Differential effects of the novel kappa opioid receptor antagonist, JDTic, on reinstatement of cocaine-seeking induced by footshock stressors vs cocaine primes and its antidepressant-like effects in rats.
BACKGROUND
Stress and depression have been linked to relapse of cocaine abuse. Antagonism of the kappa opioid receptor (KOR) has been reported to attenuate some effects of stressors, and antagonism of the KOR has been reported to have antidepressant-like properties.


OBJECTIVE
Our objective was to determine whether the potent and selective KOR antagonist, (3R)-7-hydroxy-N-{(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl}-1,2,3,4-tetrahydro-3-isoquinoline-carboxamide (JDTic), can reduce the ability of a stressor (intermittent footshock) to reinstate cocaine-seeking behavior and to have antidepressant-like effects in the forced swim test (FST).


METHODS
Male Long-Evans hooded rats were trained to lever-press, reinforced with 0.5 mg/kg i.v. infusion of cocaine, according to fixed ratio 1 reinforcement schedules during daily 2-h experimental sessions. After performance had stabilized, lever pressing was extinguished for 12 consecutive sessions, and doses of 0 (vehicle), 3, 10, and 30 mg/kg JDTic were then administered i.g. to separate groups of 12 rats. Twenty four hours later, the rats were given 15 min of intermittent footshock (0.87 mA, 0.5 s activation time, average inter-activation interval of 40 s) or a 17-mg/kg i.p. administration of cocaine prime followed by a 2-h reinstatement test session. JDTic was also evaluated for its ability to block diuresis induced by the KOR agonist, U50,488H (10 mg/kg, s.c.), during 5-h test sessions beginning 1 h after footshock reinstatement tests to verify its KOR antagonist activity. In the FST, male Sprague-Dawley rats were treated with either nor-binaltorphimine (nor-BNI) or JDTic (both at 0.3, 1, 3, or 10 mg/kg, injected s.c. 23 h before), or desipramine (5.6, 10, or 17 mg/kg, injected i.p. 23, 5, and 1 h before) and placed in a cylinder of water, during which the predominance of immobility, swimming, and climbing were scored during 5-s intervals for 5 min.


RESULTS
The 10- and 30-mg/kg doses of JDTic significantly reduced footshock-induced reinstatement of responding previously reinforced by cocaine and significantly attenuated U50,488H-induced diuresis. In contrast, JDTic did not affect cocaine-prime-induced reinstatement. Both nor-BNI and JDTic decreased immobility and increased swimming time in the FST, similar to the antidepressant desipramine.


CONCLUSIONS
Depression and stress are two states during cocaine abstinence which users identify as precipitating relapse, and JDTic may have properties which attenuate both.
Beardsley
Patrick M
PM
Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA , USA. pbeardsl@hsc.vcu.edu
Howard
James L
JL
Shelton
Keith L
KL
Carroll
F Ivy
FI
D000284:Administration, Oral; D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004597:Electroshock; D005528:Foot; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors*; D055502:Secondary Prevention; D012646:Self Administration; D013315:Stress, Psychological / Q000517:prevention & control; D013550:Swimming; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage / Q000494:pharmacology*
C433814:7-hydroxy-N-(1-((4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)methyl)-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide; D000928:Antidepressive Agents; D018765:Dopamine Uptake Inhibitors; D010880:Piperidines; D017473:Receptors, Opioid, kappa; D044005:Tetrahydroisoquinolines; D003042:Cocaine