The effects of chronic haloperidol administration on GABA‐immunoreactive. Axon terminals in rat medial prefrontal cortex

Vincent, Stephen L.; Adamec, Emil; Sorensen, Ingrid; Beneš, Francine M.

doi:10.1002/syn.890170104

Cited by 63 publications

(32 citation statements)

References 47 publications

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“…In an earlier study, GAD 65 -containing terminals showed APD dose-related increases, suggesting that these drugs may contribute to compensatory sprouting of GABAergic terminals, particularly in the SO of CA3/2 (18). Consistent with this, rats receiving chronic administrations of haloperidol showed marked increases in the number of GABAcontaining terminals forming axosomatic contacts with pyramidal neurons in the medial prefrontal cortex (19). Moreover, in the current report, mRNA for GAD 65 showed no significant changes in either SZs or BDs, suggesting that APD exposure might have increased its expression to normal levels.…”

Section: Discussionsupporting

confidence: 88%

Circuitry-based gene expression profiles in GABA cells of the trisynaptic pathway in schizophrenics versus bipolars

Beneš

Lim

Matzilevich

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Significant reductions in GABAergic cell numbers and/or activity have been demonstrated in the hippocampus of subjects with schizophrenia and bipolar disorder. To understand how different subpopulations of interneurons are regulated, laser microdissection and gene expression profiling have been used to ''deconstruct'' the trisynaptic pathway, so that subtypes of GABA cells could be defined by their location in various layers of CA3/2 and CA1. The results suggest that the cellular endophenotypes for SZ and BD may be determined by multiple factors that include unique susceptibility genes for the respective disorders and altered integration among hippocampal GABA cells with extrinsic and intrinsic afferent fiber systems. The extensive and intricate data that has come from this study has provided insights into how a complex circuit, like the trisynaptic pathway, may be regulated in human hippocampus in both health and disease.GAD67 ͉ potassium ion transport ͉ synaptic transmission ͉ kainate ͉ nicotinic G ene expression plays a central role in the regulation of neural circuitry involved in cognitive behavior. Identifying molecular mechanisms within neurons of complex circuits presents one of the foremost challenges to understanding the human brain. In the past 20 years, postmortem studies of schizophrenia (SZ) and bipolar disorder (BD) have provided evidence for a dysfunction of GABAergic neurons in frontal cortices and hippocampus (1). It is well known that GABAergic interneurons provide potent inhibitory modulation of principle neurons (2) and are critical for the regulation of feed-forward inhibition (3) and oscillatory rhythms (4, 5). A network of genes involved in the regulation of glutamate decarboxylase 67 (GAD 67 ), a key marker for the GABA cell phenotype (6), shows changes in expression in SZ that are different from those seen in BD, suggesting that there may be unique molecular endophenotypes for each disorder. To learn more about the molecular regulation of hippocampal GABA cells in SZ and BD, a combination of laser microdissection (LMD) and gene expression profiling has been used to ''deconstruct'' the trisynaptic pathway into subtypes of GABA neurons defined by their location and connectivity. Several clusters of genes have been examined across a broad array of cellular functions that include transduction, signaling, metabolism, translation, transcription and cell cycle regulation. These clusters have been separately analyzed in various layers and sectors with a preponderance of GABA cells. To our knowledge, this is the first demonstration that the regulation of gene expression in GABA cells varies not only according to diagnosis, but also to location within a complex circuit.

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Section: Discussionsupporting

confidence: 88%

Circuitry-based gene expression profiles in GABA cells of the trisynaptic pathway in schizophrenics versus bipolars

Beneš

Lim

Matzilevich

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

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“…These data suggest that there may be an intrinsic reduction of GABAergic terminals in the hippocampus of schizophrenics and the therapeutic efficacy of the neuroleptic drugs may involve, at least in part, a trophic sprouting of these terminals. This conclusion is consistent with a controlled study in rat medial prefrontal cortex (anterior cingulate region) in which chronic haloperidol administration was associated with a marked increase of GABA-IR terminals (Vincent et al 1994b). …”

Section: Postmortem Evidence For a Gaba Defect In Schizophreniasupporting

confidence: 91%

GABAergic Interneurons Implications for Understanding Schizophrenia and Bipolar Disorder

Beneš

Berretta

2001

Neuropsychopharmacology

989

643

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Neurons that express the compound, ␥ -aminobutyric acid (GABA), are broadly present throughout the central nervous system, although telencephalic structures, such as the cerebral cortex, show the most abundant quantities of this neurotransmitter (Jones 1987). In the discussion that follows, the anatomy and physiology of various types of GABAergic interneurons in the cortex and hippocampus will be discussed and related to recent postmortem studies implicating this transmitter system in the pathophysiology of schizophrenia and bi- 25 , NO . 1 polar disorder and their treatment with neuroleptic drugs (for more comprehensive reviews on cortical and hippocampal neurons see: Hof et al. 1993;Freund and Buzsaki 1996;Somogyi et al. 1998). NEUROBIOLOGY OF GABAERGIC INTERNEURONSBased on Golgi-impregnation studies, Ramon y Cajal provided the first descriptions of several different morphological subtypes of interneurons in the cerebral cortex and hippocampus (Ramon y Cajal 1893, 1911. In more recent years, it has been shown that, with some overlap, different morphological subtypes also have distinct distributions, connectivity, neurochemistry, and electrophysiological properties (for reviews see Hof et al. 1993;Freund and Buzsaki 1996). It is interesting to note that every segment of a pyramidal neuron, such as the soma, dendritic branches and spines, and the initial axonal segment, receives dense GABAergic synaptic innervation (O'Kusky and Colonnier 1982;Hendry et al. 1983;Houser et al. 1983; Beaulieu et al. 1992; for reviews see Jones 1993;Freund and Buzsaki 1996). Even more interestingly, each of these segments appears to be innervated by distinct GABAergic neuronal subtypes (see below).These differences strongly suggest that each of these subtypes plays a fundamentally different role in physiological and pathological mechanisms. In the discussion that follows, cortical interneurons will be described first, since our most basic understanding of GABAergic cells is derived from these populations. In more recent years, however, similar characterizations of interneurons in hippocampus have emerged. Although these cells show some striking similarities to their cortical counterparts, there are also some unique features that distinguish them. For this reason, interneurons in the hippocampus are discussed separately. Cortex Neuroanatomical Studies of Cortical Interneurons.Various types of GABAergic neurons can be categorized according to the type of synaptic profiles they are associated with, as this has direct implications for understanding the physiological role of these cells in cortical circuits. These categories are discussed below.A XO -S OMATIC I NHIBITORY S YNAPSES (B ASKET C ELLS ). The most commonly encountered interneurons ( Figure 1A) are multipolar in shape, i.e., they may have three or more primary dendritic branches emanating from their cell bodies, some having somata that are as large as those of pyramidal neurons (Jones and Hendry 1984). Using immunocytochemistry to localize the enzyme ). These cells also ...

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“…This compound did not, however, alter striatal D, receptor number. Finally, it should be noted that while these findings support a role for 5-HT's ability to modulate striatal DA, the findings observed with PET may also result from 5-HT's ability to modulate other neurotransmitter systems (i.e., GABA, sigma opiates) that in turn modulate striatal DA release (Vincent et al, 1994). In fact, it is conceivable that the net effect of 5-HT on striatal DA modulation is via an inhibitory role on another neurotransmitter system that inhibits striatal DA release.…”

Section: Discussionmentioning

confidence: 79%

Serotonergic modulation of striatal dopamine measured with positron emission tomography (PET) and in vivo microdialysis

et al. 1995

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Positron emission tomography and in vivo microdialysis were used to study serotonin's role in modulating striatal dopamine. Serial PET studies were performed in adult female baboons at baseline and following drug treatment, using the dopamine (D2) selective radiotracer, 11C-raclopride. The serotonergic system was manipulated by administration of the selective 5-HT reuptake inhibitor, citalopram, or by serotonergic (5-HT2) receptor blockade (using altanserin, a 5-HT2 antagonist). 11C-Raclopride time-activity data from striatum and cerebellum were combined with plasma arterial input functions and analyzed by calculating a distribution volume as described previously (Logan et al., 1990). Additionally, in vivo microdialysis studies were performed in awake freely moving rats using similar pharmacologic challenges plus SR 46349B, a new highly selective 5-HT2 receptor antagonist. Altanserin and SR 46349B increased extracellular striatal dopamine concentrations (35% and 910%, respectively) while altanserin decreased striatal 11C-raclopride binding (37%). Citalopram, however, decreased extracellular striatal dopamine concentrations (50%) and increased 11C-raclopride binding (33%). These data demonstrate that 5- HT-selective drugs produce changes in striatal dopamine that can be measured noninvasively with PET. Furthermore, the PET data obtained from anesthetized baboons is consistent with in vivo microdialysis data obtained from awake and freely moving rats. Finally, these studies have implications for understanding the therapeutic efficacy of atypical neuroleptics and their utility for treating schizophrenia and affective disorders.

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The effects of chronic haloperidol administration on GABA‐immunoreactive. Axon terminals in rat medial prefrontal cortex

Cited by 63 publications

References 47 publications

Circuitry-based gene expression profiles in GABA cells of the trisynaptic pathway in schizophrenics versus bipolars

Circuitry-based gene expression profiles in GABA cells of the trisynaptic pathway in schizophrenics versus bipolars

GABAergic Interneurons Implications for Understanding Schizophrenia and Bipolar Disorder

Serotonergic modulation of striatal dopamine measured with positron emission tomography (PET) and in vivo microdialysis

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