Comparison of effects produced by nicotine and the α4β2-selective agonist 5-I-A-85380 on intracranial self-stimulation in rats.

Abstract

Intracranial self-stimulation (ICSS) is one type of preclinical procedure for research on pharmacological mechanisms that mediate abuse potential of drugs acting at various targets including nicotinic acetylcholine receptors (nAChRs). This study compared effects of the non-selective nAChR agonist nicotine (0.032-1.0 mg/kg) and the α4β2-selective nAChR agonist 5-I-A-85380 (0.01-1.0 mg/kg) on ICSS in male Sprague-Dawley rats. Rats were implanted with electrodes targeting the medial forebrain bundle at the level of the lateral hypothalamus and trained to respond under a fixed-ratio 1 schedule for a range of brain stimulation frequencies (158-56 Hz). A broad range of 5-I-A-85380 doses produced an abuse-related increase (or “facilitation”) of low ICSS rates maintained by low brain-stimulation frequencies, and this effect was blocked by both the nonselective nAChR antagonist mecamylamine and the selective α4β2 antagonist dihyrdo-ß-erythroidine (DHßE). Conversely, nicotine produced weaker ICSS facilitation across a narrower range of doses, and higher nicotine doses decreased high rates of ICSS maintained by high brain- stimulation frequencies. The rate-decreasing effects of a high nicotine dose were blocked by mecamylamine but not DHßE. Chronic nicotine treatment produced selective tolerance to rate-decreasing effects of nicotine but did not alter ICSS rate-increasing effects of nicotine. These results suggest that α4β2 receptors are sufficient to mediate abuse-related rate-increasing effects of nAChR agonists in this ICSS procedure. Conversely, nicotine effects at non-α4β2 nAChRs appear to oppose and limit abuse-related effects mediated by α4β2 receptors, although tolerance can develop to these non-α4β2 effects. Selective α4β2 agonists may have higher abuse potential than nicotine.

Effects of repeated treatment with methcathinone, mephedrone, and fenfluramine on intracranial self-stimulation in rats

“…Similarly, repeated daily cocaine administration produced consistent levels of ICSS facilitation that neither sensitized nor tolerated in mice despite concurrent evidence for sensitization to the locomotor stimulant effects of cocaine (Riday et al 2012). The ICSS facilitating effects of some other drugs, such as mu opioid receptor agonists and nicotine, are also sustained with little evidence of tolerance during regimens of repeated daily dosing, although tolerance may develop during treatment with very high doses (Altarifi and Negus 2011;Freitas et al 2016;Kornetsky and Esposito 1979;Reid 1987). Taken together, these results provide evidence to suggest that neural mechanisms that underlie abuse-related ICSS facilitation are relatively resistant to tolerance during chronic treatment.…”

“…Surgery.-Experimental procedures were similar to those used previously to evaluate repeated treatment effects with opioids, nicotine, and Δ9-tetrahydrocannabinol on ICSS (Altarifi et al 2012;Freitas et al 2016;Kwilasz and Negus 2012). Briefly, rats were anesthetized with isoflurane (2.5-3% in oxygen; Webster Veterinary, Phoenix, AZ, USA) for implantation of stainless steel electrodes (Plastics One, Roanoke, VA, USA) into the left medial forebrain bundle at the level of the lateral hypothalamus (2.8 mm posterior to bregma, 1.7 mm lateral to the midsagittal suture, and 8.8 mm ventral to the skull).…”

Relief of Pain-Depressed Behavior in Rats by Activation of D1-Like Dopamine Receptors

“…Behavioral Procedure. To complement studies in the assay of acid-depressed ICSS, rats that failed to meet ICSS training criteria were used in studies of lactic acid-stimulated stretching as described previously (Altarifi et al, 2015;Freitas et al, 2016;Hillhouse and Negus, 2016). During test sessions, administration of test drug(s) was followed first by a pretreatment interval identical to those used for ICSS studies and then by injection of 1.8% lactic acid.…”

More than Smoke and Patches: The Quest for Pharmacotherapies to Treat Tobacco Use Disorder

“…Following electrode implantation, the animal is trained to complete an operant response to produce an electrical stimulation that can be modified in terms of both amplitude and frequency. ICSS procedures have been performed in mice (Johnson et al, 2008;Fowler et al, 2013), rats (Schaefer and Michael, 1992;Panagis et al, 2000;Kenny et al, 2009), and nonhuman primates (Routtenberg et al, 1971) to study the ability of drugs (Negus and Miller, 2014;Freitas et al, 2016) and physiologic conditions (Freitas et al, 2015) to produce increases or decreases in baseline ICSS responding. Many drugs of abuse produce increases in measures of baseline ICSS responding; this is typically interpreted as an abuse-related effect (Bonano et al, 2014) and is correlated with alterations in dopamine signaling (Bauer et al, 2013).…”

“…Furthermore, both drugs of abuse as well as drugs that do not produce abuse-related effects in animals are able to produce decreases in measures of baseline ICSS responding given sufficiently large doses; this is typically interpreted as an abuse-limiting effect (Bauer et al, 2013). Nicotine produces dose-dependent biphasic effects in ICSS, increasing responding at lower doses of nicotine and decreasing responding at higher doses (Schaefer and Michael, 1986;Huston-Lyons and Kornetsky, 1992;Bauco and Wise, 1994;Spiller et al, 2009;Freitas et al, 2016), similar to effects seen in the self-administration assay (Lau et al, 1994;Valentine et al, 1997;Le Foll et al, 2007). Thus, a favorable outcome for a potential pharmacotherapy for smoking cessation might be to attenuate nicotineinduced increases in ICSS, as seen with the N-methyl-Daspartate receptor antagonist LY235959 (Kenny et al, 2009); however, this type of ICSS procedure is not the most commonly used for evaluating pharmacotherapies for tobacco use disorder.…”