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 L.M.; KALIVAS, P.W.

Florida

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

There is substantial comorbidity betweenstress disorders and substance use disorders (SUDs). Usingrodent models of stress and substance use, most studiesreveal that previous exposure to stress predisposes animalsto the behavioral effects of psychostimulants and opioids,including the development of behavioral sensitization anddrug self-administration. While the face validity of theseanimal models relative to stress disorders can be argued,stress exposure potentiates both the rewarding andpsychomotor stimulant effects of addictive drugs. Here weendeavor to understand the neural underpinnings ofcomorbid stress disorders and drug use by determining ifthe glutamatergic neuroadaptations (glutamate transportand glutamate mediated synaptic currents) that characterizecocaine self-administration are induced by acute stress, andif restoring glutamate transport in the accumbens core(NAcore) with Ceftriaxone (CEF) the stress-induced potentiationin cocaine-induced locomotor activity and increasein cocaine self-administration is prevented.Methods: Adult male Sprague-Dawley rats were doublehoused with a 12:12 hr dark/light cycle. Acute stress groupwas restrained for 2 hours, while sham animals were leftundisturbed in their home cage. The animals appearedhealthy and no difference in body weight was measuredbetween groups. Three weeks after acute stress or sham: 1)Animals were trained to self-administer cocaine during seven days on an FR1 schedule (2 h per day), whereresponses on an active lever resulted in a drug infusion (0.2mg) paired with discrete light and tone cues. Criteriondefined as the first day animals obtain 410 infusions. 2-4)Animals were treated with CEF (200 mg/kg IP) or vehicle(saline) for 5 days and were sacrificed to measure AMPAand NMDA currents, H3-Glutamate uptake, GLT-1 expressionin NAcore, or locomotor activity in response to cocainechallenge (15 mg/kg) or saline. 5) Animals were treated withCEF (200 mg/kg IP after each operant session) or vehicle(saline) for 3 days prior and 7 days during the acquisition ofcocaine self-administration. All procedures were in accordancewith the NIH Guide for the Care and Use ofLaboratory Animals and the Assessment and Accreditationof Laboratory Animal Care.Results: 1) Stress pre-exposure potentiated the acquisitionof cocaine self-administration (Log-rank Mantel-Cox testChi2¼ 4.33, *p¼ 0.038). 2) Acute stress-induced increasein the AMPA/NMDA ratio in the NAcore (one-way ANOVAF(2,43)¼ 8.14, po0.001), which was not reversed by CEF.3) CEF pretreatment restored stress-induced decrease inglutamate uptake in Naþ-dependent, but not Naþindependentuptake of 3H-glutamate into slices of theNAcore (2-way ANOVA stress vs sham F(1,19)¼ 8.98, po0.01; VEH vs CEF F(1,19)¼ 11.12, po 0.001; interactionF(1,19)¼ 10.20, po 0.001), and restored expression of theglial glutamate transporter, GLT-1 (2-way ANOVA VEH vsCEF F(1,20)¼ 12.98, po 0.01; interaction F(1,20)¼ 19.78,po 0.001). 4) CEF pretreatment reversed stress-inducedpotentiation acute cocaine-induced locomotor activity (2-way ANOVA stress vs sham F(1,80)¼ 4.83, po 0.05; salinevs cocaine F(3,80)¼ 27.81, po 0.001; interaction F(3,80)¼5.74, po 0.01) and 5) reversed stress-induced augmentedacquisition of cocaine self-administration (Chi2(3)¼ 5.51,p¼ 0.138).Conclusions: These results probed aspects of glutamatetransmission in the NAcore known to be altered byaddictive drugs, and found that akin to cocaine, at threeweeks following a single exposure to stress the AMPA/NMDA ratio was increased, while glutamate uptake andGLT-1 content were reduced. In contrast to elevated AMPA/NMDA, which occurs after withdrawal from cocaine but notheroin, reduced GLT-1 in the NAcore is observed followingwithdrawal from all drugs of abuse examined to date, andpharmacological restoration of GLT-1 with CEF inhibitsdrug seeking. Accordingly, when we restored GLT-1function in NAcore with CEF, and we prevented acutestress-induced increases in cocaine-induced locomotionand acquisition of cocaine self-administration. These dataprovide a mechanistic link between acute stress-induceddown-regulation of glutamate transport in NAcore andstress-induced vulnerability to use cocaine, and posecommon points of pharmacological intervention that maybe particularly useful in treating stress disorder and SUDscomorbidity.Keywords: Acute Stress, cocaine, GLT-1, Nucleus AccumbensDisclosures: Nothing to disclose.