The endogenous opioid system in human alcoholics: molecular adaptations in brain areas involved in cognitive control of addiction

Chronic intermittent alcohol vapor exposure leads to increased dynorphin (DYN) A-like peptide expression and heightened kappa-opioid receptor (KOR) signaling in the central nucleus of the amygdala (CeA) and these neuroadaptive responses differentiate alcohol-dependent from non-dependent phenotypes. Important for therapeutic development efforts is understanding the nature of the stimulus that drives dependence-like phenotypes such as escalated alcohol self-administration. Accordingly, the present study examined the impact of intraCeA KOR antagonism on escalated operant alcohol self-administration and physiological withdrawal symptoms during acute withdrawal and protracted abstinence in rats previously exposed to chronic intermittent alcohol vapor. Following operant training, rats were implanted with intra-CeA guide cannula and exposed to long-term intermittent alcohol vapor exposure that resulted in escalated alcohol selfadministration and elevated physiological withdrawal signs during acute withdrawal. Animals received intra-CeA infusions of the KOR antagonist nor-binaltorphimine (nor-BNI; 0, 2, 4, or 6 μg) prior to operant alcohol self-administration sessions and physiological withdrawal assessment during acute withdrawal and protracted abstinence. The results indicated that site-specific KOR antagonism in the CeA ameliorated escalated alcohol self-administration during both acute withdrawal and protracted abstinence test sessions, whereas KOR antagonism had no effect on physiological withdrawal scores at either time point. These results dissociate escalated alcohol selfadministration from physiological withdrawal symptoms in relation to KOR signaling in the CeA and help clarify the nature of the stimulus that drives escalated alcohol self-administration during acute withdrawal and protracted abstinence.

Section: Discussionmentioning

confidence: 92%

Dissociating Motivational From Physiological Withdrawal in Alcohol Dependence: Role of Central Amygdala κ-Opioid Receptors

Kissler

Walker

2015

“…The interest lies in the apparent U50,488-mediated hedonic-like behavioral overlap with impulsive-like behavior and the fact that PDYN, DYN A and B and OPRK1 are upregulated in brain regions not only heavily implicated in the cognitive control of decision-making and impulse control (Crews and Boettiger, 2009;Bazov et al, 2013;Winstanley, 2007), but also as integrators of affect and decision-making (Aragues et al, 2011), suggesting a novel PFC/OFC-based DYN/KOR target for therapeutics to treat impulse-control symptoms in dependence and possibly other neuropsychiatric disorders. The fact that nor-BNI did not reduce levels of impulsivity beyond baseline levels suggests that KOR ligands should show utility in treating conditions of reduced impulse control involving a dysregulated DYN/KOR system.…”

Section: Discussionmentioning

confidence: 99%

“…Given that in deceased alcoholics, DYN A and B, as well as mRNA for KORs were upregulated in the dlPFC and OFC, respectively, when compared with controls (Bazov et al, 2013), and preclinical evidence corresponds well, showing upregulated Pdyn gene expression in the prefrontal cortex following repeated alcohol administration (D'Addario et al, 2013); the extent to which upregulated DYN and/or increased KOR-mediated signaling directly contributes to maladaptive behavioral regulation associated with alcohol dependence is unclear. To address this issue and test the hypothesis that KOR-mediated signaling contributes to impulsive phenotypes, the KOR agonist U50,488 was infused centrally to 'mimic' a withdrawal state in alcoholdependent animals (Berger et al, 2013) in order to assess the effects of U50,488 on the performance of animals in the DD and stop-signal reaction time (SSRT) tasks.…”

Section: Introductionmentioning

confidence: 96%

“…KORs are located in brain circuitry, mediating negative affect, decision-making, emotion, learning, motivation, and pain (Mansour et al, 1994;Mansour et al, 1987). In alcoholdependent humans and rodents, upregulation of DYN/KOR system occur within nuclei comprising the central extended amygdala (Nealey et al, 2011;Kissler et al, 2013), dorsolateral prefrontal cortex (dlPFC in humans is considered analogous to the rat ventromedial (vm) PFC), and orbitofrontal cortex (OFC) (Bazov et al, 2013) that have traditionally been proposed to regulate specific types of behaviors (for example, the dlPFC regulates decision-making and the amygdala regulates emotion). Conversely, contemporary perspectives (for example, see Goldstein et al, 2007;Pessoa et al, 2012) posit that these brain regions participate in the complex integration of information related to different behavioral domains (for example, the dlPFC is a site of integration for decision-making and negative affect) that when dysregulated by chronic alcohol exposure, could contribute to phenotypes that are hallmarks of alcohol dependence (for example, excessive alcohol consumption, heightened impulsivity, increased negative affect, decreased cognitive flexibility, and impaired inhibitory control; for review, see Crews and Boettiger, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Dissociable Effects of Kappa-Opioid Receptor Activation on Impulsive Phenotypes in Wistar Rats

Walker

Kissler

2013

The kappa-opioid receptor (KOR) is the primary target for the endogenous opioid peptide dynorphin (DYN), and KORs reside within brain circuitry underlying the complex integration of information related to different behavioral domains such as motivation, negative affect, and decision-making. Alterations in extended amygdala DYNs and KOR function following chronic alcohol exposure have been shown to mediate escalated alcohol self-administration during acute withdrawal. In addition to excessive alcohol consumption and increased negative affect, other symptoms of alcohol dependence include compromised impulse control. Given that DYN and KOR expressions are dysregulated within prefrontal brain circuitry associated with decision-making and impulse control in alcoholdependent humans and rodents, and have been shown to modify multiple neurotransmitter systems associated with impulse-control disorders, we hypothesized that KOR activation could contribute to impulsive phenotypes. To test this hypothesis, separate cohorts of male Wistar rats were trained in one of the two animal models of impulsivity: delay-discounting (DD) or stop-signal reaction time (SSRT) tasks, and once stable responding was observed, received intracerebroventricular (ICV) infusions of the KOR agonist U50,488 (0-50 mg) according to a within-subject dosing regimen. The results demonstrated a dissociable effect of U50,488 on impulsive phenotypes related to intolerance to delay or response inhibition, with selective effects in the SSRT. Furthermore, the pro-impulsive effects of KOR activation were rescued by pretreatment with the KOR antagonist nor-binaltorphimine (nor-BNI). Therefore, KOR activation was shown to induce an impulsive phenotype that was nor-BNI-sensitive. Dysregulation of impulsive behavior by increased DYN/KOR activity could serve to increase vulnerability for the initiation, or perpetuate existing patterns of excessive alcohol abuse and can enhance the probability of relapse in dependent individuals. Furthermore, KOR-mediated impulsivity has implications for numerous neuropsychiatric disorders.

“…inputs. There is post-mortem evidence of dynorphin and KOR upregulation in the PFC of alcoholics relative to controls (Bazov et al, 2013) or in subjects with a lifetime of psychostimulant use (Peckys and Hurd, 2001). Increased KOR signaling in PFC regions of alcoholics and psychostimulant users would be expected to result in a hypodopaminergic cortical state, as mPFC KORs inhibit cortical DA output and alterations in glutamate synaptic transmission from the amygdala.…”

Section: Discussionmentioning

confidence: 99%

Prefrontal Cortical Kappa Opioid Receptors Attenuate Responses to Amygdala Inputs

Tejeda

Hanks

Scott

et al. 2015

Kappa opioid receptors (KORs) have been implicated in anxiety and stress, conditions that involve activation of projections from the basolateral amygdala (BLA) to the medial prefrontal cortex (mPFC). Although KORs have been studied in several brain regions, their role on mPFC physiology and on BLA projections to the mPFC remains unclear. Here, we explored whether KORs modify synaptic inputs from the BLA to the mPFC using in vivo electrophysiological recordings with electrical and optogenetic stimulation. Systemic administration of the KOR agonist U69,593 inhibited BLA-evoked synaptic responses in the mPFC without altering hippocampus-evoked responses. IntramPFC U69,593 inhibited electrical and optogenetic BLA-evoked synaptic responses, an effect blocked by the KOR antagonist nor-BNI. Bilateral intra-mPFC injection of the KOR antagonist nor-BNI increased center time in the open field test, suggesting an anxiolytic effect. The data demonstrate that mPFC KORs negatively regulate glutamatergic synaptic transmission in the BLA-mPFC pathway and anxiety-like behavior. These findings provide a framework whereby KOR signaling during stress and anxiety can regulate the flow of emotional state information from the BLA to the mPFC.