Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: Evidence from a novel positron emission tomography method

“…provided the basis for the dopamine hypothesis of schizophrenia (Creese et al., 1976; Seeman and Lee, 1975), which posits that patients with the illness have aberrant functioning of the dopaminergic system (Abi-Dargham et al., 1998; Breier et al., 1997; Hietala et al., 1995; Laruelle et al., 1996).”

“The striatum of schizophrenia patients displays augmentation of presynaptic dopamine function, indicating an increase in dopamine synthesis capacity and/or an increase in presynaptic dopamine stores (Hietala et al. 1995, 1999; Breier et al. 1997; Abi-Dargham et al. 1998).”

“Using recently developed in vivo neurochemical imaging methods, several researchers have obtained results that suggest an association between greater amphetamine-induced striatal DA release and schizophrenia (Laruelle et al. 1996; Breier et al. 1997; Laruelle and Abi-Dargham 1999).”

“also showed that patients with schizophrenia compared with healthy volunteers had significantly greater amphetamine-related reductions in radioligand [11C] raclopride-specific binding ratio with PET [65].”

“…of schizophrenia has proved to be an enduring theoretical construct (Weinberger et al, 1988; Davis et al, 1991; Goldstein and Deutch, 1992), and recent imaging efforts have provided direct evidence that dopamine is altered in the disorder (Breier et al, 1997; Abi-Dargham et al, 1998, 2000).”

“2000) and in response to amphetamine (Abi-Dargham et al. 1998; Bertolino et al. 2000; Breier et al. 1997; Laruelle et al. 1996).”

“…THC may increase dopamine release in the human striatum, which is highly relevant to the aetiology of schizophrenia as dysfunction of the striatal dopamine system in schizophrenia has been demonstrated (Abi-Dargham et al., 2000; Breier et al., 1997; Laruelle et al., 1996; McGowan et al., 2004).”

“Hypofunctioning of the GABAergic system may be responsible for the striatal dopamine overactivity and behavioural changes noted in schizophrenic subjects (Breier et al., 1997).”

“…HPA axis impairment could be involved in the progression to psychosis by mediating both the inability to cope with stressful situations and the increased dopamine release in the meso-limbic areas in response to stress seen in patients with schizophrenia (Breier et al., 1997; Oswald et al., 2007).”

“…show increased subcortical DA release in response to an amphetamine challenge and increased baseline subcortical DA levels (Laruelle et al, 1996; Breier et al, 1997; Abi-Dargham et al, 1998, 2000), lending additional support to the hypothesis of increased subcortical DA in schizophrenia.”

“It should be noted, however, that enhanced rather than attenuated striatal dopamine release has been observed in other paradigms of sensitization to psychostimulants (for review, see Spanagel and Weiss, 1999) as well as in a subgroup of schizophrenics as evidenced by recent SPECT studies (Laruelle et al., 1996; Breier…”

“Assuming a ratio between the increase in dopamine levels and reduction in [ 11 C]raclopride binding of approximately 40:1 (Breier et al. 1997; Laruelle et al. 1997), the 25–100 % increase in striatal dopamine levels measured with microdialysis techniques after THC administration to animals (Chen et…”

“Kapur S, Zipursky R, Jones C, Remington G, Houle S (2000): Relationship between dopamine D(2) occupancy, clinical response, and side effects: A double-blind PET study of first-episode schizophrenia.”

“Receptor binding D1: [11C]NNC 112 [4,5] [11C]SCH23390 [67,121,137,228,230,289] D2: [76Br]spiperone [55,56,190,191] [76Br]lisuride [192–194] [11C]FLB 457 [211,290,332] [11C]methylspiperone [226,235,236,303,304,324–327] [11C]raclopride [35,79,80,117,120,123,134,207,211,212,238,255,274,280,291,305,319,328] [18F]fallyprid…”

“The decrement in striatal binding potential (b.p.) or V300 for benzamide DA D2/D3 radioligands following D-AMPH administration in primates has been shown to be linearly related to the level of D-AMPH-induced DA release (Laruelle et al, 1997; Breier et al, 1997).”

“…may blunt psychostimulant-induced increases in DA, and this effect may be particularly sensitive to comparisons between microdialysis and PET data (Breier et al., 1997; Butcher et al., 1991; Di Chiara and Imperato, 1988; Drevets et al., 1999; Guix et al., 1992; Hurd et al., 1998; Hurd and…”

“…administration of amphetamine has been well validated as a noninvasive measure of the change in extracellular DA concentration induced by the challenge drug (Breier et al., 1997; Carson et al., 1997; Endres et al., 1997; Kegeles et al., 1999; Laruelle et al., 1995, 1997; Villemagne et al., 1999).”

“Dopamine receptor ligands might, however, become the method of choice for neuroimaging of task-related endogenous neurotransmitter release (Koepp et al., 1998) and drug-induced changes in neurotransmitter release ( Breier et al., 1997 ).”

“Using methylphenidate and amphetamine challenges, brain PET confirmed the earlier SPECT finding of heightened release of dopamine in schizophrenic patients compared with controls (Breier et al, 1997; Kegeles et al, 2010; Laruelle et al, 1999, 2003).”

“In both studies functional neuroimaging methods were used, based on the observation that drug-induced increases in extracellular DA levels lead to linear decreases in either [C] raclopride or [I]IBZM binding to DA D2/D3 receptors in the striatum (Laruelle et al., 1997; Breier et al., 1997; Laruelle, 2000).”

“…dopamine for D2R binding, allowing an indirect measure of synaptic dopamine levels based on changes in D2 receptor availability, and it is estimated that a 10% reduction in D2 receptor binding by 11C-raclopride reflects a fivefold increase in synaptic dopamine levels (Breier et al., 1997).”

“…abnormalities in the PFC (Weinberger et al, 1986; Glantz and Lewis, 2000; Callicott et al, 2003) and hippocampus (Bogerts et al, 1985; Csernansky et al, 1998; Heckers et al, 1998) as well as dysregulation in the striatal DA system (Laruelle et al, 1996; Breier et al, 1997; Abi-Dargham et al, 1998).”

“Given the large increase in striatal DA release, 44%, needed to produce a 1% decrease in striatal [11C]raclopride binding potential (Breier et al, 1997), it is unlikely that clozapine-induced DA release could lead to the preferential occupancy seen with clozapine or quetiapine.”

“6 Regional Differences in Striatal Dopamine Release 695 orders, and mood disorders (Breier et al. 1997; Fibiger 1991; Grace 1991; Laruelle et al. 1996; Schlaepfer et al. 1997; Swerdlow & Koob 1987; Volkow et al. 1994; Willner 1995).”

“For the striatum, altered levels of dopamine in patients with schizophrenia has been shown in both challenge studies and in studies of baseline dopamine levels (Abi-Dargham et al., 1998, 2000 ; Breier et al., 1997 ; Laruelle et al., 1996).”

“…emission tomography studies consistently indicate that patients release more DA in response to amphetamine, compared to controls (Abi-Dargham et al. 1998; Breier et al. 1997; Laruelle et al. 1996), as well as having increased uptake and synthesis of DA (Hietala et al. 1995; Lindstrom et al. 1999).”

“However, a raclopride displacement trial design may have major limitations: (1) PD patients may not be able to maintain constant learning-related activation over the prolonged scanning period of a raclopride study; (2) in raclopride displacement studies, 8% extraneuronal dopamine increases translate into only 1% raclo…”

“LI is also disrupted in amphetamine-treated normal humans, in high-schizotypal humans, and in the acute stages of schizophrenia associated predominantly with positive symptomatology and increased DA transmission (Laruelle et al. 1996, 1999; Breier et al. 1997; Abi-Dargham et al. 1998).”

“For example, such studies have been used to examine patients with schizophrenia (Abi-Dargham et al., 1998; Breier et al., 1997; Laruelle et al., 1996) and substance and alcohol abusers (Martinez et al., 2005; Martinez et al., 2007; Munro et al., 2006a).”

“In a simple form: (1) animals experience a motivationally salient outcome (for example, food) and determine the value of that reinforcer, (2) cues predictive of those outcomes are detected and attended to, and (3) any actions necessary to produce and obtain the reinforcer are acquired and performed.”

“Although evidence for increased dopaminergic transmission in schizophrenia is not conclusive (Carlsson 2001), several studies have reported increased striatal dopaminergic activity in schizophrenic patients (Breier et al. 1997; Laruelle et al. 1996).”

“These doses are similar to those used for PET imaging and microdialysis studies in nonhuman primates (Breier et al., 1997; Laruelle et al., 1997; Moghaddam et al., 1993).”

“striatal DA release following acute AMPH challenge (Laruelle et al. 1996, 1999; Breier et al. 1997; Abi-Dargham et al. 1998) and elevated striatal DA synthesis capacity (Hietala et al.”

“These experiments were carried out in an effort to try and replicate the abnormalities noted in patients with schizophrenia after an amphetamine challenge, as measured by [ 11 C]raclopride and [ 123 I]IBZM (Laruelle et al., 1996; Brier et al., 1997; Abi-Dargham et al., 1998).”

“Increased sensitivity to AMPH mimics the well documented subcortical dopaminergic hyperfunction in SCZ, and in particular the exacerbation of psychotic symptoms in response to AMPH in SCZ patients (Abi-Dargham et al., 1998; Breier et al., 1997; Guillin et al., 2007; Laruelle et al., 1999, 1996).”

“Results by Laruelle et al. (1999) have been replicated and expanded by other researchers (Breier et al., 1997: Bertolino et al., 2000).”

“…compared to baseline described after similar doses of d-amphetamine and similar post-intake scanning intervals lie generally between approximately 10 and 15% for the whole striatum (Breier et al, 1997; Cardenas et al, 2004; Farde et al, 1992; Laruelle et al, 1997; Abi-Dargham et al, 1998).”

“In the presence of an elevated dopaminergic tone in ventral striatum as suspected in schizophrenia (Laruelle et al. 1996; Breier et al. 1997), ARI might contribute to normalize dopaminergic transmission in this area by replacing endogenous DA at a high occupancy level (~80%) and dampening intracellular signals due to…”

“This phenomenon has been well documented in nonhuman primates (Innis et al., 1992; Carson et al., 1997; Laruelle et al., 1997; Drevets et al., 1999) and humans (Laruelle et al., 1995; Breier et al., 1997; Drevets et al., 2001).”

“In fact it has been estimated that a 1% decrease in [11C]raclopride binding corresponds to at least an eightfold increase in extracellular DA (Breier et al. 1997).”

“Studies providing baseline radioligand binding data from mostly mixed samples of drug-naı̈ve and neuroleptic-free, acute and chronic schizophrenic patients, found no significant differences of baseline D2 receptor availability (Abi-Dargham et al., 1998; Breier et al., 1997; Laruelle et al., 1996), too.”

“…a dopamine D2 radiotracer, by SPECT or PET, provided strong support for the hypothesis that a 'hyperdopaminergic state' contributes to the symptoms during onset and subsequent periods of illness exacerbation (Abi-Dargham et al, 1998; Breier et al, 1997; Laruelle, 2000; Laruelle et al, 1996, 1999).”

“, 1976), patients with schizophrenia have increased dopamine release under amphetamine challenge compared to healthy control subjects (Abi-Dargham et al., 1998; Breier et al., 1997; Laruelle et al., 1996), and contemporary data suggest that dopamine is involved in learning from feedback (Schultz, 2002).”

“This finding has been replicated in several cohorts using in vivo PET and SPECT imaging (Abi-Dargham et al, 1998; Breier et al, 1998, 1997; Kegeles et al, 1999; Laruelle et al, 1998, 1999, 1996, 1995, 1997a, b).”

“D-Amphetamine administration reduces [(11)C]raclopride binding in proportion to the increase in extracellular dopamine.([20]) Postsynaptic function was assessed with the baseline PET with [(11)C]raclopride.”

“Although evidence for increased dopaminergic transmission in schizophrenia is not conclusive (Carlsson 2001), several studies have reported increased striatal dopaminergic activity in schizophrenic patients (Breier et al. 1997; Laruelle et al. 1996).”

“In addition, imaging studies have revealed a greater increase in DA levels upon amphetamine challenge in patients with schizophrenia compared to controls as measured by a decrease in D2/D3 receptor binding by [11C]raclopride (Breier et al., 1997) and [123I]iodobenzamide (Laruelle and Abi-Dargham, 1999) with the latter…”

“Based on data from animal studies, it has been estimated that a 1% decrease in striatal [11C]raclopride BP reflects at least an 8% increase in extracellular endogenous dopamine levels [4].”

“, 1986) that can provide quantitative information about striatal D2/3 receptor levels, but is also sensitive to fluctuations in endogenous dopamine release as increasing dopamine levels reduce (11)C-raclopride binding due to competitive binding (Breier et al., 1997; Laruelle, 2000).”