ABSTRACT
BACKGROUND: Excessive alcohol intake is a serious but preventable public health problem in the United States and worldwide. Alcohol and other substance use disorders occur co-morbid with more generalized reward deficiency disorders, characterized by a reduction in dopamine (DA) signaling within the reward pathway, and classically associated with increased impulsivity, risk taking and subsequent drug seeking behavior. It is postulated that increasing dopamine availability and thus restoring DA homeostasis in the mesocorticolimbic system could reduce the motivation to seek and consume ethanol. Here, we treated animals with a neuro-nutrient, KB220Z also known as Synaptamine, designed to augment DA signaling. METHOD: KB220Z was administered to genetically alcohol-preferring (P) adult male and female rats by oral gavage (PO), intraperioneally (IP), or subcutaneously (SQ) for 4 consecutive days at a 3.4â¯mL/Kg rat equivalent dose and compared to saline (SQ, IP) or water (PO) controls. Subsequent to treatment, lever pressing and consumption of 10 % ethanol or control 3% sucrose during operant responding was assessed using a drinking in the dark multiple scheduled access (DIDMSA) binge drinking protocol. Locomotor and elevated zero maze activity, and DRD2 mRNA expression via in situ hybridization (ISH) were assessed independently following 4 days of a SQ regimen of KB220Z. RESULTS: KB220Z administered via IP and SQ markedly and immediately reduced binge drinking of 10 % ethanol in both male and female rats whereas PO administration took at least 3 days to decrease lever pressing for ethanol in both male and female rats. There was no effect of SQ KB220Z on 3% sucrose drinking. Elevated activity in the open field was significantly decreased, and time spent in the open arm of the EZM was moderately reduced. The regimen of SQ KB220Z did not impact the number of DRD2 punctae in neurons of the NAc, but the NAc shell expressed more DRD2 mRNA/cell than NAc core independent of KB220Z. CONCLUSION: KB220Z attenuates ethanol drinking and other RDS behaviors in P rats possibly by acting on the dopaminergic system, but not by effecting an increase in NAc DRD2 mRNA expression.
Subject(s)
Behavior, Animal/drug effects , Binge Drinking/physiopathology , Catecholamines/pharmacology , Central Nervous System Depressants/administration & dosage , Drug-Seeking Behavior/drug effects , Ethanol/administration & dosage , Locomotion/drug effects , Monoamine Oxidase/pharmacology , Neprilysin/pharmacology , Receptors, Dopamine D2/drug effects , Animals , Binge Drinking/genetics , Binge Drinking/metabolism , Conditioning, Operant , Dopamine/metabolism , Female , Male , Maze Learning/drug effects , RNA, Messenger/drug effects , RNA, Messenger/metabolism , Rats , Receptors, Dopamine D2/genetics , Reward , Self AdministrationABSTRACT
The experience of early life stress can trigger complex neurochemical cascades that influence emotional and addictive behaviors later in life in both adolescents and adults. Recent evidence suggests that excessive alcohol drinking and drug-seeking behavior, in general, are co-morbid with depressive-like behavior. Both behaviors are reported in humans exposed to early life adversity, and are prominent features recapitulated in animal models of early life stress (ELS) exposure. Currently, little is known about whether or how ELS modulates reward system nuclei. In this study we use operant conditioning of rats to show that the maternal separation stress (MS) model of ELS consumes up to 3-fold greater quantities of 10% vol/vol EtOH in 1-h, consistently over a 3-week period. This was correlated with a significant 22% reduction in the number of dopaminergic-like neurons in the VTA of naïve MS rats, similar to genetically alcohol-preferring (P) rats which show a 35% reduction in tyrosine hydroxylase (TH)-positive dopaminergic neurons in the VTA. MS rats had a significantly higher 2-fold immobility time in the forced swim test (FST) and reduced sucrose drinking compared to controls, indicative of depressive-like symptomology and anhedonia. Consistent with this finding, stereological analysis revealed that amygdala neurons were 25% greater in number at P70 following MS exposure. Our previous examination of the dentate gyrus of hippocampus, a region involved in encoding emotional memory, revealed fewer dentate gyrus neurons after MS, but we now report this reduction in neurons occurs without effect on the number of astrocytes or length of astrocytic fibers. These data indicate that MS animals exhibit neuroanatomical changes in reward centers similar to those reported for high alcohol drinking rats, but aspects of astrocyte morphometry remained unchanged. These data are of high relevance to understand the breadth of neuronal pathology that ensues in reward loci following ELS.
