Enhanced [³H]DOPA and [³H]Dopamine Turnover in Striatum and Frontal Cortex In Vivo Linked to Glutamate Receptor Antagonism

Abstract

Abstract:We tested the hypothesis that blockade of NMDA glutamate receptors in brain enhances dopamine turnover. We blocked this class of glutamate receptors in the rat brain in vivo with dizocilpine (MK-801 ) and measured the accumulation of radiolabeled DOPA and its metabolites as functions of time after intravenous bolus injection. Using the time courses of the accumulated metabolites, we calculated the turnover constants of enzymes mediating dopamine synthesis and catabolism. Dizocilpine treatment for 8 days enhanced the rates of DOPA decarboxylation and dopamine oxidation (monoamine oxidation) 4-and 16-fold, respectively, in neostriaturn and 10-and 3-fold, respectively, in frontal cortex. The findings are not inconsistent with the hypothesis that the psychotomimetic properties of dizocilpine may be the manifestation of denervation hypersensitivity linked to activation of key enzymes of dopamine turnover in striatum.

Elevated [18F]Fluorodopamine Turnover in Brain of Patients with Schizophrenia: An [18F]Fluorodopa/Positron Emission Tomography Study

“…Reduced task-related cerebral blood flow activation of the frontal cortex correlates with increased FDOPA utilization in striatum of patients with schizophrenia (Meyer-Lindenberg et al, 2002), consistent with our finding of increased turnover of [ 3 H]dopamine in the striatum of rats treated with an NMDA antagonist (Reith et al, 1998), a pharmacological treatment intended to emulate loss of corticostriatal input. Abnormal dopamine transmission in schizophrenia may thus reflect the cerebrometabolic response of a striatal dopamine innervation that is "mis-informed" with respect to its modulation by the frontal cortex.…”

Serotonergic modulation of receptor occupancy in rats treated with l‐DOPA after unilateral 6‐OHDA lesioning

“…In addition to the inhibition in serotonergic neurons of l ‐DOPA metabolism and DA release, stimulation of 5‐HT 1A receptors also may affect motor activity in animals with impaired dopaminergic neurotransmission. This effect may be mediated by stimulation of post‐synaptic 5‐HT 1A receptors which modulate the glutamatergic cortico‐striatal innervation that affects general activity (Reith et al. 1998; Mignon and Wolf 2005).…”

MK-801 inhibits l-DOPA-induced abnormal involuntary movements only at doses that worsen parkinsonism

“…; Murase et al, 1993; Zhang et al, 1992), to cause dopamine release after systemic (0.1 mg/kg; Mathe et al, 1998) or intracerebral administration (10–100 μM, i.c. ; Hondo et al, 1994), and to increase dopamine turnover (0.2 mg/kg; Reith et al, 1998). In the 6-OHDA rat, MK-801 causes ipsiversive rotation (0.05–0.25 mg/kg MK-801; Goto et al, 1993), and reduces contraversive turning in response to an acute challenge with 25 mg/kg L-DOPA (0.3 mg/kg MK-801; Spooren et al, 2000) or 0.05 mg/kg apomorphine (0.1 mg/kg MK-801; Robinson et al, 2001).…”