Effects of the novel endocannabinoid uptake inhibitor, LY2183240, on fear-potentiated startle and alcohol-seeking behaviors in mice selectively bred for high alcohol preference.
BACKGROUND
Alcohol-use disorders often occur together with anxiety disorders in humans which may be partly due to common inherited genetic factors. Evidence suggests that the endocannabinoid system (ECS) is a promising therapeutic target for the treatment of individuals with anxiety and/or alcohol-use disorders.


OBJECTIVE
The present study assessed the effects of a novel endocannabinoid uptake inhibitor, LY2183240, on anxiety- and alcohol-seeking behaviors in a unique animal model that may represent increased genetic risk to develop co-morbid anxiety and alcohol-use disorders in humans. Mice selectively bred for high alcohol preference (HAP) show greater fear-potentiated startle (FPS) than mice selectively bred for low alcohol preference (LAP). We examined the effects of LY2183240 on the expression of FPS in HAP and LAP mice and on alcohol-induced conditioned place preference (CPP) and limited-access alcohol drinking behavior in HAP mice.


RESULTS
Repeated administration of LY2183240 (30 mg/kg) reduced the expression of FPS in HAP but not LAP mice when given prior to a second FPS test 48 h after fear conditioning. Both the 10 and 30 mg/kg doses of LY2183240 enhanced the expression of alcohol-induced CPP and this effect persisted in the absence of the drug. LY2183240 did not alter limited-access alcohol drinking behavior, unconditioned startle responding, or locomotor activity.


CONCLUSIONS
These findings suggest that ECS modulation influences both conditioned fear and conditioned alcohol reward behavior. LY2183240 may be an effective pharmacotherapy for individuals with anxiety disorders, such as post-traumatic stress disorder, but may not be appropriate for individuals with co-morbid anxiety and alcohol-use disorders.
Powers
Matthew S
MS
Department of Psychological Sciences, Purdue University, West Lafayette, IN 47907-2081, USA.
Barrenha
Gustavo D
GD
Mlinac
Nate S
NS
Barker
Eric L
EL
Chester
Julia A
JA
D000161:Acoustic Stimulation; D000428:Alcohol Drinking / Q000235:genetics / Q000378:metabolism* / Q000523:psychology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000009:adverse effects / Q000494:pharmacology*; D001007:Anxiety / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000523:psychology; D001522:Behavior, Animal / Q000187:drug effects*; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D015897:Comorbidity; D003213:Conditioning, Psychological / Q000187:drug effects; D004195:Disease Models, Animal; D063388:Endocannabinoids; D000431:Ethanol / Q000008:administration & dosage*; D005260:Female; D006573:Heterocyclic Compounds, 1-Ring / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D013216:Reflex, Startle / Q000187:drug effects*; D012201:Reward; D013997:Time Factors; D014508:Urea / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology
D014151:Anti-Anxiety Agents; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D006573:Heterocyclic Compounds, 1-Ring; C522826:LY2183240; D000431:Ethanol; D014508:Urea