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

Abstract

Methamphetamine (meth) addiction is a costly burden to both the individual user and society as a whole. Establishing effective pharmacotherapies to treat meth dependence is needed to help solve this health problem. The study reported herein examined the effects of varenicline, a partial α4β2 and full α7 nicotinic acetylcholine receptor agonist, on meth self-administration and reinstatement in male Sprague-Dawley rats. Following indwelling jugular catheter surgery, rats were either trained to self-administer meth or saline on a variable ratio (VR) 3 schedule of reinforcement. Self-administration sessions (2 hour duration; 19 total sessions) were conducted daily. The effect of varenicline pretreatment on meth and saline self-administration was then determined using a within-study design. All rats received varenicline (0.0, 0.3, 1.0, and 3.0 mg/kg) prior to 4 different test sessions. Dose order was randomly assigned and each test was separated by 2 standard self-administration sessions to assess stability of responding. Fifteen extinction sessions (no meth available) followed the last test. Extinction was followed by meth-primed (0.3 mg/kg IP) reinstatement tests to examine the effect of varenicline on meth-seeking behavior. All rats again received all doses of varenicline over 4 separate reinstatement tests performed on 4 consecutive days. Varenicline did not alter self-administration of meth or saline. Additionally, the 0.3 and 1.0 doses of varenicline non-specifically increased active lever responding during the reinstatement test sessions. This latter finding suggests that varenicline may increase relapse liability and should not be utilized as pharmacotherapy to treat meth dependence.

Ghrelin Receptor Antagonism of Methamphetamine-Induced Conditioned Place Preference and Intravenous Self-Administration in Rats

“…We can speculate that this particular rat responded to the sudden lack of expected reward with increased effort to get it. According to the literature, similar observations can be found for the first day during the extinction period, when the active lever-pressing is often higher in comparison to baseline and to further days of extinction (methamphetamine [ 53 ], ketamine [ 54 ]). Similarly, we observed increased activity within some saline pretreated rats during the relapse-like behavior testing session.…”

Nicotine- and cocaine-triggered methamphetamine reinstatement in female and male Sprague-Dawley rats

“…Concordant with previous work, males and females robustly self-administered meth (Cox et al, 2013; Holtz et al, 2012; Pittenger et al, 2016; Pittenger et al, 2017; Reichel et al, 2012). Differences in active lever pressing were detected, however these were likely due to the slight difference in meth dose.…”

“…This finding suggests that nicotine is not unique in its ability to reinstate meth-seeking. The ability of nicotine and cocaine to serve as triggers for meth-seeking may be a result of their overlapping interoceptive stimulus effects with meth (Czoty et al, 2004; Desai et al, 2010a; Dasai et al, 2010b; Gatch et al, 2008) As discussed, it is well established that a meth injection can reinstate meth-seeking behavior (Pittenger et al, 2016; Pittenger et al, 2017). While nicotine and meth, as well as cocaine and meth differ in biological mechanism, they also share significant overlap.…”

MicroRNA cluster miR199a/214 are differentially expressed in female and male rats following nicotine self-administration

“…Following acclimation and food restriction, rats were trained to lever press in our lab’s standard procedure 20 , 64 , 65 . Preliminary lever training sessions were initiated by illumination of the house light and insertion of one of the two levers (randomly selected).…”

“…This process was repeated until the end of the 1-h session. These procedures produce robust lever responding with each lever having an equivalent learning history 65 .…”