However, the high rate of relapse

during prolonged treatment discontinuation suggests that this endogenous sensitization process might resume upon environmental, physiological, or pharmacological stress. DA hyperactivity, neuroplasticity, and positive symptoms The data derived from the brain-imaging studies reviewed above are consistent with the hypothesis that subcortical DA transmission mediates the expression of positive symptoms in patients with schizophrenia. However, the data also suggest, that a component, of the positive symptomatology Inhibitors,research,lifescience,medical is independent of increased activity of subcortical DA transmission. First, as discussed earlier, the increase in DA transmission at striatal D2 receptors following amphetamine explained only 30% of the variability in the psychotic response to d-amphetamine. Second, the severity of positive symptoms was not associated with increased synaptic DA Inhibitors,research,lifescience,medical concentration as revealed by the α-MPT challenge. Thus, a simple relationship between intensity of DA transmission at the D2 receptors and Inhibitors,research,lifescience,medical severity of positive symptoms is an NLG919 manufacturer oversimplification.

In addition, such a simple relationship is not supported by the delay between D2 receptor blockade and antipsychotic response, or by resistance of positive symptoms to even sustained dopaminergic blockade in about 25% of patients with schizophrenia.69 In this context, it is also important to note a critical difference in the propsychotic effects of DA agonists, on the Inhibitors,research,lifescience,medical one hand, and NMDA antagonists or serotonin 5-HT2A agonists, on the other. In healthy individuals, drugs such

as ketamine or lysergic acid diethylamide (LSD) induce a psychotic state immediately upon drug exposure, while sustained administration of DA agonists Inhibitors,research,lifescience,medical the is required for the emergence of psychotic symptoms (for a review, see reference 95). This unique effect of DA agonists suggests that some plasticity or neuroadaptation is required between the hyperstimulation of D2 receptors and the psychotic experience. To account, for these data, one must, postulate that, with time, increased DA activity triggers neuroplastic adaptation “downstream” from the mesolimbic dopaminergic synapse and that, once established, these neuroplastic changes become independent, of increased DA activity. Positive symptoms circuits might become “hard wired” inprefrontal-ventrostriatal-ventropallidal-mediodorsalthalamoprefrontal loops67,96 (Figure 3).