IV nicotine self-administration in rats using a consummatory operant licking response: Sensitivity to serotonergic, glutaminergic and histaminergic drugs

Abstract

Tobacco smoking is characterized by repeated self-administration of nicotine by placing the cigarette in the mouth. The repeated hand-to-mouth self-administration is essentially a consummatory act. We recently developed a paradigm in which rats lick one of two spouts to trigger intravenous (IV) delivery of nicotine, which combines a consummatory act with rapid delivery of nicotine to model the act of tobacco smoking. We have found that rats will lick hundreds of times per nicotine infusion. In the current study, using the operant licking nicotine self-administration model with young adult Sprague-Dawley rats (0.03 mg/kg/infusion of nicotine), we tested the effect of antagonists of H1 histamine receptors pyrilamine, serotonin (5HT) type 2 receptors ketanserin and lorcaserin and N-methyl-D-aspartate (NMDA) glutamate receptors with D-cycloserine in dose ranges that we have found in previous studies to significantly reduce IV nicotine self-administration with the operant lever press operand. The H1 antagonist pyrilamine significantly reduced operant licking for nicotine self-administration. Pyrilamine caused significant reductions in the operant licking paradigm at lower doses (10 and 20 mg/kg) than those we previously observed to affect responding in the operant lever press paradigm. In contrast, the 5HT2A and C antagonist ketanserin did not show an effect of reducing nicotine self-administration in the same dose range we had found in a previous study to significantly reduce operant lever press nicotine self-administration. The 5HT2C agonist lorcaserin significantly decreased nicotine self-administration in the licking paradigm at the same dose threshold as with lever press responding. The NMDA glutamate partial agonist D-cycloserine did not produce any change in nicotine self-administration with the licking operand, in contrast to its effect on the classic lever-pressing task. The rat model incorporating consummatory aspects of tobacco addiction can provide distinct and potentially more relevant information concerning possible new avenues of treatment to combat tobacco addiction.

Rats quit nicotine for a sweet reward following an extensive history of nicotine use

“…). For example, conditioned sensory cues associated with the ingestion of nicotine in humans are essential for the development of tobacco dependence (Rose & Levin ) and can promote nicotine‐seeking in rats (Cousins, Rose & Levin ). Such oral consummatory cues are also present with the ingestion of saccharin by rats but are absent when nicotine is delivered intravenously.…”

Reduction of nicotine self-administration by chronic nicotine infusion with H1 histamine blockade in female rats

“…Our research has previously shown that systemic administration of pyrilamine, an histamine H1 receptor antagonist, reduces nicotine self-administration in rats (Levin et al 2011c); (Cousins et al 2014). The rationale for targeting H1 receptors arose from the finding that the antipsychotic drug clozapine reduces smoking in schizophrenic patients (McEvoy et al 1995).…”

Choice between delayed food and immediate opioids in rats: treatment effects and individual differences

“…Third, we tested the effects of the serotonin 5-HT 2C receptor agonist lorcaserin (Smith et al 2008), which is prescribed as a treatment for obesity, but might have anti-addiction effects since it can decrease self-administration of nicotine (Briggs et al 2016; Cousins et al 2014; Higgins et al 2013; Higgins et al 2012; Levin et al 2011), cocaine (Collins et al 2016; Harvey-Lewis et al 2016), methamphetamine (Gerak et al 2016) and oxycodone (Neelakantan et al 2017) in rats. With respect to choice behavior and opioid self-administration, agonists of 5-HT 2C are also interesting because they decrease premature operant responding that is considered a form of impulsivity (Higgins et al 2012; Navarra et al 2008), and they block some effects of opioid administration and withdrawal (Wu et al 2015; Zhang et al 2016).…”