No abstract

Recent work indicates an important role for excitatory amino acids in behavioral sensitization to amphetamine. We therefore examined, using in vivo microdialysis in awake rats, the effects of amphetamine on efflux of glutamate, aspartate, and serine in the ventral tegmental area and nucleus accumbens, brain regions important for the initiation and expression of amphetamine sensitization, respectively. Water-pretreated and amphetaminepretreated rats were compared to determine if sensitization altered such effects. In both brain regions, Ca 2~dependent efflux of glutamate accounted for~2O% of basal glutamate efflux. A challenge injection of water or 2.5 mg/kg of amphetamine did not significantly alter glutamate, aspartate, or serine efflux in the ventral tegmental area or nucleus accumbens of water-or amphetaminepretreated rats. However, 5 mg/kg of amphetamine produced a gradual increase in glutamate efflux in both regions that did not reverse, was observed in both waterand amphetamine-pretreated rats, and was prevented by haloperidol. Although increased glutamate efflux occurred with too great a delay to mediate acute behavioral responses to amphetamine, it is possible that repeated augmentation of glutamate efflux during repeated amphetamine administration results in compensatory changes in levels of excitatory amino acid receptors in the ventral tegmental area and nucleus accumbens that contribute to development or expression of amphetamine sensitization.

We examined the effect of 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX), an antagonist of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) subtype of glutamate receptor, on the development and expression of behavioral sensitization to amphetamine and cocaine in rats. A single injection of NBQX (12.5 mg/kg) administered 30 min prior to cocaine during the induction phase (days 1-5) prevented the development of cocaine sensitization, assessed by responsiveness to cocaine challenge on day 8. This NBQX regimen did not affect development of amphetamine sensitization. Two pretreatment injections of NBQX, one 20 min before and one 70 min after amphetamine on each day of the induction phase (days 1-6), did not affect sensitization of stereotypy but prevented sensitization of post-stereotypy ambulatory hyperactivity (both assessed by responsiveness to amphetamine challenge on day 8). The effect of NBQX on ambulatory sensitization was dose-dependent (attenuation with 12.5 mg/kg, complete prevention with 25 mg/kg). In contrast to its effects on development, NBQX (25 mg/kg) did not prevent expression of sensitization to cocaine or amphetamine. NBQX itself exerted no significant effects on locomotor activity in either drug-naive rats or rats that had received either NBQX or amphetamine repeatedly. These findings support a requirement for AMPA receptor stimulation in the development of locomotor sensitization to cocaine and amphetamine, but suggest a different mechanism for sensitization of amphetamine stereotypy.

Amphetamine or selective D1 and D2 dopamine receptor agonists and antagonists were administered to the ventral tegmental area (VTA) through a microdialysis probe to determine their effects on glutamate and aspartate efflux in rats pretreated for 5 days with vehicle or 5 mg/kg (+)‐amphetamine sulfate. In vehicle rats, glutamate efflux declined during 2 h of perfusion with the D1 receptor agonist SKF‐82958 (10 and 100 µM). After SKF‐82958 perfusion ended, glutamate efflux rebounded to basal levels and continued to increase gradually over the next 2 h. A similar biphasic pattern was observed with intra‐VTA amphetamine (10 and 100 µM) and with another D1 agonist (100 µM SKF‐38393). The biphasic effects of SKF‐82958 were prevented by coperfusion with a D1 antagonist (SCH‐23390; 30 µM). Glutamate efflux was unaffected by a D2 agonist (100 µM quinpirole) and by D1 or D2 antagonists administered alone (SCH 23390 and eticlopride; 30 µM). In amphetamine‐pretreated rats tested 2 days after the last injection, both the decrease during SKF‐82958 perfusion and the delayed increase in glutamate efflux were attenuated. In rats tested 12–14 days after the last amphetamine injection, only the decrease during SKF‐82958 perfusion was attenuated. None of these drug treatments produced consistent effects on aspartate efflux. We showed previously that systemic amphetamine (5 mg/kg, i.p.) has no immediate effect on VTA glutamate efflux but produces a delayed increase in glutamate efflux that reaches statistical significance 2–3 h after injection. Because behavioral sensitization can be elicited either by repeated systemic or repeated intra‐VTA administration, neurochemical effects common to both routes (such as the delayed increase in glutamate efflux) are most likely to contribute to its induction.

Recent evidence suggests that behavioral sensitization to amphetamine is associated with alterations in excitatory amino acid (EAA) transmission in perikarya (ventral tegmental area) and terminal regions (nucleus accumbens [NAc]) of the mesoaccumbens dopamine system. The present study determined whether repeated amphetamine administration alters expression of mRNAs for AMPA receptor subunits. We studied the NAc, because it is the site of expression of amphetamine sensitization, and the prefrontal cortex (PFC), because it is the origin of EAA projections that regulate the mesoaccumbens dopamine system. Rats were treated for 5 days with 5 mg/kg/day amphetamine sulfate or vehicle (controls) and perfused 3 or 14 days after the last injection. We used a novel in situ hybridization method that allows quantification of mRNA levels [Lu et al. (1996) J. Neurosci. Methods, 65:69-76]. Repeated amphetamine administration decreased levels of GluR1 and GluR2 but not GluR3 mRNAs in both core and shell subregions of the NAc at the 14 day withdrawal time; no changes were observed after 3 days of withdrawal. In contrast, levels of GluR1 mRNA in the PFC were increased at 3 but not 14 days of withdrawal, while GluR2 and 3 mRNAs were unchanged. Levels of GluR4 mRNA were very low in both NAc and PFC. Functional properties of heteromeric AMPA receptors are determined by subunit composition. Thus, the observed changes in mRNAs for AMPA receptor subunits may result in altered AMPA transmission in NAc and PFC. This, in turn, may influence the responsiveness of the mesoaccumbens DA system to psychomotor stimulants and potentially contribute to behavioral sensitization.