Maladaptive behavioral regulation in alcohol dependence: Role of kappa-opioid receptors in the bed nucleus of the stria terminalis

Abstract

There is an important emerging role for the endogenous opioid dynorphin (DYN) and the kappa-opioid receptor (KOR) in the treatment of alcohol dependence. Evidence suggests that the DYN/KOR system in the bed nucleus of the stria terminalis (BNST) contributes to maladaptive behavioral regulation during withdrawal in alcohol dependence. The current experiments were designed to assess dysregulation of the BNST DYN/KOR system by evaluating alcohol dependence-induced changes in DYN/KOR gene expression (Pdyn and Oprk1, respectively), and the sensitivity of alcohol self-administration, negative affective-like behavior and physiological withdrawal to intra-BNST KOR antagonism during acute withdrawal. Wistar rats trained to self-administer alcohol, or not trained, were subjected to an alcohol dependence induction procedure (14 h alcohol vapor/10 h air) or air-exposure. BNST micropunches from air- and vapor-exposed animals were analyzed using RT-qPCR to quantify dependence-induced changes in Pdyn and Oprk1 mRNA expression. In addition, vapor- and air-exposed groups received an intra-BNST infusion of a KOR antagonist or vehicle prior to measurement of alcohol self-administration. A separate cohort of vapor-exposed rats was assessed for physiological withdrawal and negative affective-like behavior signs following intra-BNST KOR antagonism. During acute withdrawal, following alcohol dependence induction, there was an upregulation in Oprk1 mRNA expression in alcohol self-administering animals, but not non-alcohol self-administering animals, that confirmed dysregulation of the KOR/DYN system within the BNST. Furthermore, intra-BNST KOR antagonism attenuated escalated alcohol self-administration and negative affective-like behavior during acute withdrawal without reliably impacting physiological symptoms of withdrawal. The results confirm KOR system dysregulation in the BNST in alcohol dependence, illustrating the therapeutic potential of targeting the KOR to treat alcohol dependence.

Moderate adolescent chronic intermittent ethanol exposure sex-dependently disrupts synaptic transmission and kappa opioid receptor function in the basolateral amygdala of adult rats

“…Increased dynorphin-A immunoreactivity and dynorphin-A stimulated G-protein receptor coupling were also found in the central amygdala following induction of ethanol dependence and acute withdrawal (Kissler et al, 2014). Consistent with findings in the amygdala, KOR mRNA expression was also increased in the BNST during acute withdrawal from chronic ethanol exposure (Erikson et al, 2018). Finally, withdrawal from chronic ethanol exposure increases KOR regulation of dopamine transmission in the nucleus accumbens which may underlie reduced dopamine release in ethanol-dependent rats (Karkhanis et al, 2016;Rose et al, 2016).…”

“…In the central amygdala, increased levels of dynorphin release and receptor coupling have been linked to elevated alcohol consumption and negative affect following chronic alcohol exposure (Kissler et al, 2014;Kissler & Walker, 2016). Finally, blockade of KORs in the BNST reduced alcohol consumption, negative affect, and physiological withdrawal symptoms following chronic alcohol exposure (Erikson, Wei, & Walker, 2018), while activation of KORs in this region enhanced alcohol seeking following chronic alcohol exposure (Funk, Coen, Tamadon, & Le, 2019). Together, these studies clearly demonstrate that parts of the extended amygdala which regulate negative affective states and modulation of reward have disrupted KOR function following chronic alcohol exposure; however, whether similar adaptations occur in the BLA, particularly in response to exposure in adolescence, is unknown.…”

The role of matrix metalloproteinase‐9 in negative reinforcement learning and plasticity in alcohol dependence

“…Within the NAc, plasticity‐related adaptations such as silent synapse formation have been implicated in incubation of craving, and an amygdala/accumbens circuit, consistent with the present results, has been shown to be important in drug relapse . Although we did not observe alterations in BNST MMP expression under the conditions tested, it should be noted that BNST dysregulation does contribute to escalated alcohol self‐administration during acute withdrawal . Future research could delineate BNST contributions to the formation or removal of negative affective states that appear to be required for escalated alcohol self‐administration in dependence .…”

The Kappa Opioid Receptor Is Associated With Naltrexone-Induced Reduction of Drinking and Craving

“…It has been shown that mu receptor agonist binding in the ventral tegmentum area, the origin of mesolimbic dopaminergic projections, increases tonic dopamine levels, whereas KOR agonists decrease basal dopamine (43)(44)(45)(46)(47). KOR activity induces a decrease in mood, whereas KOR antagonism can block drug withdrawal effects (48,49). Recent studies have suggested that the underlying KOR-mediated hyperpolarization of dopaminergic neurons could vary according to the target region of those neurons (50,51).…”