Combined administration of varenicline and bupropion produces additive effects on accumbal dopamine and abolishes the alcohol deprivation effect in rats

Abstract

Alcohol use disorder (AUD) is detrimental to health and causes preterm death. Unfortunately, available pharmacological and nonpharmacological treatments have small effect sizes, and improved treatments are needed. Smoking and AUD share heritability and are pharmacologically associated, since drug‐induced dopamine (DA) output in nucleus accumbens (nAc) involves nicotinic acetylcholine receptors (nAChRs) in both cases. Smoking therapy agents, such as the partial nAChR agonist varenicline or the DA/noradrenaline transporter inhibitor bupropion, could potentially also be used for AUD. To investigate this hypothesis, the effects of varenicline, bupropion, or a combination of the two on nAc DA levels, ethanol intake, and the alcohol deprivation effect (ADE) were examined. In vivo microdialysis showed that varenicline (1.5 mg/kg) and bupropion (2.5, 5, or 10 mg/kg) elevated nAc DA levels and that the combination produced additive effects. Five days treatment with varenicline, bupropion, or the combination did not suppress ethanol consumption, as compared with vehicle‐treated control. However, combined administration of varenicline and bupropion completely blocked the ADE when readministering ethanol following 14 days of abstinence. Since ADE is considered highly predictive for the clinical outcome in man, our data suggest that the combination of varenicline and bupropion could be a promising treatment for AUD.

In utero Δ9-tetrahydrocannabinol exposure confers vulnerability towards cognitive impairments and alcohol drinking in the adolescent offspring: Is there a role for neuropeptide Y?

“…Moreover, after a week of forced abstinence, both PCE and CTRL rats elevated their responses for alcohol compared to the acquisition phase, but PCE rats displayed a greater increase than CTRL animals. Indeed, re-presentation of alcohol after a period of forced abstinence usually leads to a robust but temporary increase in alcohol intake over baseline drinking – a relapse-like behaviour referred to as the alcohol deprivation effect (Vengeliene et al, 2014), which reflects increased craving or increased reinforcing value of alcohol in humans (Söderpalm et al, 2019). Preclinical and clinical findings have consistently reported that alcohol taking and craving are modulated, at least in part, by endocannabinoid transmission (De Vries and Schoffelmeer, 2005; Serra et al, 2002).…”

Effects of systemic glycine on accumbal glycine and dopamine levels and ethanol intake in male Wistar rats

“…The bottles were added concurrent with the beginning of the dark period and removed after 24 h. For the first five sessions, the animals had access to 6% (v/v) ethanol in addition to water, and to 12% ethanol for the remaining experiment. Previous observations from our laboratory using Wistar rats indicate that ethanol consumption is maximal approximately at these concentrations that therefore have been applied in our previous ethanol consumption studies (Söderpalm et al 2019). Water and ethanol intake were monitored intermittently for seven weeks.…”

Different dopamine tone in ethanol high‐ and low‐consuming Wistar rats

“…At the same time, acamprosate and varenicline, which both modestly increase nAc dopamine and interfere with ethanol's dopamine‐elevating mechanisms, reduce alcohol intake both in rats and alcoholics . Further, co‐administration of varenicline and the dopamine/noradrenaline reuptake inhibitor bupropion produces additive effects on dopamine output and blocks the alcohol deprivation effect in rats (Söderpalm et al,) supporting the notion that a modest increase of nAc dopamine influences voluntary ethanol intake.…”