Stress and Drug-induced sensitization to Psychostimulant drugs: common neuroadaptations in nucleus accumbens shell and core.
Cancela LM
Departamento de Farmacología. Fac. de Cs. Químicas, Univ. Nac. Córdoba, Ciudad Universitaria 5000 Córdoba Argentina. Email:lcancela@fcq.unc.edu.ar
A single and chronic restraint stress induce sensitization to the stimulating properties of d-amphetamine (AMPH), morphine (MOR), cocaine (COC), as measured by locomotor activity and/or place preference conditioning test. The mesolimbic system innervating the accumbens (NAc) is implicated in the development and/or expression of sensitization. Different functions have been attributed to the (DA) in NAc core and shell activated by drugs and /or stress. In addition, many reports have pointed out a dopaminergic-glutamatergic interaction in the development of behavioural sensitization. Our main goals were to study: 1) the long term influence of restraint psychostimulant drug-induced DA release by microdialysis from NAc core and shell and caudate putamen (CPu); 2) the involvement of GLU receptors in the restraint stress-induced sensitization; 3) the expression of the Activator of G-protein signalling 3 (AGS3), GluR1 and NR2A in the NAc and or dorsal PFC in the model of chronic restraint stress 24h and 21 days after restraint. Wistar male rats (250-350 g) were implanted stereotaxically. After 2 days. MK-801 (0.1 mg.kg i.p.) or vehicle (VEH) were administered 30 min before restraint stress. Control animals did not receive the stress session. Following 8 days, we evaluated the effect of AMPH ( 0,5 mg/kg i.p. ), MOR (1 mg/kg i.p.) and COC (10 mg/kg i.p.) on DA release from NAc core and shell, and CPu by microdialysis during 3 h. AMPH, MOR and COC in significant higher increase in DA release from NAc core and shell in the restraint group, compared with the no restraint group. MK-801 blocked restraint stress-induced effects of drug on DA release from NAc. Three weeks after of the last restraint stress we found a significant (43,4 %) of AGS3 in NAC Shell compared with the no-stress group, while no difference was observed in NAC Core, PfC, dPfC and CPu. Twenty-four hours after chronic restraint stress the AGS3 protein levels were not modified. Chronic restraint stress did not have any influence on the levels of GluR1 24hs or 21 days following the last restraint or on NR2a 24 hs following the last session. It should be noticed that either 24 h or 21 days after the last restraint stress, a sensitized behavioural response to psychostimulant drug was observed in these chronically stressed animals. These findings showed a long-term restraint-induced sensitization to stimulating effects of psychostimulant drug on behavioural and on DA release from NAc core and an involment of NMDA receptors on it. Since the up-regulation in AGS-3 could be altered by stimulated Gsa signalling in NAcShell, it is likely that this molecular mechanism may be associated to the restraint stress-induced behavioural sensitization to psychostimulating drug. These results support the hypothesis that common mechanisms between drugs and stress underlie long term effects at the dopaminergic and glutamatergic transmission as well as in specific proteins (i.e. AGS3) in NAc.
