Glutamatergic Mechanisms Mediate Enduring Vulnerability to Drug Use Following an Acute Stressor

GARCIA KELLER C; KUPCHIK Y; GIPSON C; BROWN RM; SPENCER S; BOLLATI F; ESPARZA MA; ROBERTS-WOLFE D; HEINSBROEK J; BOBADILLA AC; CANCELA LM; KALIVAS PW

Florida

Congreso; 54th Annual Meeting of the American College of Neuropsychopharmacology; 2015

There issubstantial comorbidity between stress disorders and substance use disorders(SUDs). Using rodent models of stress and substance use, most studies revealthat previous exposure to stress predisposes animals to the behavioral effectsof psychostimulants and opioids, including the development of behavioralsensitization and drug self-administration. While the face validity of these animalmodels relative to stress disorders can be argued, stress exposure potentiatesboth the rewarding and psychomotor stimulant effects of addictive drugs. Herewe endeavor to understand the neural underpinnings of comorbid stress disordersand drug use by determining if the glutamatergic neuroadaptations (glutamatetransport and glutamate mediated synaptic currents) that characterize cocaineself-administration are induced by acute stress, and if restoring glutamatetransport in the accumbens core (NAcore) with Ceftriaxone (CEF) thestress-induced potentiation in cocaine-induced locomotor activity and increase incocaine self-administration is prevented.Methods: Adult maleSprague-Dawley rats were double housed with a 12:12 hr dark/light cycle. Acutestress group was restrained for 2 hours, while sham animals were left undisturbedin their home cage. The animals appeared healthy and no difference in bodyweight was measured between groups. Three weeks after acute stress or sham: 1) Animalswere trained to self-administer cocaine during seven days on an FR1 schedule (2h per day), where responses on an active lever resulted in a drug infusion (0.2mg) paired with discrete light and tone cues. Criterion defined as the firstday animals obtain 410 infusions. 2-4) Animalswere treated with CEF (200 mg/kg IP) or vehicle (saline) for 5 days and weresacrificed to measure AMPA and NMDA currents, H3-Glutamate uptake, GLT-1expression in NAcore, or locomotor activity in response to cocaine challenge(15 mg/kg) or saline. 5) Animals were treated with CEF (200 mg/kg IP after eachoperant session) or vehicle (saline) for 3 days prior and 7 days during theacquisition of cocaine self-administration. All procedures were in accordance withthe NIH Guide for the Care and Use of Laboratory Animals and the Assessment andAccreditation of Laboratory Animal Care.Results: 1) Stresspre-exposure potentiated the acquisition of cocaine self-administration(Log-rank Mantel-Cox test Chi2¼4.33, *p¼ 0.038). 2) Acute stress-induced increase in theAMPA/NMDA ratio in the NAcore (one-way ANOVA F(2,43)¼ 8.14, po0.001), which was not reversed by CEF. 3) CEFpretreatment restored stress-induced decrease in glutamate uptake in Naþ-dependent, but not Naþindependent uptake of 3H-glutamate into slices of the NAcore(2-way ANOVA stress vs sham F(1,19)¼ 8.98, po 0.01; VEH vs CEF F(1,19)¼ 11.12, po 0.001; interaction F(1,19)¼ 10.20, po 0.001), and restored expression of the glial glutamatetransporter, GLT-1 (2-way ANOVA VEH vs CEF F(1,20)¼ 12.98, po 0.01; interaction F(1,20)¼ 19.78, po 0.001). 4) CEF pretreatment reversed stress-induced potentiationacute cocaine-induced locomotor activity (2-way ANOVA stress vs sham F(1,80)¼ 4.83, po 0.05; saline vs cocaine F(3,80)¼ 27.81, po 0.001; interaction F(3,80)¼ 5.74, po 0.01) and 5) reversed stress-induced augmented acquisitionof cocaine self-administration (Chi2(3)¼ 5.51, p¼0.138).Conclusions: These resultsprobed aspects of glutamate transmission in the NAcore known to be altered by addictivedrugs, and found that akin to cocaine, at three weeks following a singleexposure to stress the AMPA/ NMDA ratio was increased, while glutamate uptakeand GLT-1 content were reduced. In contrast to elevated AMPA/ NMDA, whichoccurs after withdrawal from cocaine but not heroin, reduced GLT-1 in theNAcore is observed following withdrawal from all drugs of abuse examined todate, and pharmacological restoration of GLT-1 with CEF inhibits drug seeking.Accordingly, when we restored GLT-1 function in NAcore with CEF, and weprevented acute stress-induced increases in cocaine-induced locomotion and acquisitionof cocaine self-administration. These data provide a mechanistic link betweenacute stress-induced down-regulation of glutamate transport in NAcore and stress-inducedvulnerability to use cocaine, and pose common points of pharmacologicalintervention that may be particularly useful in treating stress disorder andSUDs comorbidity.