Pre- and postsynaptic localization of GABAB receptors in the basal ganglia in monkeys

Charara, Ali; Heilman, Craig J.; Levey, Aĺlan I.; Smith, Yoland

doi:10.1016/s0306-4522(99)00409-1

Cited by 125 publications

(105 citation statements)

References 94 publications

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“…This line of reasoning is consistent with the fact that systemic baclofen decreases cocaine or amphetamine-induced dopamine levels in the striatum by B40-50% (Fadda et al, 2003;Zhou et al, 2004). Less is known about the cellular distribution of GABA B receptors and their coupling in the dorsal and ventral striatum of rodents, but Charara et al (2000) demonstrated GABA B immunoreactivity in striatal boutons that make asymmetric contacts with labeled and unlabeled dendritic spines. The presynaptic localization in glutamatergic afferents is consistent with electrophysiological evidence that the predominant effect of baclofen in the striatum is to decrease excitatory synaptic input (Nisenbaum et al, 1993).…”

Section: Effects Of Intracerebral Baclofen On Amphetamine-induced Behsupporting

confidence: 56%

“…In support of the regional differences in baclofen's effectiveness, perfusion of baclofen into the SN decreased basal and nomifensine-induced extracellular dopamine levels in the SN and CPu, but infusion into the CPu did not decrease striatal dopamine levels (Westerink et al, 1992;Santiago et al, 1993;Balon et al, 2002). GABA B receptors are expressed by striatonigral, striatopallidal, and glutamatergic afferents as well as by dopamine and GABA neurons in the SN and VTA (Sugita et al, 1992;Charara et al, 2000;Boyes and Bolam, 2003). However, the amphetaminesuppressing effect of baclofen in the ventral mesencephalon is most consistent with a direct action on dopamine neurons.…”

Section: Effects Of Intracerebral Baclofen On Amphetamine-induced Behmentioning

confidence: 84%

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Intracerebral Baclofen Administration Decreases Amphetamine-Induced Behavior and Neuropeptide Gene Expression in the Striatum

Zhou

Mailloux

McGinty

2004

Neuropsychopharmacol

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In a previous study, systemic administration of the GABA B receptor agonist, R-( þ )-baclofen (2.5 mg/kg, i.p.) blocked acute amphetamine (2.5 mg/kg, i.p.)-induced rearing and neuropeptide (preprodynorphin (PPD), preprotachykinin (PPT), preproenkephalin (PPE), and secretogranin II (SGII)) mRNA expression in the striatum (Zhou et al, 2004). The purpose of the present study was to investigate the site(s) of action of these baclofen effects in the dorsal and ventral striatal circuitries. Infusion of baclofen (75 ng/side) into the ventral tegmental area (VTA), substantia nigra (SN), nucleus accumbens (NA), caudate-putamen (Cpu), or medial prefrontal cortex (mPFC) had no effect on behavioral activity in saline-treated rats habituated to a photocell apparatus. However, intra-VTA infusion of baclofen (75 ng/ side) completely blocked, whereas intra-NA and intra-SN infusion of baclofen attenuated, amphetamine-induced vertical activity without affecting amphetamine-induced total distance traveled. In contrast, intramedial PFC and intra-CPu infusion of baclofen had no effect on behavioral activity in amphetamine-treated rats. Infusion of baclofen into the VTA, NA, or SN decreased amphetamine-induced neuropeptide gene expression in the striatum. These results indicate that GABA B receptor stimulation within the ventral striatal circuitry is involved in mediating acute amphetamine-induced behaviors and neuropeptide gene expression in the dorsal and ventral striatum. The present study provides information on the potential targets in the brain for baclofen in the initial behavioral and genomic response to amphetamine.

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Section: Effects Of Intracerebral Baclofen On Amphetamine-induced Behsupporting

confidence: 56%

Section: Effects Of Intracerebral Baclofen On Amphetamine-induced Behmentioning

confidence: 84%

Intracerebral Baclofen Administration Decreases Amphetamine-Induced Behavior and Neuropeptide Gene Expression in the Striatum

Zhou

Mailloux

McGinty

2004

Neuropsychopharmacol

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“…Instead, GABA B(1) protein was mostly detected on glutamatergic and dopaminergic terminals. GABA B(1) is also expressed on glutamatergic and dopaminergic terminals in monkey brain (68). This localization implies that GABA B receptors are activated by spillover GABA from adjacent synapses.…”

Section: Cellular and Subcellular Distributionmentioning

confidence: 99%

Molecular Structure and Physiological Functions of GABA_BReceptors

Bettler

Kaupmann

Mosbacher

et al. 2004

Physiological Reviews

804

720

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GABAB receptors are broadly expressed in the nervous system and have been implicated in a wide variety of neurological and psychiatric disorders. The cloning of the first GABAB receptor cDNAs in 1997 revived interest in these receptors and their potential as therapeutic targets. With the availability of molecular tools, rapid progress was made in our understanding of the GABAB system. This led to the surprising discovery that GABAB receptors need to assemble from distinct subunits to function and provided exciting new insights into the structure of G protein-coupled receptors (GPCRs) in general. As a consequence of this discovery, it is now widely accepted that GPCRs can exist as heterodimers. The cloning of GABAB receptors allowed some important questions in the field to be answered. It is now clear that molecular studies do not support the existence of pharmacologically distinct GABAB receptors, as predicted by work on native receptors. Advances were also made in clarifying the relationship between GABAB receptors and the receptors for γ-hydroxybutyrate, an emerging drug of abuse. There are now the first indications linking GABAB receptor polymorphisms to epilepsy. Significantly, the cloning of GABAB receptors enabled identification of the first allosteric GABAB receptor compounds, which is expected to broaden the spectrum of therapeutic applications. Here we review current concepts on the molecular composition and function of GABAB receptors and discuss ongoing drug-discovery efforts.

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“…The recent development of highly sophisticated electron microscopic immunocytochemical approaches allowed us and others to better characterize the subsynaptic and subcellular localization of neurotransmitter receptors involved in mediating synaptic communication at various GABAergic and glutamatergic synapses in the primate basal ganglia (Paquet and Smith, 1996;Waldvogel et al, 1998Waldvogel et al, , 1999Charara et al, 1999Charara et al, , 2000aHanson and Smith, 1999;Smith et al, 2000a). Unfortunately, due to problems inherent to postmortem tissue with the preservation of ultrastructural features, such studies cannot be carried out in human material.…”

Section: Introductionmentioning

confidence: 99%

Kainate Receptors in the Striatum: Implications for Excitotoxicity in Huntington's Disease

Smith¹

2004

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302, and yolands@rmy.emory.edu Huntington's disease (HD) is a neurodegenerative condition characterized by a loss of projection neurons in the striatum. Although various hypotheses have been proposed to explain the mechanisms that underlie the striatal neuronal death, excitotoxicity still deserves major interest. Recent findings indicate that changes in the genotype of the kainate receptor subunit, GluR6, are associated with variation in the age of onset of HD, which implicates the kainate receptors in the pathogenesis of HD. The rationale of this project is that pre-synaptic kainate receptors control the release of glutamate from cortical or thalamic terminals, and that an abnormal regulation of these receptors is involved in the death of striatal neurons in HD. We, therefore, propose to use state-of-the-art electron microscope techniques to test a series of hypotheses that will help to elucidate the localization and understand better the role of kainate receptors in the primate striatum. The results of these studies will provide a strong basis for studying the potential mechanisms by which these receptors participate in the death of striatofugal neurons in HD. Moreover, they will help the development of novel therapeutic strategies aimed at targeting presynaptic kainate receptors in HD and other basal ganglia disorders. PERFORMING ORGANIZATION NAME(S) AND ÄDDRESS(ES)Emory SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES)U SUBJECT TERMS INTRODUCTION:Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by the death of striatal neurons. Chorea is the most common involuntary movement in patients who suffer of HD. This could be combined with cognitive and memory deficits at a later stage of the disease. The HD mutation was identified in 1993 as an unstable expansion of CAG (trinucleotide) repeats on the gene which encodes the protein "Huntingtin" on chromosome 4. In more than 60% of HD patients, there is a high degree of inverse correlation between the number of CAG repeats and the age of onset of the disease or degree of striatal degeneration (Vonsatell and DiFiglia, 1998). However, about 15% of the HD cases of which the age of onset cannot be explained by the CAG repeats, were found to have mutations in the gene encoding the GluR6 subunit of the glutamatergic kainate receptor (Rubinztein et al., 1997;MacDonald et al., 1999) which highlight the importance of those receptors in the pathogene...

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Pre- and postsynaptic localization of GABAB receptors in the basal ganglia in monkeys

Cited by 125 publications

References 94 publications

Intracerebral Baclofen Administration Decreases Amphetamine-Induced Behavior and Neuropeptide Gene Expression in the Striatum

Intracerebral Baclofen Administration Decreases Amphetamine-Induced Behavior and Neuropeptide Gene Expression in the Striatum

Molecular Structure and Physiological Functions of GABA_BReceptors

Kainate Receptors in the Striatum: Implications for Excitotoxicity in Huntington's Disease

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Pre- and postsynaptic localization of GABAB receptors in the basal ganglia in monkeys

Cited by 125 publications

References 94 publications

Intracerebral Baclofen Administration Decreases Amphetamine-Induced Behavior and Neuropeptide Gene Expression in the Striatum

Intracerebral Baclofen Administration Decreases Amphetamine-Induced Behavior and Neuropeptide Gene Expression in the Striatum

Molecular Structure and Physiological Functions of GABABReceptors

Kainate Receptors in the Striatum: Implications for Excitotoxicity in Huntington's Disease

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Product

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Molecular Structure and Physiological Functions of GABA_BReceptors