A preponderant role of the glutamatergic transmission in nucleus accumbens core vs shell underlies the long term sensitization to cocaine after a single restraint stress

GARCÍA KELLER, C; MARTÍNEZ, S; ESPARZA, A; KALIVAS, PW; CANCELA, L.M.

Buenos Aires

Congreso; The 5th Special Conference of the International Society for Neurochemistry. Synapses and Dendritic Spines in Health and Disease.; 2012

ISN

Several evidences indicate that cocaine is able to induce behavioural and molecular sensitization in both, the dopaminergic (DA) and glutamatergic (Glu) mesocorticolimbic systems. It has been shown that a single restraint stress induces sensitization to behavioural and neurochemical effects of psychostimulants (Pacchioni et al., 2007). The aim of this work was to study the mechanisms in the nucleus accumbens (NAc) whereby an acute restraint stress augments the acute locomotor response to cocaine. This was accomplished by a combination of behavioural pharmacology, microdialysis measures and Western blotting for GluR1, AMPA glutamate receptor (AMPAR) subunit. Male Wistar rats (250-350 g) were restrained for two hours (acute¬¬-stress group) while control animals were left undisturbed in their cages. Twenty-one days after this single stress episode, all animals were assigned to one of the following experiments: I) Microdialysis: DA and Glu release was measured by HPLC in NAc Core and NAc Shell in response to saline and cocaine (15 mg/kg i.p.); and basal Glu levels were measured by no-net-flux technique. II) Locomotor activity in response to saline or cocaine (15 mg/kg i.p.); and locomotor activity followed by intra-Core and Shell microinfusions of increasing doses of AMPA (0.03 or 0.10 µg/side) or CNQX (0.01; 0.1; 1.0 nmol/side). III) AMPAR expression in Core after i.p. injection of saline or cocaine (15 mg/kg i.p.). Our results demonstrate that pre-stressed animals after a single exposure to restraint stress 3 weeks before testing revealed enduring locomotor sensitization to cocaine and was paralleled by an increase in extracellular DA in the Core, but not the Shell. Rats pre-exposed to acute stress showed increased basal levels of Glu in the core but the increase in Glu by acute cocaine was blunted. The alterations in extracellular Glu appeared consequential since blocking AMPAR by CNQX microinjection into the Core prevented both the behavioral cross-sensitization and the augmented increase in cocaine-induced extracellular DA. This study shows that long-term neurobiological changes induced in the Core by acute stress are consequential in the expression of cross-sensitization to cocaine.