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

• Published in: Neuropsychopharmacology (New York, N.Y.) N.Y.), 2016-01, Vol.41 (2), p.560-567
• Main Authors: Kissler, Jessica L, Walker, Brendan M
• Format: Article
• Language: English
• Subjects: Administration, Intranasal; Alcoholism - drug therapy; Alcoholism - metabolism; Alcoholism - psychology; Animals; Central Amygdaloid Nucleus - metabolism; 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; Original; Rats, Wistar; Receptors, Opioid, kappa - antagonists & inhibitors; Receptors, Opioid, kappa - metabolism; Self Administration; Substance Withdrawal Syndrome - drug therapy; Substance Withdrawal Syndrome - metabolism; Substance Withdrawal Syndrome - psychology
• ISSN: 0893-133X; 1740-634X
• DOI: 10.1038/npp.2015.183

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.