Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects.

Abstract

The dopamine hypothesis of schizophrenia proposes that hyperactivity of dopaminergic transmission is associated with this illness, but direct observation of abnormalities of dopamine function in schizophrenia has remained elusive. We used a newly developed single photon emission computerized tomography method to measure amphetamineinduced dopamine release in the striatum of fifteen patients with schizophrenia and fifteen healthy controls. Amphetamine-induced dopamine release was estimated by the amphetamine-induced reduction in dopamine D2 receptor availability, measured as the binding potential of the specific D2 receptor radiotracer [1231] The dopamine hypothesis of schizophrenia, formulated over 30 years ago, proposes that hyperactivity of dopaminergic transmission is associated with this illness (1). This hypothesis is based on the observation that dopamine D2 receptor antagonists alleviate symptoms of the illness (mostly positive symptoms), while dopamine agonists can induce psychotic states characterized by some salient features of schizophrenia (2). These pharmacological effects suggest, but do not establish, a dysregulation of dopamine systems in schizophrenia. Despite decades of effort to validate this hypothesis, documentation of abnormalities of dopamine function in schizophrenia has remained elusive. Postmortem studies measuring dopamine and its metabolites in the brain of schizophrenic patients have yielded inconsistent results (for review, see ref.3). Increased density of striatal dopamine D2 and D2-like receptors has been reported in postmortem studies, but this observation is difficult to interpret, given that neuroleptic drugs upregulate these receptors (4, 5). Positron emission tomography and single photon emission computerized tomography (SPECT) studies of striatal D2 and D2-like receptors density in neurolepticnaive schizophrenic patients have been inconclusive. While one group reported increased striatal D2-like receptors density in schizophrenia (6, 7), other groups reported negative results (8-12). The lack of clear evidence for increased dopaminergic indices in schizophrenia might indicate that dopaminergic transmission is enhanced only relative to other systems, such as serotonergic or glutamatergic systems (13,14). On the other hand, the absence of data supporting the dopamine hypothesis of schizophrenia might be due to the difficulty of obtaining direct measurement of dopamine transmission in the living human brain.Over the past few years, several groups have provided evidence that competition between neurotransmitters and radioligands for neuroreceptor binding allows measuring changes in synaptic neurotransmitter levels with in vivo binding techniques. In rodents, decreased uptake of D2 radioligands has been measured following amphetamine and other dopamine enhancing drugs, whereas the opposite effect (i.e., increased tracer accumulation) has been induced by drugs that decrease dopamine concentration (15)(16)(17). In baboons, decreased specific uptake of positron emission to...

Stress-Induced Dopamine Release in Humans at Risk of Psychosis: a [11C]Raclopride PET Study

“…Previous studies have shown that schizophrenic and schizotypal personality disorder patients have an exaggerated DA response to amphetamine (Laruelle et al, 1996;Breier et al, 1997;Abi-Dargham et al, 2004). Our data extend these findings by showing an elevated DA response to an ecological social stress as opposed to a pharmacological challenge.…”

“…In schizophrenic patients, increases in striatal DA release have generally been associated with the presence of positive symptoms (Laruelle et al, 1996(Laruelle et al, , 1999Abi-Dargham et al, 1998). However, the genetic liability for schizophrenia is thought to be better indexed by negative than positive symptom schizotypy (Tsuang et al, 1991).…”

“…In schizophrenia, a prototypical psychotic illness, there is clinical evidence of abnormal DA response to pharmacological challenge, metabolic stressor, and psychological stressor. For example, schizophrenic patients have a higher DA response to amphetamine than controls as measured by receptor binding studies (Laruelle et al, 1996;Breier et al, 1997), and do not show the expected decrease in plasma homovanillic acid (HVA, a DA metabolite) in response to a mental stressor (Sumiyoshi et al, 1999). Schizotypal personality disorder patients also show greater amphetamine-induced DA release than controls, though less than that seen in acute schizophrenic patients (Abi-Dargham et al, 2004).…”

Effects of Amphetamine on Visuospatial Working Memory Performance in Schizophrenia Spectrum Personality Disorder

“…Psychotic-like symptoms in the schizophrenia spectrum group did not worsen after administration of amphetamine in contrast to schizophrenic patients who experience a transient worsening of their symptoms (see reviews by Angrist et al 1980;van Kammen et al 1982). We hypothesize this may be because schizophrenia spectrum patients release less dopamine after amphetamine as compared to schizophrenic patients whose increased dopamine release correlates with the worsening of their psychotic symptoms (Laruelle et al 1996). We hypothesize that schizophrenia spectrum patients' dopamine release after amphetamine is similar to normal subjects' release after amphetamine consistent with our pilot data measuring dopamine release after amphetamine via SPECT utilizing an IBZM displacement paradigm (Koenigsberg et al 1999).…”

Effects of Atypical Antipsychotic Drug Treatment on Amphetamine-Induced Striatal Dopamine Release in Patients with Psychotic Disorders

“…The change in striatal radiotracer binding levels is attributable to changes in the concentration of synaptic dopamine that competes with the radiotracer for receptor binding. Using this approach, we ) and others (Laruelle et al 1996) have reported that amphetamine produced greater D-2 tracer binding reductions in schizophrenic patients than healthy controls suggesting enhanced synaptic dopamine concentrations in this illness.…”