Targeting the dopamine D₂receptor in schizophrenia

Abstract

After a 12-year search for the antipsychotic receptor, the binding site was discovered and labelled by [3H]haloperidol in 1975. Of the various neurotransmitters, dopamine was the most potent in inhibiting the binding of [3H]haloperidol, indicating that the antipsychotic receptor was a dopamine receptor, now named the dopamine D2 receptor, a major targeting site in schizophrenia. All antipsychotic drugs, including traditional and newer antipsychotics, either bind to D2 in direct relation to their clinical potencies or hinder normal dopamine neurotransmission, as in the case of partial dopamine agonists. In fact, the antipsychotic concentrations found in the plasma water of treated patients closely match the predicted therapeutic absolute concentrations, adjusted for the 60-75% D2 occupancy needed for clinical efficacy. Antipsychotics that elicit low or no Parkinsonism or prolactinaemia are loosely attached to D2 and rapidly dissociate from D2, whereas those eliciting Parkinsonism stay tightly attached to D2 for many hours. Because animal models of psychosis (amfetamine sensitisation, brain lesions) all show a marked elevation in the number of high-affinity states of D2, the antipsychotics are thought to specifically target these D2High states in psychosis in general and schizophrenia in particular.

Clozapine, a Fast-Off-D2 Antipsychotic

“…16 However, here too there is no correlation between the risk of parkinsonism and the (K i at M1)/(K i at D2) ratio for the atypical antipsychotics, including clozapine. Such data do not make it likely that clozapine prevents parkinsonism by occluding the M1 muscarinic receptor.…”

MK-801-induced impairments on the trial-unique, delayed nonmatching-to-location task in rats: effects of acute sodium nitroprusside

“…Within the striatum and nucleus accumbens, D 2 receptors are abundant and patients with schizophrenia have increased D 2 receptor densities as well as heightened amphetamine sensitivity (Seeman 1987;Seeman 2006;Vinson and Conn 2012). Increased dopamine resulting from hyperactivity of the mesolimbic system is thought to underlie the positive symptoms (e.g.…”

Dopamine D2Receptor Activity Modulates Akt Signaling and Alters GABAergic Neuron Development and Motor Behavior in Zebrafish Larvae

“…Furthermore, it was recently shown that a balance between D 1 and D 2 receptor signaling could control the migration of newly generated GABAergic neurons in the forebrain (Crandall et al, 2007). These findings have important implications for understanding the neurodevelopmental basis of several behavioral disorders, for which alterations in DA and GABAergic neuronal systems have been implicated (Benes and Berretta, 2001;Seeman, 2006;Souza et al, 2006). However, the molecular mechanisms underlying DA modulation of GABAergic neuron development remain to be elucidated, and its direct impact on behavior has not yet been firmly established.…”