Long-term alterations in benzodiazepine, muscarinic and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor density following continuous cocaine administration.

Abstract

Animal models of clinical phenomena, such as stimulant-induced psychosis have focused primarily on persisting alterations that develop in brain after chronic stimulant administration. The present study utilized autoradiographic measures to examine changes in the density of benzodiazepine ([3H] flunitrazepam), muscarinic ([3H] quinuclidinyl benzilate), and non-NMDA glutamatergic (3H alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid: AMPA) receptor binding in rats 21 days following two exposures to cocaine administered continuously for 5 days via subcutaneous pellets. A marked, selective increase in [3H] flunitrazepam binding in both the lateral and medial habenula nucleus was observed. Reduced [3H] quinuclidinyl benzilate binding was observed in various brain areas, including large decreases in the anterior cingulate cortex and ventral thalamus. A reduction in [3H]AMPA binding was observed in the ventral striatum and was suggested in the nucleus accumbens. [3H] Flunitrazepam binding was also examined 12 hr following a single 5 day cocaine exposure to determine if the long-term habenular changes were evident at acute withdrawal. No alterations in [3H] flunitrazepam binding were observed in the habenula or any other structure analyzed at this time point. The relation of these results to persisting alterations in mesocorticolimbic pathways and previous findings of cocaine-induced degeneration in lateral habenula circuitry is discussed.