Year of Publication
Doctor of Philosophy (PhD)
Arts and Sciences
Dr. Mark A. Prendergast
Stress promotes the use of methamphetamine and other recreational substances and is often implicated in relapse to stimulant use. Thus, it is of critical importance to examine the consequences of the co-occurance of stress and methamphetamine use. Activity of the glutamatergic N-methyl D-aspartate (NMDA) receptor system appears to be involved in the neurotoxic effects of both chronic stress and methamphetamine exposure. The current studies investigated the hypothesis that chronic pre-exposure to the stress hormone corticosterone (CORT) results in an increase of NMDA receptor activity and that this will potentiate the neurotoxic effects of methamphetamine (METH). Co-cultures of the ventral tegmental area, nucleus accumbens, and medial prefrontal cortex were pre-exposed to CORT (1 μM) for 5 days prior to co-exposure to METH (100 μM) for 24 hours to investigate the combined effects on neurotoxicity and protein density of NMDA receptor subunits. The combination of CORT and METH resulted in significant neurotoxicity within the medial prefrontal cortex compared to either CORT or METH alone. The CORT+METH-induced toxicity was attenuated by co-exposure to the NMDA receptor antagonist (2R)-amino-5-phosphonovaleric acid (APV; 50 μM) during the 24 hour CORT and METH co-exposure. Although CORT alone did not significantly alter the density of the NR1 and NR2B subunits of the NMDA receptor, METH exposure for 24 hours resulted in a significant loss of the polyamine sensitive NR2B subunit. Co-exposure to CORT and METH also resulted in decreased extracellular glutamate while not significantly altering extracellular dopamine. These results suggest an enhancement of NMDA receptor systems or downstream effectors in areas of the mesolimbic reward pathway following chronic pre-exposure to CORT, which leads to enhanced neuronal vulnerability to future excitotoxic insults. This may be of critical importance as use of psychostimulants such as METH and other drugs of abuse may produce excitotoxic events in these areas, thus further compromising neuronal viability.
Berry, Jennifer N., "THE MESOCORTICOLIMBIC DOPAMINE PATHWAY RECONSTITUTED IN VITRO: GLUTAMATE RECEPTORS AND CORTICOSTEROID-METHAMPHETAMINE NEUROTOXICITY" (2013). Theses and Dissertations--Psychology. 28.