown in our preliminary data, but the mechanisms are probably not simply additive. These studies may lead to a more personalized medicine approach to treating CUD.