Psychosis pathways converge via D2High dopamine receptors

Abstract

The objective of this review is to identify a target or biomarker of altered neurochemical sensitivity that is common to the many animal models of human psychoses associated with street drugs, brain injury, steroid use, birth injury, and gene alterations. Psychosis in humans can be caused by amphetamine, phencyclidine, steroids, ethanol, and brain lesions such as hippocampal, cortical, and entorhinal lesions. Strikingly, all of these drugs and lesions in rats lead to dopamine supersensitivity and increase the high-affinity states of dopamine D2 receptors, or D2High, by 200-400% in striata. Similar supersensitivity and D2High elevations occur in rats born by Caesarian section and in rats treated with corticosterone or antipsychotics such as reserpine, risperidone, haloperidol, olanzapine, quetiapine, and clozapine, with the latter two inducing elevated D2High states less than that caused by haloperidol or olanzapine. Mice born with gene knockouts of some possible schizophrenia susceptibility genes are dopamine supersensitive, and their striata reveal markedly elevated D2High states; suchgenes include dopamine-beta-hydroxylase, dopamine D4 receptors, G protein receptor kinase 6, tyrosine hydroxylase, catechol-O-methyltransferase, the trace amine-1 receptor, regulator of G protein signaling RGS9, and the RIIbeta form of cAMP-dependent protein kinase (PKA). Striata from mice that are not dopamine supersensitive did not reveal elevated D2High states; these include mice with knockouts of adenosine A2A receptors, glycogen synthase kinase GSK3beta, metabotropic glutamate receptor 5, dopamine D1 or D3 receptors, histamine H1, H2, or H3 receptors, and rats treated with ketanserin or aD1 antagonist. The evidence suggests that there are multiple pathways that convergetoelevate the D2High state in brain regions and that this elevation may elicit psychosis. This proposition is supported by the dopamine supersensitivity that is a common feature of schizophrenia and that also occurs in many types of genetically altered, drug-altered, and lesion-altered animals. Dopamine supersensitivity, in turn, correlates with D2High states. The finding that all antipsychotics, traditional and recent ones, act on D2High dopamine receptors further supports the proposition.

The selective antagonist EPPTB reveals TAAR1-mediated regulatory mechanisms in dopaminergic neurons of the mesolimbic system

“…Taar1 Ϫ/Ϫ mice exhibit an increase in the high-affinity states of striatal D2 receptors (8), which is indicative of DA supersensitivity (20,21). We therefore investigated whether acute blockade of TAAR1 activity modulates D2 receptors in DA neurons of the VTA.…”

Phenotypic characterization of spatial cognition and social behavior in mice with ‘knockout’ of the schizophrenia risk gene neuregulin 1

“…There is also evidence for α7 nicotinic acetylcholine receptor [α7nAChR] dysregulation in schizophrenia (Leonard and Freeman, 2006;Olincy et al, 2006), for NRG1 modulation of α7nAChR currents (Chang and Fischbach, 2006) and for the involvement of the α7nAChR in social recognition (van Kampen et al, 2004). Regarding the long-standing dopamine [DA] hyperfunction hypothesis of schizophrenia (Kapur et al, 2005;Seeman et al, 2006), NRG1 can regulate aspects of DAergic neurotransmission (Yurek et al, 2004) and DAergic dysfunction, particularly in the medial prefrontal cortex, has been implicated in the detection of salient social and non-social stimuli (O'Tuathaigh et al, 2003;Bassareo et al, 2002;De Leonibus et al, 2006). However, while there is some evidence to suggest that DA plays a more significant role in the detection of novel, unfamiliar stimuli rather than in the discrimination of conspecifics based on prior exposure (De Leonibus et al, 2006), the present findings indicate NRG1 to be involved in the latter process.…”

Dopamine D2High receptors measured ex vivo are elevated in amphetamine‐sensitized animals

“…However, dopamine supersensitivity in rats is invariably associated with a major increase in brain striatal dopamine D2 High receptors, which are dopamine D2 receptors in the high-affinity state for dopamine (Seeman et al 2005a(Seeman et al , 2006a. Dopamine D2 receptors exist in a state of high affinity for dopamine D2…”