Alcohol self-administration, anxiety, and cortisol levels predict changes in delta opioid receptor function in the ventral tegmental area.

Abstract

The delta opioid receptor (DOR) agonist DPDPE decreases ethanol (EtOH) consumption when injected into the ventral tegmental area (VTA). We previously showed that DPDPE inhibition of GABAA receptor-mediated inhibitory postsynaptic currents (GABAAR IPSCs) is associated with reduced EtOH consumption. To determine whether self-administration of EtOH is required to change VTA DOR function, we compared the effects of passively administered (gavaged) and self-administered (two-bottle choice) EtOH. Because rats showed variability in DOR regulation of drinking and inhibition of GABAAR IPSCs, we examined whether these changes can be predicted before EtOH exposure by behavioral measures of anxiety or intoxication. Functional DORs were seen with both gavaged and self-administered EtOH, although the magnitude of DPDPE-induced inhibition correlated with behavioral measures only when EtOH was self-administered. Specifically, DPDPE-induced inhibition correlated with predrinking measures of open arm time in the plus maze (n = 19, R = .69, p = .001), with change in maximum fall latency on the rotarod (n = 17, R = .89, p = .000001), and with blood corticosterone (n = 17, R = .66, p = .004) in drinking animals. This DOR-mediated inhibition persisted for at least 14 days after EtOH access was terminated. Together, these findings indicate that anxious animals and those with the greatest EtOH-induced motor impairment have the most robust DPDPE-induced inhibition of GABAAR IPSCs in VTA neurons. These data also extend our understanding of the possible therapeutic value of the DOR for treatment of alcoholism by showing that its relevant synaptic action persists during abstinence.

Molecular Pharmacology ofδ-Opioid Receptors

“…This is consistent with the observation that DOPr knockout mice consume more ethanol than their wild-type littermates (Roberts et al, 2001). Subsequent studies reported that the neuroprotective effects of VTA DOPr in modulating ethanol consumption were positively correlated with the occurrence of affective-like behaviors and higher corticosterone blood levels prior to ethanol self-administration (Mitchell et al, 2012). Importantly, although much of the literature cited above (in this section) highlights changes in DOPr function, few studies have demonstrated that drugs of abuse regulate DOPr membrane trafficking.…”

Recent advances on the δ opioid receptor: from trafficking to function

“…There has also been evidence of DOPrs playing a role in the addiction profile induced by alcohol where behavioural responding to ethanol increases DOPr function in several regions. This suggests that DOPrs may play a protective role in chronic alcohol disorders and is being further explored (Margolis et al ., ; Mitchell et al ., ; Nielsen et al ., ; van Rijn et al ., ). It is tempting to suggest that the influence of DOPrs on the addiction profile of these compounds may not be a direct result of DOPr signalling within the effected cells or pathways but rather an indirect, and concurrent, anxiolytic action of DOPrs (Lutz and Kieffer, ; Charbogne et al ., ).…”

Substance Use Disorder

“…They also play a proximal role in the transition from controlled to compulsive drug seeking in humans Volkow 2010, 2016). For example, nearly all drug intoxication is accompanied by the release of dopamine and opioid peptides into the ventral striatum (Mitchell et al 2012;Volkow et al 2007;Koob 2015). This serves to elicit appetitive, positive affective emotions (Baldo and Kelley 2007;Burgdorf and Panksepp 2006), high incentive salience (Berridge and Robinson 1998) and to reinforce drug consumption via stimulus-response and conditioned learning processes (Delgado 2007;Daniel and Pollmann 2014).…”