Nicotinic Acetylcholine α4β2 Receptor Regulates the Motivational Effect of Intracranial Self Stimulation Behavior in the Runway Method

Abstract

Abstract.Recently, it was demonstrated that the priming stimulation effect (PSE) of intracranial self-stimulation (ICSS) with the runway method can be used as a model system to study the motivation that contributes to specific behaviors. It was postulated that these behaviors could be used to compare the effects of various drugs on the mechanism of motivation. In the present study, the influences of nicotine, methyllycaconitine (α7 nicotine-receptor antagonist), and dihydro-β-erythroidine (α4β2 nicotine-receptor antagonist) on motivation were examined using the runway method for ICSS. Electrodes were implanted into the medial forebrain bundle of Wistar rats. The rats ran to the goal lever to get the reward (50 -200 μA, 0.2 ms, 60 Hz) and pretrial electric stimulation (priming stimulation) in the medial forebrain bundle was performed. The experiment measured the running time from the start box until the rat pressed the goal lever for the reward stimulation. Under these reward and priming stimulation conditions, nicotine (0.2 mg / kg) induced a significant increase in running speed. The nicotine receptor antagonist α4β2 rather than α7 showed a dose-dependent antagonistic action on the effect of nicotine on running speed. These results demonstrate that nicotine enhances the running speed towards the goal lever via α4β2 nicotinic receptors and suggest that α4β2 nicotinic receptors influence the brain mechanism of motivation.

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

“…Specifically, the rate-increasing effects of 5-I-A-85380 in the present study were blocked by both the non-selective nAChR antagonist mecamylamine and the α4β2-selective antagonist DHßE. Studies to antagonize nicotine-induced facilitation of ICSS were not attempted in the present study because this nicotine effect was deemed too small to permit reliable assessment of antagonism; however, our results with 5-I-A-85380 are consistent with previous reports that mecamylamine and DHßE also block nicotine-induced facilitation of ICSS (Huston-Lyons & Kornetsky, 1992; Sagara et al, 2008). Conversely, the rate-decreasing effects of nicotine were blocked by mecamylamine but not by DHßE.…”

Effects of the specific α4β2 nAChR antagonist, 2-fluoro-3-(4-nitrophenyl) deschloroepibatidine, on nicotine reward-related behaviors in rats and mice

“…The involvement of α4β2* nAChR subtypes in these effects is supported by findings that DHβE (Sagara et al 2008), varenicline (Spiller et al 2009; Vann et al 2011), and 4-nitro-PFEB (present study) antagonize nicotine’s facilitating effects on ICSS. However, unlike varenicline, which facilitated ICSS when injected alone (Spiller et al 2009; but see also Vann et al 2011), 4-nitro-PFEB did so without altering autotitration reset thresholds.…”

Effect of GBR12909 on affective behavior：Distinguishing motivational behavior from antidepressant-like and addiction-like behavior using the runway model of intracranial self-stimulation

“…Moreover, we demonstrate that the motivational effects of drugs as evaluated in the ICSS runway model are quite distinct from the addictive effects of drugs. These results verify previous reports on the effects of nicotine and methamphetamine that reflected the motivational effects of these drugs [14,15].…”

“…Previous research has reported that quinpirole had no effect on locomotor activity after a single administration of 0.05 and 0.1 mg/kg [33], although in the present study quinpirole decreased running speed in the runway at these doses. We previously reported that 14 nicotine increases the PSE in the ICSS runway model without affecting locomotor activity [15]. In addition, it was reported that low doses of haloperidol (under 0.1 mg/kg) seem to not significantly affect locomotor activity, especially in combination with GBR12909 or methamphetamine [34][35][36][37].…”

“…Since ICSS 3 measures have been proposed as experimental models for evaluating altered interest or pleasure/hedonia, ICSS has been recognized as a valid measure of motivational state [12]. Indeed, our previous studies demonstrated that both nicotine and methamphetamine enhanced motivated behavior as observed in the runway model of ICSS [13][14][15]. However, it is not clear whether these behavioral alterations reflect a motivational enhancement for receiving ICSS reward or a reinforcing effect of these addictive drugs.…”