ABSTRACT
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 intra-CeA 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 self-administration 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 self-administration 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.
Subject(s)
Alcoholism/metabolism , Alcoholism/psychology , Central Amygdaloid Nucleus/metabolism , Receptors, Opioid, kappa/metabolism , Substance Withdrawal Syndrome/metabolism , Substance Withdrawal Syndrome/psychology , Administration, Intranasal , Alcoholism/drug therapy , Animals , Central Nervous System Depressants/administration & dosage , Conditioning, Operant/drug effects , Conditioning, Operant/physiology , Disease Models, Animal , Dose-Response Relationship, Drug , Ethanol/administration & dosage , Male , Motivation/drug effects , Motivation/physiology , Naltrexone/analogs & derivatives , Naltrexone/pharmacology , Narcotic Antagonists/pharmacology , Rats, Wistar , Receptors, Opioid, kappa/antagonists & inhibitors , Self Administration , Substance Withdrawal Syndrome/drug therapyABSTRACT
BACKGROUND: The dynorphin (DYN)/kappa-opioid receptor (KOR) system undergoes neuroadaptations following chronic alcohol exposure that promote excessive operant self-administration and negative affective-like states; however, the exact mechanisms are unknown. The present studies tested the hypothesis that an upregulated DYN/KOR system mediates excessive alcohol self-administration that occurs during withdrawal in alcohol-dependent rats by assessing DYN A peptide expression and KOR function, in combination with site-specific pharmacologic manipulations. METHODS: Male Wistar rats were trained to self-administer alcohol using operant behavioral strategies and subjected to intermittent alcohol vapor or air exposure. Changes in self-administration were assessed by pharmacologic challenges during acute withdrawal. In addition, 22-kHz ultrasonic vocalizations were utilized to measure negative affective-like states. Immunohistochemical techniques assessed DYN A peptide expression and [(35)S]GTPγS coupling assays were performed to assess KOR function. RESULTS: Alcohol-dependent rats displayed increased alcohol self-administration, negative affective-like behavior, DYN A-like immunoreactivity, and KOR signaling in the amygdala compared with nondependent control rats. Site-specific infusions of a KOR antagonist selectively attenuated self-administration in dependent rats, whereas a mu-opioid receptor/delta-opioid receptor antagonist cocktail selectively reduced self-administration in nondependent rats. A mu-opioid receptor antagonist/partial KOR agonist attenuated self-administration in both cohorts. CONCLUSIONS: Increased DYN A and increased KOR signaling could set the stage for a one-two punch during withdrawal that drives excessive alcohol consumption in alcohol dependence. Importantly, intracentral nucleus of the amygdala pharmacologic challenges functionally confirmed a DYN/KOR system involvement in the escalated alcohol self-administration. Together, the DYN/KOR system is heavily dysregulated in alcohol dependence and contributes to the excessive alcohol consumption during withdrawal.
Subject(s)
Alcoholism/metabolism , Central Amygdaloid Nucleus/metabolism , Central Nervous System Depressants/administration & dosage , Ethanol/administration & dosage , Receptors, Opioid, kappa/metabolism , Receptors, Opioid/metabolism , Animals , Central Amygdaloid Nucleus/drug effects , Male , Rats , Rats, Wistar , Self Administration , Substance Withdrawal Syndrome/metabolismABSTRACT
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 alcohol-dependent 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 µg) 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.
