29 These findings suggest that chronic opiate self-administration is associated with a redistribution of postsynaptic plasma membrane glutamate receptor subunits that play an important role in neural plasticity in brain circuitry regulating homeostatic processes. These adaptations may be an important neural substrate for alterations in drug reward, autonomic function, and behavioral processes, each of which may be associated with the acquisition and persistence of an addiction.28,29 In four separate earlier studies from our laboratory we have shown that chronic (14 days) binge-pattern

cocaine administration increases mu-opioid receptor mRNA levels and also Inhibitors,research,lifescience,medical increases density of mu-opioid receptors in specific brain regions where there are abundant dopaminergic terminals from neurons located in the ventral tegmental area.30-33 In recent studies, Inhibitors,research,lifescience,medical Bailey and our group have shown that early withdrawal from chronic binge cocaine administration results in a recurrence of an increase in mu-opioid receptor mRNA levels in the rat frontal cortex, but only in this region.34 In further studies, Bailey found

that there is a persistent Selleck 3-Methyladenine upregulation of mu-opioid receptors following long-term Inhibitors,research,lifescience,medical withdrawal from escalating-dose binge-pattern cocaine.35 In these studies, animals were treated with our new modified paradigm of escalating-dose binge cocaine over 14 days, which also results in an increase

of mu-opioid receptor density, but with no increase in endogenous endorphin levels.35 Following 14 days of withdrawal, there was still a highly significant increase Inhibitors,research,lifescience,medical in mu-opioid receptor density, and primarily in specific brain regions, again where there Inhibitors,research,lifescience,medical are dopaminergic terminals from the ventral tegmental area neurons and in fields in close proximity to both muopioid receptor mRNA levels in the neurons producing mu-opioid receptors and presenting them on the cell surface.35 In a further set of studies, Bailey explored changes in the kappa-opioid receptors following 14-day withdrawal from escalating-dose binge-pattern cocaine.36 Here, very different findings were made. Whereas in multiple studies from our laboratory we have found both increases in gene expression of dynorphin, and increases in kappaopioid receptor densities, and a correlated increase in kappa-opioid receptor mRNA levels, with kappa, unlike mu-opioid receptors, which are found to be Thiamine-diphosphate kinase persistently increased in density following 14 days of withdrawal from binge-pattern escalating-dose cocaine, in this study there was lowering of kappa-opioid receptors in two specific brain regions in animals in long-term withdrawal from cocaine. These areas included the basolateral amygdala and septum. Such a decrease in density was not found in other regions, but also with no persistence of increase in density.