Gamma Vinyl-GABA Differentially Modulates NMDA Antagonist-Induced Increases in Mesocortical Versus Mesolimbic DA Transmission

Schiffer, Wynne K.; Gerasimov, Madina R.; Hofmann, Lauren; Marsteller, Douglas; Ashby, Charles R.; Brodie, Jonathan D.; Alexoff, David; Dewey, Stephen L.

doi:10.1016/s0893-133x(01)00268-8

Cited by 20 publications

(11 citation statements)

References 64 publications

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“…Similarly, Santiago et al (1993a) observed, significant reduction of basal DA release in PFC and substantia nigra (SN) by baclofen, but no significant effect in the STR. As in the present study, the inhibitory effect of gamma-vinyl GABA, a GABA-transaminase inhibitor (GVG) over PCP-induced DA release were more pronounced in PFC than in subcortical regions (Schiffer et al, 2001). …”

Section: Discussionsupporting

confidence: 70%

GABAB/NMDA receptor interaction in the regulation of extracellular dopamine levels in rodent prefrontal cortex and striatum

et al. 2009

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Deficits in N-methyl-d-aspartate receptor (NMDAR)-mediated neurotransmission may underlie dopaminergic hyperactivity in schizophrenia. Dysregulation of the GABAergic system has also been implicated. In this study we investigated a role for GABAB receptors as an intermediate step in the pathway leading from NMDAR stimulation to DA regulation. Since glycine (GLY) has been found to ameliorate treatment resistant negative symptoms in schizophrenia, we treated a group of rats with 16% GLY food for 2 weeks. DA levels in prefrontal cortex (PFC) and striatum (STR) were assessed by dual-probe microdialysis and HPLC–EC in freely moving rats. Infusion of the GABAB receptor agonists SKF97541 and baclofen into PFC and STR significantly reduced basal DA, an effect that was reversed by the antagonist, CGP52432. In PFC, GABAB agonists also reduced AMPH-induced DA release following treatment with either 1 or 5 mg/kg AMPH. Similar effects were seen following subchronic glycine treatment in the absence, but not presence of CGP52432 during 5 mg/kg AMPH treatment. In STR SKF97541 decreased only the 1 mg/kg AMPH-induced DA release. Subchronic GLY treatment in STR leads to a significant reduction in basal DA levels, but did not affect AMPH (5 mg/kg)-induced release. Our findings support a model in which NMDA/glycine-site agonists modulate DA release in part through presynaptic GABAB receptors on DA terminals, with both GABAB ligands and GLY significantly modulating AMPH-induced DA release. Both sites, therefore, may represent appropriate targets for drug development in schizophrenia and substance abuse disorders.

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Section: Discussionsupporting

confidence: 70%

GABAB/NMDA receptor interaction in the regulation of extracellular dopamine levels in rodent prefrontal cortex and striatum

et al. 2009

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“…If NMDA receptor antagonism diminishes GABA neuron firing (Hondo et al, 1995), then systemically increasing GABAergic inhibition (via GABA A or GABA B receptor agonists) should have little consequence. In fact, our previous in vivo microdialysis results in freely moving animals demonstrated that increased GABAergic activity produced a preferential inhibition of cortical over subcortical DA release (Schiffer et al, 2001a). Similarly, local application of specific GABA receptor agonists (muscimol, baclofen, or bicuculline) in cortical (Yonezawa et al, 1998) or subcortical (Westerink et al, 1996) areas produced a Figure 3 Time-activity data from striatum and cerebellum ROIs from four PET studies where primates were pretreated with GVG (300 mg/kg) prior to a PCP challenge (0.5 mg/kg) before the second 11 C-raclopride scan.…”

Section: Discussionmentioning

confidence: 97%

“…Further, Tsukada et al (2001) attribute ketamine's lack of effect on extracellular systems to an increased efficacy of DAT sites, while our data suggest that PCP specifically, is a more potent blocker of these proteins than was previously thought. Thus, microdialysis measures of increases in extracellular DA in response to PCP might reflect spillover secondary to monoamine transporter blockade at higher doses (Schiffer et al, 2001a), while lower doses of PCP may be absent from this effect. In fact, recent findings using MK-801 have provided evidence that this drug increases the availability of DAT sites (Nakano et al, 1998;Page et al, 2000;Schiffer et al, 2001b;Kagawa et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…Further, if the present reductions in 11 C-raclopride binding were due to a direct competition for D 2 receptor sites Seeman, 2001, 2002), then it is unlikely that a priori increases in GABAergic tone would influence this effect. Thus, it appears that PCP-induced decreases in 11 Craclopride binding are related to a combination of direct stimulation from glutamatergic spillover (Adams and Moghaddam, 1998) and DAT blockade itself (Schiffer et al, 2001a) and that like cocaine, these decreases are susceptible to partial modulation by GABAergic systems.…”

Section: Discussionmentioning

confidence: 99%

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Positron Emission Tomography Studies of Potential Mechanisms Underlying Phencyclidine-Induced Alterations in Striatal Dopamine

Schiffer

Logan

Dewey

2003

Neuropsychopharmacol

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Positron emission tomography (PET), in combination with 11 C-raclopride, was used to examine the effects of phencyclidine (PCP) on dopamine (DA) in the primate striatum. In addition, we explored the hypotheses that GABAergic pathways as well as molecular targets beyond the N-methyl-D-aspartate (NMDA) receptor complex (ie dopamine transporter proteins, DAT) contribute to PCP's effects. In the first series of experiments, 11 C-raclopride was administered at baseline and 30 min following intravenous PCP administration. In the second series of studies, g-vinyl GABA (GVG) was used to assess whether enhanced GABAergic tone altered NMDA antagonistinduced changes in DA. Animals received an initial PET scan followed by pretreatment with GVG (300 mg/kg), then PCP 30 min prior to a second scan. Finally, we explored the possible contributions of DAT blockade to PCP-induced increases in DA. By examining 11 Ccocaine binding a paradigm in which PCP was coadministered with the radiotracer, we assessed the direct competition between these two compounds for the DAT. At 0.1, 0.5, and 1.0 mg/kg, PCP decreased 11 C-raclopride binding by 2.1, 14.9 7 2.2 and 8.18 7 1.1%, respectively. These effects were completely attenuated by GVG (3.38 7 3.1% decrease in 11 C-raclopride binding). Finally, PCP (0.5 mg/ kg) decreased 11 C-cocaine binding by 25.5 7 4.3%, while at 1.0 mg/kg this decrease was 13.5%, consistent with a competitive interaction at the DAT. These results suggest that PCP may be exerting some direct effects through the DAT and that GABA partially modulates NMDA-antagonist-induced increases in striatal DA.

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“…Conversely, enhancement of GABAergic activity by either γ-vinyl-GABA (GVG) or lorazepam in baboons inhibits dopamine transmission in the striatum as indicated by increased [""C]raclopride binding (Dewey et al, 1992). Furthermore, GVG treatment has been shown to increases phencyclidine-induced release of dopamine in a dose-dependent manner in the rat prefrontal cortex but not in the striatum (Schiffer et al, 2001). Hypofunctioning of the GABAergic system may be responsible for the striatal dopamine overactivity and behavioural changes noted in schizophrenic subjects (Breier et al, 1997).…”

Section: Historical Perspectivesmentioning

confidence: 99%

The GABAergic system in schizophrenia

Blum

Mann

2002

Int. J. Neuropsychopharm.

118

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A defect in neurotransmission involving γ-amino butyric acid (GABA) in schizophrenia was first proposed in the early 1970s. Since that time, a considerable effort has been made to find such a defect in components of the GABAergic system. After a brief introduction focusing on historical perspectives, this paper reviews postmortem and other biological studies examining the following components of the GABAergic system in schizophrenic subjects : the GABA biosynthetic enzyme, glutamate decarboxylase ; free GABA ; the GABA transporter ; the GABA A , GABA B and benzodiazepine receptors ; and the catabolic enzyme GABA transaminase. Additionally, post-mortem studies using morphology or calcium-binding protein to identify GABAergic neurons are also reviewed. Substantial evidence argues for a defect in the GABAergic system of the frontal cortex in schizophrenia which is limited to the parvalbumin-class of GABAergic interneurons.

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Gamma Vinyl-GABA Differentially Modulates NMDA Antagonist-Induced Increases in Mesocortical Versus Mesolimbic DA Transmission

Cited by 20 publications

References 64 publications

GABAB/NMDA receptor interaction in the regulation of extracellular dopamine levels in rodent prefrontal cortex and striatum

GABAB/NMDA receptor interaction in the regulation of extracellular dopamine levels in rodent prefrontal cortex and striatum

Positron Emission Tomography Studies of Potential Mechanisms Underlying Phencyclidine-Induced Alterations in Striatal Dopamine

The GABAergic system in schizophrenia

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