Is schizophrenia a dopamine supersensitivity psychotic reaction?

Abstract

Adolf Meyer (1866-1950) did not see schizophrenia as a discrete disorder with a specific etiology but, rather, as a reaction to a wide variety of biopsychosocial factors. He may have been right. Today, we have evidence that gene mutations, brain injury, drug use (cocaine, amphetamine, marijuana, phencyclidine, and steroids), prenatal infection and malnutrition, social isolation and marginalization, can all result in the signs and symptoms of schizophrenia. This clinical picture is generally associated with supersensitivity to dopamine, and activates dopamine neurotransmission that is usually alleviated or blocked by drugs that block dopamine D2 receptors. While the dopamine neural pathway may be a final common route to many of the clinical symptoms, the components of this pathway, such as dopamine release and number of D2 receptors, are approximately normal in schizophrenia patients who are in remission. Postmortem findings, however, reveal more dimers of D1D2 and D2D2 receptors in both human schizophrenia brains and in animal models of schizophrenia. Another finding in animal models is an elevation of high-affinity state D2High receptors, but no radioactive ligand is yet available to selectively label D2High receptors in humans. It is suggested that synaptic dopamine supersensitivity in schizophrenia is an attempt at compensation for the original damage by heightening dopamine neurotransmission pathways (preparing the organism for fight or flight). The dopamine overactivity is experienced subjectively as overstimulation, which accounts for some of the clinical symptoms, with attempts at dampening down the stimulation leading to still other symptoms. Reaction and counter-reaction may explain the symptoms of schizophrenia.

Antipsychotic-Induced Dopamine Supersensitivity Psychosis: Pharmacology, Criteria, and Therapy

“…However, long-term administration of antipsychotics can increase brain dopamine binding sites [6,7] and produce behavioral supersensitivity to dopamine receptor stimulation in animals [6,7,8,9,10,11,12,13]. In humans, behavioral supersensitivity to dopamine [14,15,16,17,18] can be expressed through supersensitivity psychosis (SP) [19] and movement disorders such as tardive dyskinesia (TD) [20]. Moreover, drug-induced SP may superimpose on dopamine supersensitivity already present in schizophrenia [16,21,22,23].…”

“…In humans, behavioral supersensitivity to dopamine [14,15,16,17,18] can be expressed through supersensitivity psychosis (SP) [19] and movement disorders such as tardive dyskinesia (TD) [20]. Moreover, drug-induced SP may superimpose on dopamine supersensitivity already present in schizophrenia [16,21,22,23]. In 1978/1979, Chouinard and Jones [21,22] proposed that a decrease in functional brain dopamine leads to dopamine supersensitivity, compensatory dopamine overactivity, and psychotic positive symptoms in schizophrenia.…”

“…An increase in D 2 receptor occupancy by dopamine can occur in first-episode drug-naïve schizophrenia and in previously treated patients experiencing an untreated exacerbation of psychosis [24]. Seeman et al [25,26] proposed that in several regions of the brain an increase in the number of D 2 receptors in the high-affinity state (D 2 High ) for dopamine is the pharmacological basis of antipsychotic-induced SP and idiopathic psychosis [16]. The D 2 receptor, like other receptors, can exist in either a high- or low-affinity state for dopamine and dopamine agonists (D 2 High or D 2 Low , respectively).…”

A Novel Aminotetralin-Type Serotonin (5-HT)2CReceptor-Specific Agonist and 5-HT2ACompetitive Antagonist/5-HT2BInverse Agonist with Preclinical Efficacy for Psychoses

“…Psychotic disorders, which affect approximately 3% of the population (Perala et al, 2007), are associated with an overactive striatal dopamine system (Abi-Dargham et al, 1998;Seeman and Seeman, 2014). Specifically, persons with schizophrenia are hypersensitive to psychostimulants (Curran et al, 2004), show elevated psychostimulant-induced dopamine release (Abi-Dargham et al, 1998), and display increased presynaptic dopamine synthesis in the striatum (Seeman and Seeman, 2014).…”

“…Specifically, persons with schizophrenia are hypersensitive to psychostimulants (Curran et al, 2004), show elevated psychostimulant-induced dopamine release (Abi-Dargham et al, 1998), and display increased presynaptic dopamine synthesis in the striatum (Seeman and Seeman, 2014). Most existing antipsychotic medications interact primarily with dopamine D 2 receptors to, theoretically, normalize dopamine signaling.…”