The role of dopamine, nicotine acetylcholine, opioid and sigma receptors in ketamine self -administration and reward

The rewarding effects of ketamine were postulated to involve dopaminergic neural tracts modulated by nicotinic, sigma, or opioid receptor mechanisms. In support of the hypothesized involvement of dopamine, an increase in extracellular dopamine was detected in the nucleus accumbens using electrochemical chronoamperometry following intravenous ketamine self-administration. When rats were permitted unlimited access to ketamine via self-administration, a greater concentration of dopamine, was detected in the nucleus accumbens; than was detected when self-administration was limited. In a subsequent set of experiments, the effects of agonists or antagonists of dopaminergic nicotinic, sigma, or opioid receptors were examined for their effect on ketamine self-administration. Decreases in the rate of self-administration following treatment were interpreted to represent an increase in rewarding effect, whereas increases in self-administration were interpreted as a decrease in rewarding effect. The rate of self-administration was diminished when the sigma antagonist, BMS 181-100, was administered intraperitoneally prior to ketamine self-administration sessions, but intravenous BMS 181-100 would not substitute for ketamine in the self-administration design. A decrease in the rate of ketamine self-administration occurred following intraperitoneal (i.p.) administration of: ketamine, SCH23390 (a D1 receptor antagonist), naloxonazine (a mu opioid receptor antagonist), and mecamylamine, a central nicotinic acetylcholine receptor antagonist. An increase in the rate of ketamine self-administration followed nicotine and dihydrexidine (a D1 receptor agonist) intraperitoneal injection. In previous studies, published in the literature, SCH23390 increased the rate of self-administration of amphetamines and cocaine, indicating a competitive effect on drug reward. However, the current studies indicate that the rewarding effects of ketamine were facilitated by SCH23390. The results are consistent with the hypothesis that the rewarding effects of ketamine are mediated through dopaminergic neural pathways. The rewarding effects of ketamine may be modulated, in an inhibitory fashion, via sigma receptors, presynaptic D1 receptors, nicotinic acetylcholine receptors, and/or mu opioid receptors. Ligands at nicotinic acetylcholine and dopamine receptors yielded effects opposite to that hypothesized based on their ability to modulate the rewarding effects of other abused chemicals.