Dopamine receptors and the dopamine hypothesis of schizophrenia

Abstract

The discovery of neuroleptic drugs in 1952 provided a new strategy for seeking a biological basis of schizophrenia. This entailed a search for a primary site of neuroleptic action. The Parkinsonian effects caused by neuroleptics suggested that dopamine transmission may be disrupted by these drugs. In 1963 it was proposed that neuroleptics blocked "monoamine receptors" or impeded the release of monoamine metabolites. The neuroleptic concentration in plasma water or cerebrospinal fluid was of the order of 2 nM for haloperidol in clinical therapy. A systematic research was made between 1963 and 1974 for a primary site of neuroleptic action which would be sensitive to 2 nM haloperidol and stereoselective for (+)-butaclamol. Direct evidence that neuroleptics selectively blocked dopamine receptors occurred in 1974 with the finding that nanomolar concentrations of these drugs stereoselectively inhibited the binding of [3H]-dopamine or [3H]-haloperidol. These binding sites, now termed D2 dopamine receptors (which inhibit adenylate cyclase), are blocked by neuroleptics in direct relation to the antipsychotic potencies of the neuroleptics. No such correlation exists for D1 receptors (which stimulate adenylate cyclase). Based on the fact that dopamine-mimetic drugs elicited hallucinations, and that neuroleptics caused rigidity, Van Rossum in 1966 had suggested a hypothesis that dopamine pathways may be overactive in schizophrenia. The D2-selective blockade by all neuroleptics (except the monoamine-depleting reserpine) provided strong support for the dopamine hypothesis. Further support now comes from postmortem data and in vivo positron tomographic data, both of which indicate that the density of D2 receptors are elevated in the schizophrenic brain. The postmortem data indicate a bimodal pattern with half the schizophrenics having striatal D2 densities of 14 pmol/g (control is 13 pmol/g) and the other half having 26 pmol/g. Current positron tomographic data indicate D2 densities of 14 pmol/g in control subjects, but values of 34 pmol/g in drug-naive schizophrenics. Future tests of the dopamine hypothesis of schizophrenia may entail an examination of the amino acid composition and genes for D2 receptors in schizophrenic tissue, an examination of the ability of the D2 receptor to become phosphorylated and to desensitize into the low-affinity state, and an examination of the interaction of D2 receptors with D1 receptors or other neurotransmitters.

In Vivo Measurement of the Vesicular Monoamine Transporter in Schizophrenia

“…Since the 1960's, indirect evidence has implicated dopamine systems in schizophrenia and psychosis (Angrist et al 1974;Creese et al 1976;Seeman 1987;Snyder 1972). In the last 10 years, neuroimaging studies targeting dopamine systems have begun to characterize the role of dopamine in schizophrenia, although many questions remain.…”

“…Twelve schizophrenic subjects on stable doses of medications, along with 12 age and sex-matched healthy control subjects, underwent positron emission tomography (PET) studies with [ 11 C]dihydrotetrabenazine (DTBZ), which binds to the vesicular monoamine transporter, type 2 (VMAT2).Since the 1960's, indirect evidence has implicated dopamine systems in schizophrenia and psychosis (Angrist et al 1974;Creese et al 1976;Seeman 1987;Snyder 1972). In the last 10 years, neuroimaging studies targeting dopamine systems have begun to characterize the role of dopamine in schizophrenia, although many questions remain.…”

Animal models of cognitive dysfunction and negative symptoms of schizophrenia: Focus on NMDA receptor antagonism

“…It was initially hypothesized that a hyperdopaminergic state resulting from an excess of dopamine in the brain was the main cause for the condition of schizophrenia (Carlsson and 7 Lindqvist 1963;Seeman 1987). While there is much supporting evidence to validate this theory, including recent demonstration that psychotic patients release more dopamine at the synapse on stimulation with amphetamine than normal control groups suggesting increased midbrain dopamine activity (Abi-Dargham et al 2009), a revision of this theory became necessary when it was observed that the negative and cognitive symptoms of schizophrenia could not be accounted for by an excess of dopamine in the system (Thaker & Carpenter 2001).…”

Modulation of Amphetamine-Induced Dopamine Release by Group II Metabotropic Glutamate Receptor Agonist LY354740 in Non-Human Primates Studied with Positron Emission Tomography

“…While the fundamental pathophysiology of schizophrenia remains unknown, several lines of evidences suggest that this illness is associated with increased dopamine (DA) transmission at D 2 receptors (see, for reviews, Carlsson, 1978;Seeman, 1987;Weinberger, 1987;Davis et al, 1991;Laruelle, 2003) and decreased glutamate (GLU) transmission at N-methyl-D-aspartate (NMDA) receptors (see, for reviews, Javitt and Zukin, 1991;Olney and Farber, 1995;Jentsch and Roth, 1999;Konradi and Heckers, 2003;van Berckel, 2003). With the advance of brain imaging techniques, direct evidence of dysregulation of DA transmission in schizophrenia has emerged.…”