Methamphetamine-Like Discriminative-Stimulus Effects of Nicotinic Agonists

Abstract

Nicotine was recently shown to engender d-methamphetamine (MA)-like discriminative-stimulus effects in rats, which may be indicative of shared psychomotor stimulant properties. To further investigate such overlapping discriminative-stimulus effects, nicotinic agonists varying in efficacy and selectivity were studied in squirrel monkeys that discriminated a moderate intramuscular dose of MA (0.1 mg/kg) from vehicle. These included a4b2-selective ligands that may vary in efficacy from relatively high [nicotine, (1) (ED 50 ) values, corresponded more closely with their relative affinities at a4b2 than at a7 receptors. Regardless of selectivity or efficacy, nicotinic agonists also were observed to produce untoward effects, including salivation and emesis during or after experimental sessions. In pretreatment studies, the a4b2-selective antagonist dihydro-b-erythroidine hydrobromide (DHbE) (0.032 and 0.1 mg/kg) and the partial agonists varenicline (0.0032-0.1 mg/kg) and (2)-cytisine (0.032 and 0.1 mg/kg) surmountably antagonized (.10-fold rightward shift) nicotine's MA-like effects but were ineffective in blocking nicotine's emetic effects. Overall, our results show that 1) MA-like discriminative-stimulus effects of nicotinic agonists likely are mediated through a4b2 nicotinic acetylcholine receptor actions, and 2) nicotinic a4b2 partial agonists, like the nicotinic antagonist DHbE, can reduce MA-like behavioral effects of nicotine.

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

“…First, varenicline may be substituting for meth, effectively increasing the dose of meth utilized as a drug-prime during the reinstatement tests. Indeed, varenicline has been shown to partially substitute for the discriminative-stimulus effects of meth (Desai & Bergman, 2014). Additionally, the level of responding evoked by meth in a reinstatement test is sensitive to the dose (Anggadiradja et al, 2004; Reichel et al, 2012).…”

Effects of the Nanoparticle-Based Vaccine, SEL-068, on Nicotine Discrimination in Squirrel Monkeys

“…The housing and feeding protocols for all subjects were comparable to those employed previously in our laboratory (Desai and Bergman, 2014 …”

“…During experimental sessions, monkeys sat in customized Plexiglas chairs (Kelleher and Morse, 1968;Desai and Bergman, 2014) that were enclosed in ventilated, sound-attenuating chambers; white noise was present at all times to mask extraneous sounds. While seated, monkeys faced a panel containing two sets of colored stimulus lights and two response levers that were comfortably within the subject's reach, one below each set of stimulus lights.…”

“…Prior to each behavioral session, a shaved portion of the monkey's tail was secured under brass electrodes by a small stock for the delivery of brief, lowintensity stimuli (3 mA for 200 msec; current delivery). These parameters were chosen on the basis of previous research in our laboratory (Tidey and Bergman, 1998;Desai and Bergman, 2014). The shaved area was coated with electrode paste to ensure a low-resistance electrical contact between electrodes and tail.…”

“…The present behavioral studies were conducted to address this question by determining how a treatment regimen of SEL-068 that can be expected to produce a robust immune response also modifies nicotine's discriminative-stimulus effects, which have been related to its subjective effects in man (eg, Smith and Stolerman, 2009;Kamien et al, 1993). Standard drug discrimination procedures (eg, Smith and Stolerman, 2009;Jutkiewicz et al, 2011;Cunningham et al, 2012;Perkins, 2009;Desai and Bergman, 2014) were employed to determine whether vaccination with SEL-068 might prevent, or when already established, attenuate nicotine's discriminativestimulus effects in nonhuman primates.…”