The effects of varenicline on methamphetamine self-administration and drug-primed reinstatement in female rats

Abstract

While research has revealed heightened vulnerability to meth addiction in women, preclinical models rarely use female subjects when investigating meth seeking and relapse. The goal of the present study was to examine the effects of varenicline (Chantix®), a partial α4β2 and full α7 nicotinic acetylcholine receptor agonist, on meth self-administration and reinstatement in female rats. Sprague-Dawley rats were surgically implanted with an indwelling jugular catheter. Half of the rats were then trained to self-administer meth (0.056 mg/kg/infusion) on a variable ratio 3 schedule of reinforcement; the other half earned intravenous saline during daily, 2 hour sessions. When responding stabilized, varenicline (0.0, 0.3, 1.0, 3.0 mg/kg) was tested to determine how it altered meth taking. Varenicline was probed on 4 test days; each test separated by 2 standard self-administration sessions to assure responding remained stable. Following this testing was 15 extinction sessions. Twenty-four hours after the last extinction session were four consecutive days of meth-primed reinstatement. The same 4 doses of varenicline were examined to determine how it altered reinstatement triggered by 0.3 mg/kg meth (IP). Rats readily self-administered meth. The higher doses of varenicline did not affect meth-taking in a specific fashion as active lever pressing wasalso slightly reduced in rats that has access to saline in the self-administration phase. Female rats displayed robust meth-primed reinstatement. Notably, the lower doses of varenicline increased meth-primed reinstatement. This amplified susceptibility to reinstatement (i.e., relapse) may be an impediment for the use of varenicline as a therapeutic to treat meth use disorder.

The effects of varenicline on methamphetamine self-administration and drug-primed reinstatement in male rats

“…A similar non-specific enhancement was reported in female rats (Pittenger et al, 2016). The increase in general locomotor activity following administration of both 0.3 and 1.0 mg/kg varenicline may suggest possible non-specific activation resulting in increased responding.…”

“…In the study presented herein, varenicline did not alter methamphetamine self-administration. The inability of varenicline to alter meth-taking behavior in male rats is similar to findings with female rats in that there were no specific effects of varenicline on meth self-administration in either sex (Pittenger et al, 2016). In the female rats, there was a non-specific effect of varenicline slightly reducing responding in both the saline and meth groups.…”

“…However, other investigators have reported increases in ethanol and cocaine intake, as well as no effect with varenicline pretreatment; for a mini-review of the effects of varenicline on nicotine, ethanol, and cocaine self-administration and reinstatement see Pittenger et al (2016). In the study presented herein, varenicline did not alter methamphetamine self-administration.…”

“…Preliminary training with the levers, indwelling jugular catheters surgery and subsequent variable ratio 3 (VR3) training with sucrose reinforcement was conducted using our labs standard protocol detailed in Pittenger et al (2016). Two rats were excluded from the study for non-patent catheters.…”

“…However, research in preclinical models has raised some concerns with this premise, at least in females. Pittenger et al (2016) examined the effects of varenicline on meth self-administration and meth-primed reinstatement in female rats. While varenicline reduced meth self-administration in that study, the reduction was not specific to meth (i.e., responding was also reduced in rats that received saline and timeout cues).…”