Increased Synaptic Dopamine Function in Associative Regions of the Striatum in Schizophrenia

Abstract

These findings suggest that schizophrenia is associated with elevated dopamine function in associative regions of the striatum. Because the precommissural dorsal caudate processes information from the dorsolateral prefrontal cortex, this observation also suggests that elevated subcortical dopamine function might adversely affect performance of the dorsolateral prefrontal cortex in schizophrenia. On the other hand, the absence of a group difference in the limbic striatum brings into question the therapeutic relevance of the mesolimbic selectivity of second-generation antipsychotic drugs.

The effect of striatal dopamine depletion on striatal and cortical glutamate: A mini-review

“…This is at least prima facie consistent with the notion that increased dopaminergic activity in the striatum should also result in greater glutamatergic activity therein. This also mirrors the findings in persons with schizophrenia, wherein both increased striatal dopamine and striatal glutamate levels are observed compared to healthy controls; albeit in the dorsal striatum (Caravaggio et al, 2015;Kegeles et al, 2010). However, a negative correlation was observed between glutamate concentrations in the left prefrontal cortex and dopamine synthesis capacity in the left ventral striatum (r 2 = .17).…”

“…Consistent with the basal ganglia model, persons with cocaine addiction have also been observed to have less glutamate-to-creatine in the rostral anterior cingulate (Yang et al, 2009), and less glutamateto-glutamine in the dorsal anterior cingulate (Yucel et al, 2007) In patients affected by schizophrenia, it has been demonstrated with PET that there is more endogenous dopamine occupying D 2/3 R in the dorsal caudate (Caravaggio et al, 2015;Kegeles et al, 2010). In accordance with the classical model, it has been demonstrated with 1 HMRS that persons at ultra-high risk for psychosis (characterized by sub-threshold psychotic symptoms, a high likelihood of a family history of schizophrenia, and a decline in everyday functioning) and patients with a first episode of psychosis have increased glutamate levels in the dorsal caudate compared to healthy controls (de la Fuente-Sandoval et al, 2013a,b;de la Fuente-Sandoval et al, 2011).…”

“…Acute dopamine depletion is possible in humans via administration of the tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (AMPT). Challenges with AMPT have been successfully employed in conjunction with PET to estimate endogenous dopamine levels at D 2/3 R in living humans (Caravaggio et al, 2015;Caravaggio et al, 2014;Kegeles et al, 2010;Laruelle et al, 1997;Martinez et al, 2009;Verhoeff et al, 2001). Thus, measuring glutamate concentrations with 1 H-MRS before and after AMPT administration could help elucidate how dopamine depletion alters glutamatergic functioning in healthy persons and persons with neuropsychiatric diseases.…”

“…Abnormalities in these dopaminergic and glutamatergic systems have been observed in numerous neuropsychiatric disorders, including Parkinson's disease (Griffith et al, 2008;Loane and Politis, 2011;Pavese et al, 2011), depression (Musazzi et al, 2012;Treadway and Zald, 2011), drug addiction (Martinez et al, 2009;Yang et al, 2009;Yucel et al, 2007), and schizophrenia (de la Fuente-Sandoval et al, 2013a,b;de la Fuente-Sandoval et al, 2011;Kegeles et al, 2010). The classical model of the basal ganglia developed in the 1980s (Obeso and Lanciego, 2011) predicts that loss of striatal dopamine will decrease extracellular levels of glutamate in the striatum and cortex (Albin et al, 1989(Albin et al, , 1995Jones, 2012).…”

Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings

“…Studies have also suggested an increased affinity of D 2 receptors for DA in schizophrenia, that may produce a D 2 receptor supersensitivity in the NAc contributing to psychosis [79]. Additionally, a PET study found higher synaptic DA concentrations in the ventral striatum in schizophrenia [425]. …”