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Journal of Neuroscience, Vol 16, 274-282, Copyright © 1996 by Society for Neuroscience
Drugs of abuse and stress increase the expression of GluR1 and NMDAR1 glutamate receptor subunits in the rat ventral tegmental area: common adaptations among cross-sensitizing agents
LW Fitzgerald, J Ortiz, AG Hamedani and EJ Nestler
Department of Psychiatry, Yale University School of Medicine, Connecticut Mental Health Center, New Haven 06508, USA.
Behavioral and electrophysiological evidence suggests that glutamatergic
neurotransmission plays an important role in some of the long-term effects
of cocaine and other drugs of abuse on brain function. We therefore
examined the effect of repeated cocaine treatment on glutamate receptor
subunit expression in central dopamine (DA) pathways implicated in many of
cocaine's behavioral actions. By immunoblotting procedures using
subunit-specific antibodies, we found that repeated, but not acute, cocaine
treatment increased the levels of immunoreactivity of GluR1 (an AMPA
receptor subunit) and NMDAR1 (an NMDA receptor subunit) in the ventral
tegmental area (VTA), a nucleus containing mesolimbic DA neurons. In
contrast, chronic cocaine treatment did not alter levels of GluR2 (an AMPA
receptor subunit), NMDA2A/B (NMDA receptor subunits), or GluR6/7 (kainate
receptor subunits) in this brain region. Moreover, GluR1 and NMDAR1 levels
were not regulated in other regions of the mesolimbic or nigrostriatal DA
pathways, including the substantia nigra. Because several drugs of abuse
and stress can elicit common and cross-sensitizing effects on mesolimbic DA
function, we next examined whether repeated morphine and stress treatments
would regulate these proteins similarly in the VTA. Although morphine
delivered by subcutaneous pellet implantation had no significant effect on
subunit levels, morphine delivered intermittently by subcutaneous
injections of escalating doses elevated GluR1 levels in the VTA. Repeated
restraint stress also paradigm (2 stressors/d under variable conditions)
increased both GluR1 and NMDAR1 levels in this brain region. Unlike
cocaine, morphine, and stress, repeated treatment with other psychotropic
drugs (haloperidol, raclopride, sertraline, and desipramine) that lack
reinforcing or sensitizing properties did not regulate GluR1 or NMDAR1
subunit levels in the VTA. Increased glutamate receptor subunit expression
in the VTA may represent an important molecular mechanism by which drugs of
abuse and stress exert common, long-term effects on mesolimbic DA function.
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|
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|
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25929 - 25938.
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|
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