Subclinical levels of polysubstance use are a prevalent and understudied phenomenon. Alcohol is a substance commonly co‐used with other substances of other drug classes. These studies sought to determine the consumption effects of combining alcohol drinking and methamphetamine (MA) self‐administration. Male alcohol‐preferring P rats had continuous access to a two‐bottle alcohol drinking procedure in the home cage. Control rats remained alcohol naïve. Rats were also surgically implanted with intra‐jugular catheters and trained to self‐administer saline (control) or MA in daily 2‐hour sessions. We first measured the acquisition and maintenance of MA intake in alcohol‐consuming or control rats. MA intake was initially enhanced by alcohol consumption on a fixed ratio 1 schedule of reinforcement, but this effect did not prevail as the difficulty of the schedule (FR5 and progressive ratio) was increased. We next measured both alcohol consumption and preference before, during and after MA (or saline) self‐administration. MA self‐administration significantly reduced alcohol intake and preference ratios, a robust effect that persisted across several experimental variations. Interestingly, alcohol consumption rebounded following the cessation of MA self‐administration. The effects of MA self‐administration were specific to alcohol intake because it did not alter total fluid consumption or consumption of sucrose. MA self‐administration did not impact blood‐alcohol concentrations or alcohol‐induced loss of righting reflex suggesting no effect of MA intake on the alcohol metabolism or sensitivity. Together, the results suggest that MA intake disrupts alcohol consumption and preferences but not the reverse in alcohol‐preferring P rats.

Rationale and objective: Previous work has demonstrated that dopamine and adenosine receptors are involved in drug seeking behaviors, yet the pharmacological interactions between these receptors in methamphetamine (MA) seeking are not well characterized. The present studies examined the role of the dopamine D 2 -like receptors in MA seeking and identified the interactive effects of adenosine receptor stimulation.Methods: Adult male Sprague-Dawley rats were trained to lever press for MA in daily 2-hour self-administration sessions on a fixed-ratio 1 schedule for 10 consecutive days. After 1 day of abstinence, lever pressing was extinguished in 6 daily extinction sessions. Treatments were administered systemically prior to a 2-hour reinstatement test session.Results: An increase in MA seeking was observed following the administration of the dopamine D 2 -like agonist, quinpirole, or the D 3 receptor agonist, 7-OH-DPAT. Stimulation of D 2 or D 4 receptors was ineffective at inducing MA seeking. Quinpirole-induced MA seeking was inhibited by D 3 receptor antagonism (SB-77011A or PG01037), an adenosine A 1 agonist, CPA, and an adenosine A 2A agonist, CGS 21680. MA seeking induced by a MA priming injection or D 3 receptor stimulation was inhibited by a pretreatment with the adenosine A 1 agonist, CPA, but not the adenosine A 2A agonist, CGS 21680. Conclusions:These results demonstrate the sufficiency of dopamine D 3 receptors to reinstate MA seeking that is inhibited when combined with adenosine A 1 receptor stimulation.

Background: Methamphetamine (METH) is a psychostimulant drug that remains a popular and threatening drug of abuse with high abuse liability. There is no established pharmacotherapy to treat METH dependence, but evidence suggests that stimulation of adenosine receptors reduces the reinforcing properties of METH and could be a potential pharmacological target. This study examines the effects of adenosine receptor subtype stimulation on METH seeking using both a cue-induced reinstatement and cue-craving model of relapse. Methods: Male and female rats were trained to self-administer METH during daily 2-h sessions. Cue-induced reinstatement of METH seeking was evaluated after extinction training. A systemic pretreatment of an adenosine A1 receptor (A1R) or A2A receptor (A2AR) agonist was administered prior to an extinction or cue session to evaluate the effects of adenosine receptor subtype stimulation on METH seeking. The effects of a systemic pretreatment of A1R or A2AR agonists were also evaluated in a cue-craving model where the cued-seeking test was conducted after 21 days of forced home-cage abstinence without extinction training. Results: Cue-induced reinstatement was reduced in both male and female rats that received A1R or A2AR agonist pretreatments. Similarly, an A1R or A2AR agonist pretreatment also inhibited cue craving in both male and female rats. Conclusion: Stimulation of either adenosine A1R or A2AR subtypes inhibits METH-seeking behavior elicited by METH-associated cues. These effects may be attributed to the ability of A1R and A2AR stimulation to disrupt cue-induced dopamine and glutamate signaling throughout the brain.