A variety of neural systems are involved in nicotine addiction, presenting the opportunity to develop drugs with different mechanisms of action for reducing nicotine self-administration (SA) and enhancing cessation of tobacco use. Previously, we found that drug treatments affecting several different neurotransmitter systems significantly reduce nicotine SA in female rats. However, potential sex-differences in the effects of these drugs on nicotine SA have not yet been characterized. In this study, we compared the effects of a variety of drugs affecting dopamine, serotonin, histamine, norepinephrine and glutamate systems on nicotine SA in both male and female rats. The drugs tested in male and female Sprague-Dawley rats included lorcaserin, a serotonin 5HT2c agonist; SCH-23390, a dopamine D1 antagonist; pyrilamine, a histamine H1 antagonist; dextromethorphan, a glutamate N-methyl-D-aspartate receptor (NMDA receptor) antagonist; and amitifadine, a triple dopamine, norepinephrine and serotonin reuptake inhibitor. We directly compared their efficacy in reducing nicotine SA in male and female rats. In addition, we compared the effects of these drugs by sex with regard to food-motivated responding and locomotor activity. We found that all of the above-mentioned drugs except dextromethorphan (5 mg/kg) significantly decreased nicotine SA in both sexes. There were significant sex differences in the timing of expression of drug effects on nicotine SA across the initial and repeated phases of drug treatment. Male rats showed greater effects after repeated treatment and females showed greater effect during initial treatment. These drugs also reduced food self-administration and locomotor activity. However, notably, amitifadine and pyrilamine produced significantly greater effects in reducing nicotine SA than both food self-administration and locomotor activity. Subtle differential effects between male and female rats were seen with drugs acting on monoaminergic transmitter systems with respect to nicotine self-administration.
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