Dopamine supersensitivity correlates with D2^Highstates, implying many paths to psychosis

Abstract

Dopamine supersensitivity occurs in schizophrenia and other psychoses, and after hippocampal lesions, antipsychotics, ethanol, amphetamine, phencyclidine, gene knockouts of Dbh (dopamine ␤-hydroxylase), Drd4 receptors, Gprk6 (G protein-coupled receptor kinase 6), Comt (catechol-O-methyltransferase), or Th ؊/؊ , Dbh Th/؉ (tyrosine hydroxylase), and in rats born by Cesarean-section. The functional state of D2, or the high-affinity state for dopamine (D2 High ), was measured in these supersensitive animal brain striata. Increased levels and higher proportions (40 -900%) for D2 High were found in all these tissues. If many types of brain impairment cause dopamine behavioral supersensitivity and a common increase in D2 High states, it suggests that there are many pathways to psychosis, any one of which can be disrupted.addiction ͉ dopamine receptors ͉ gene knockouts ͉ schizophrenia

There and Back Again: A Tale of Norepinephrine and Drug Addiction

“…To explain the underlying mechanisms of this paradoxical hypersensitivity to psychostimulants on the part of Dbh À/À mice, we examined DA transmission by microdialysis and radioligand binding. We found that Dbh À/À mice have a reduction in basal extracellular DA in the NAc and CP, whereas amphetamine-induced DA release is abolished in the NAc and attenuated in the CP and PFC (Schank et al, 2006;Seeman et al, 2005). It is important to note that the 'ectopic' DA produced in 'noradrenergic' neurons in Dbh À/À mice is not the cause of the hypersensitivity; although Dbh À/À mice indeed produce more DA in brain tissue than normal mice (Thomas et al, 1998; Bourdelat-Parks et al, 2005), overall DA release is hampered.…”

“…It has been well established that the DA system compensates for a loss of dopaminergic tone by upregulating DA receptor signaling capacity, and that is exactly what happens in Dbh À/À mice. Using radioligand binding in the presence and absence of guanine nucleotide, which can discriminate between lowand high-affinity state DA receptors, we found that the density of high-affinity state DA receptors is increased three to to six-fold in the NAc and CP of Dbh À/À mice (Seeman et al, 2005;Schank et al, 2006). Furthermore, Dbh À/À mice are behaviorally hypersensitive to quinpirole, a direct D2 agonist (Weinshenker et al, 2002a).…”

The incentive sensitization theory of addiction: some current issues

“…This suggests a hypodopaminergic state rather than a sensitized state (Volkow et al 2004 (Seeman et al 2005). Most important for the discussion here, cocaine self-administration experience ) and sensitization to amphetamine (Seeman et al 2002(Seeman et al , 2007 have also been reported to produce a persistent increase in the number of striatal D high 2 receptors, with no change in total D 2 binding (and therefore presumably a proportionate decrease in D low 2 receptors).…”

Cocaine self-administration produces a persistent increase in dopamine D2High receptors

“…The ligands used in the human and non-human primate imaging studies do not discriminate between the low-and high-affinity states of the D2 receptor and would be, therefore, insensitive to changes in the number of D2 High receptors (Seeman et al, 2003;. Furthermore, there are many examples where an increase in D2 High receptors has been associated with dopamine supersensitivity, even when there was no change or even a decrease in total D2 receptors (Seeman et al, 2005). It is also worth mentioning that the human and non-human primate studies were performed in vivo and thus the apparent decrease in binding could be due to an increase in endogenous dopamine, which would interfere with ligand binding.…”

“…The transmitter dopamine binds primarily to the high-affinity state of the D2 receptor (D2 High ), making this the most functionally relevant state (Seeman, et al, 2005). Furthermore, many different treatments that produce a functional supersensitivity to dopamine (including repeated amphetamine administration) produce a large increase in the number of D2 High receptors in the dorsal striatum, even if they produce no change or even a decrease in the total number of D2 receptors (Seeman, et al, 2004, Seeman, et al, 2005. Unfortunately, the ligands used in the human imaging and non-human primate studies do not discriminate between the low-and high-affinity states of the D2 receptor and are, therefore, insensitive to changes in the number of D2 High receptors.…”