A prior history of binge-drinking increases sensitivity to the motivational valence of methamphetamine in female C57BL/6J mice.

Methamphetamine (MA) and alcohol use disorders exhibit a high degree of co-morbidity and sequential alcohol-MA mixing increases risk for co-abuse. Recently, we reported greater MA-conditioned reward in male C57BL/6J mice with a prior history of binge alcohol-drinking (14 days of 2-hour access to 5, 10, 20 and 40% alcohol). As female mice tend to binge-drink more alcohol than males and females tend to be more sensitive than males to the psychomotor-activating properties of MA, we first characterized the effects of binge-drinking upon MA-induced place-conditioning (four pairings of 0.25, 0.5, 1, 2, or 4 mg/kg IP) in females and then incorporated our prior data to analyze for sex differences in MA-conditioned reward. Prior binge-drinking history did not significantly affect locomotor hyperactivity or its sensitization in female mice. However, the dose-response function for place-conditioning was shifted to the left of water-drinking controls, indicating an increase in sensitivity to MA-conditioned reward. The examination of sex differences revealed no sex differences in alcohol intake, although females exhibited greater MA-induced locomotor stimulation than males, irrespective of their prior drinking history. No statistically significant sex difference was apparent for the potentiation of MA-conditioned reward produced by prior binge-drinking history. If relevant to humans, these data argue that both males and females with a prior binge-drinking history are similarly vulnerable to MA abuse and it remains to be determined whether or not the neural substrates underpinning this increased vulnerability reflect common or sex-specific adaptations in reward-related brain regions

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

An alcohol use disorder is a major predisposing factor for methamphetamine (MA) abuse. Further, MA-alcohol co-abuse is a risk factor for treatment discontinuation and non-compliance in MA-dependent individuals. No effective treatment exists for MA addiction, let alone treatments directed at those suffering from MA-alcohol addiction co-morbidity. Thus, it is imperative that we develop high-throughput animal models to study the biobehavioral interactions between MA and alcohol of relevance to the etiology and treatment of co-abuse. To this end, we reported that a history of binge alcohol-drinking [5,10, 20 and 40% (v/v); 2 h/day for 10-14 days] reduces MA reinforcement and intake, but it augments MA-preference and intake when drug availability is behaviorally non-contingent. To reconcile this apparent discrepancy in findings, we employed a comparable 2-week binge-drinking paradigm as that employed in our previous studies followed by place-conditioning procedures (4 pairings of 0.25, 0.5, 1, 2 or 4 mg/kg MA, i.p.). This was meant to determine how a prior binge-drinking history impacts the affective valence of MA and sensitivity to MA-induced psychomotor-activation/sensitization. Prior binge-drinking history blunted spontaneous locomotor activity and shifted the MA dose-place-preference function upwards of water drinking controls. The potentiation of MA-conditioned reward by prior binge-drinking history was independent of any alcohol effects upon the locomotor-activating or -sensitizing effects of MA. Based on these results we propose that the reduced MA reinforcement reported previously by our group likely reflects a compensatory response to an increased sensitivity to MA's positive subjective effects rather than increased sensitivity to the drug's psychomotor-activating effects

Methamphetamine-alcohol interactions in murine models of sequential and simultaneous oral drug-taking

BackgroundA high degree of co-morbidity exists between methamphetamine (MA) addiction and alcohol use disorders and both sequential and simultaneous MA-alcohol mixing increases risk for co-abuse. As little preclinical work has focused on the biobehavioral interactions between MA and alcohol within the context of drug-taking behavior, we employed simple murine models of voluntary oral drug consumption to examine how prior histories of either MA- or alcohol-taking influence the intake of the other drug.MethodsIn one study, mice with a 10-day history of binge alcohol-drinking [5,10, 20 and 40% (v/v); 2h/day] were trained to self-administer oral MA in an operant-conditioning paradigm (10-40mg/L). In a second study, mice with a 10-day history of limited-access oral MA-drinking (5, 10, 20 and 40mg/L; 2h/day) were presented with alcohol (5-40% v/v; 2h/day) and then a choice between solutions of 20% alcohol, 10mg/L MA or their mix.ResultsUnder operant-conditioning procedures, alcohol-drinking mice exhibited less MA reinforcement overall, than water controls. However, when drug availability was not behaviorally-contingent, alcohol-drinking mice consumed more MA and exhibited greater preference for the 10mg/L MA solution than drug-naïve and combination drug-experienced mice. Conversely, prior MA-drinking history increased alcohol intake across a range of alcohol concentrations.DiscussionThese exploratory studies indicate the feasibility of employing procedurally simple murine models of sequential and simultaneous oral MA-alcohol mixing of relevance to advancing our biobehavioral understanding of MA-alcohol co-abuse

Hnrnph1 is a novel regulator of alcohol reward

BackgroundHnrnph1 is a validated quantitative trait gene for methamphetamine behavioral sensitivity that encodes for heterogeneous nuclear ribonucleoprotein H1 (hnRNP H1). This RNA-binding protein is involved in all stages of RNA metabolism that impacts mesocorticolimbic dopamine neurotransmission to influence addiction-related behavior.MethodsWe characterized the alcohol behavioral phenotypes of mice heterozygous for a deletion in the first coding exon of Hnrnph1 (Hnrnph1+/-). We examined alcohol intake under both continuous- and limited-access procedures, as well as alcohol-induced place-conditioning. Follow-up studies examined genotypic differences in the psychomotor-activating and sedative-hypnotic effects of acute and repeated alcohol, and a behavioral test battery was employed to determine the effects of Hnrnph1 deletion on the manifestation of negative affect during alcohol withdrawal.ResultsRelative to wild-type (WT) controls, Hnrnph1+/- males exhibited blunted intake of high alcohol concentrations under both drinking procedures. Hnrnph1 deletion did not impact the conditioned rewarding properties of low-dose alcohol, but reversed the conditioned place-aversion elicited by higher alcohol doses (2 and 4 g/kg), with more robust effects in male versus female mice. No genotypic differences were observed for alcohol-induced locomotor activity. Hnrnph1+/- mice exhibited a modest increase in sensitivity to alcohol's sedative-hypnotic effects, but did not differ from WT mice with regard to tolerance to alcohol's sedative-hypnotic effects or alcohol metabolism, Inconsistent effects of Hnrnph1 deletion were observed in models for withdrawal-induced negative affect.ConclusionsThese data identify Hnrnph1 as a novel, male-selective, driver of alcohol consumption and high-dose alcohol aversion that is potentially relevant to the neurobiology of alcohol abuse and alcoholism

ERK-Directed Phosphorylation of mGlu5 Gates Methamphetamine Reward and Reinforcement in Mouse.

Methamphetamine (MA) is a highly addictive psychomotor stimulant drug. In recent years, MA use has increased exponentially on a global scale, with the number of MA-involved deaths reaching epidemic proportions. There is no approved pharmacotherapy for treating MA use disorder, and we know relatively little regarding the neurobiological determinants of vulnerability to this disease. Extracellular signal-regulated kinase (ERK) is an important signaling molecule implicated in the long-lasting neuroadaptations purported to underlie the development of substance use disorders, but the role for this kinase in the propensity to develop addiction, particularly MA use disorder, is uncharacterized. In a previous MA-induced place-conditioning study of C57BL/6J mice, we characterized mice as MA-preferring, -neutral, or -avoiding and collected tissue from the medial prefrontal cortex (mPFC). Using immunoblotting, we determined that elevated phosphorylated ERK expression within the medial prefrontal cortex (mPFC) is a biochemical correlate of the affective valence of MA in a population of C57BL/6J mice. We confirmed the functional relevance for mPFC ERK activation for MA-induced place-preference via site-directed infusion of the MEK inhibitor U0126. By contrast, ERK inhibition did not have any effect upon MA-induced locomotion or its sensitization upon repeated MA treatment. Through studies of transgenic mice with alanine point mutations on T1123/S1126 of mGlu5 that disrupt ERK-dependent phosphorylation of the receptor, we discovered that ERK-dependent mGlu5 phosphorylation normally suppresses MA-induced conditioned place-preference (MA-CPP), but is necessary for this drug's reinforcing properties. If relevant to humans, the present results implicate individual differences in the capacity of MA-associated cues/contexts to hyper-activate ERK signaling within mPFC in MA Use Disorder vulnerability and pose mGlu5 as one ERK-directed target contributing to the propensity to seek out and take MA

ERK-Directed Phosphorylation of mGlu5 Gates Methamphetamine Reward and Reinforcement in Mouse.

Methamphetamine (MA) is a highly addictive psychomotor stimulant drug. In recent years, MA use has increased exponentially on a global scale, with the number of MA-involved deaths reaching epidemic proportions. There is no approved pharmacotherapy for treating MA use disorder, and we know relatively little regarding the neurobiological determinants of vulnerability to this disease. Extracellular signal-regulated kinase (ERK) is an important signaling molecule implicated in the long-lasting neuroadaptations purported to underlie the development of substance use disorders, but the role for this kinase in the propensity to develop addiction, particularly MA use disorder, is uncharacterized. In a previous MA-induced place-conditioning study of C57BL/6J mice, we characterized mice as MA-preferring, -neutral, or -avoiding and collected tissue from the medial prefrontal cortex (mPFC). Using immunoblotting, we determined that elevated phosphorylated ERK expression within the medial prefrontal cortex (mPFC) is a biochemical correlate of the affective valence of MA in a population of C57BL/6J mice. We confirmed the functional relevance for mPFC ERK activation for MA-induced place-preference via site-directed infusion of the MEK inhibitor U0126. By contrast, ERK inhibition did not have any effect upon MA-induced locomotion or its sensitization upon repeated MA treatment. Through studies of transgenic mice with alanine point mutations on T1123/S1126 of mGlu5 that disrupt ERK-dependent phosphorylation of the receptor, we discovered that ERK-dependent mGlu5 phosphorylation normally suppresses MA-induced conditioned place-preference (MA-CPP), but is necessary for this drug's reinforcing properties. If relevant to humans, the present results implicate individual differences in the capacity of MA-associated cues/contexts to hyper-activate ERK signaling within mPFC in MA Use Disorder vulnerability and pose mGlu5 as one ERK-directed target contributing to the propensity to seek out and take MA