Methamphetamine self‐administration reduces alcohol consumption and preference in alcohol‐preferring P rats

Abstract

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.

Prior binge-drinking history promotes the positive affective valence of methamphetamine in mice

“…The reduction in MA reinforcement reported previously in alcohol-experienced rats (Winkler et al, 2016) and mice (Fultz et al, 2017) has been speculated to reflect cross-tolerance of MA’s positive subjective effects (Winkler et al, 2016) or a cross-sensitization of MA’s psychomotor-sensitizing, anxiogenic and/or positive subjective effects (Fultz et al, 2017). Based on the observations that prior alcohol-experience (1) augmented MA intake under limited-access procedures in the home-cage and (2) shifted the dose-response function for oral MA intake under operant-conditioning procedures to the left of alcohol-naïve controls (Fultz et al, 2017), we argued previously in favor of the latter mechanism as a major contributory factor.…”

“…Although drug self-administration procedures are considered the gold-standard in the addiction field, study outcomes are subject to many interpretational confounds that require complementary approaches to resolve (Sanchis-Segura and Spanagel, 2006). Indeed, the very limited extant literature pertaining to MA-alcohol interactions in drug-taking (Fultz et al, 2017; Winkler et al, 2016) provides an excellent example of how behavior manifested under operant-conditioning procedures is insufficient to fully understand the psychopharmacological mechanisms underpinning drug-taking behavior.…”

“…Consistent with these data from humans, drug-naïve C57BL/6J (B6) mice prefer to consume a mixed solution of MA and alcohol over either alone (Fultz et al, 2017), and alcohol-experienced B6 mice exhibit greater oral MA intake than alcohol-naïve animals (Fultz et al, 2017). However, in both rats (Winkler et al, 2016) and mice (Fultz et al, 2017) a prior and/or concurrent history of alcohol-drinking blunts MA-directed responding and intake under operant-conditioning procedures. This argues that alcohol experience reduces MA reinforcement.…”

Effects of Clavulanic Acid Treatment on Reinstatement to Methamphetamine, Glial Glutamate Transporters, and mGluR 2/3 Expression in P Rats Exposed to Ethanol

“…Despite the evidence of the high rate of the co-abuse of METH and ethanol, little is known about the effects of co-exposure of these drugs or METH on ethanol drinking in rodent models. However, a recent study showed that METH self-administration decreased ethanol intake (Winkler et al, 2016). In this study, we examined the effects of METH co-exposure for seven consecutive days on home-cage voluntary ethanol intake in alcohol-preferring (P) rats and the role of the glutamatergic system in this drug co-exposure animal model.…”

Agmatine Inhibits Behavioral Sensitization to Ethanol Through Imidazoline Receptors

“…The alcohol‐induced behavioral sensitization is believed to occur due to neuronal adaptation in dopaminergic, glutamatergic, and GABAergic circuitry in VTA, NAc, prefrontal cortex, and amygdala (Di Chiara, ; Koob et al., ; Meyer et al, ; Richtand, ; Shim et al., ; Steketee and Kalivas, ; Vezina and Leyton, ; Zislis et al., ). Similarly, other neurochemical systems including serotonergic and opioidergic have also been implicated in EtOH sensitization (Knapp et al., ; Overstreet et al., ; Winkler et al., ). Although EtOH acts on multiple neurological substrates, the mechanism for its behavioral sensitization or drug seeking behavior remains poorly defined.…”