Showing papers on "GABAergic published in 1993"

GABAergic Neurons and Their Role in Cortical Plasticity in Primates

Abstract: GABA neurons and GABA receptors are conspicuous elements of cerebral cortical organization. They serve to shape the stimulus-response properties of neurons in the sensory areas and undoubtedly play a comparable role in the nonsensory areas as well. Although non-GABAergic local circuit neurons exist in the cerebral cortex, the variety of forms adopted by the GABAergic neurons and their important functional role have served to focus attention on the latter in investigations of local cortical circuitry. In primate neocortex, GABAergic neurons constitute approximately 25-30% of the neuronal population. In addition to their known or postulated functions in shaping neuronal receptive fields and response profiles, some of which are still controversial (Sillito, 1984; Ferster, 1986), their transmitter, GABA, and the major class of receptor upon which it acts are regulated in an activity-dependent manner even in the adult (Jones, 1990). In this, there is a potential mechanism for the plasticity of representational maps that is demonstrable in somatic sensory, motor, auditory, and visual cortex (Merzenich et al., 1983; Sanes et al., 1988; Robertson and Irvine, 1989; Kaas et al., 1990).

The GABAergic nervous system of Caenorhabditis elegans

Abstract: gamma-Aminobutyric acid (GABA) is the most abundant inhibitory neurotransmitter in vertebrates and invertebrates. GABA receptors are the target of anxiolytic, antiepileptic and antispasmodic drugs, as well as of commonly used insecticides. How does a specific neurotransmitter such as GABA control animal behaviour? To answer this question, we identified all neurons that react with antisera raised against the neurotransmitter GABA in the nervous system of the nematode Caenorhabditis elegans. We determined the in vivo functions of 25 of the 26 GABAergic neurons by killing these cells with a laser microbeam in living animals and by characterizing a mutant defective in GABA expression. On the basis of the ultrastructurally defined connectivity of the C. elegans nervous system, we deduced how these GABAergic neurons act to control the body and enteric muscles necessary for different behaviours. Our findings provide evidence that GABA functions as an excitatory as well as an inhibitory neurotransmitter.

Fixation cells in monkey superior colliculus. II: Reversible activation and deactivation

Abstract: 1. We tested the hypothesis that a subset of neurons, which we have referred to as fixation cells, located within the rostral pole of the monkey superior colliculus (SC) controls the generation of saccadic eye movements. We altered the activity of these neurons with either electrical stimulation or GABAergic drugs. 2. An increase in the activity of fixation cells in the rostral SC, induced by a train of low-frequency electrical stimulation, delayed the initiation of saccades. With bilateral stimulation the monkey was able to make saccades only after stimulation ceased. 3. Pulses of stimulation delivered during the saccade produced an interruption of the saccade in midflight. The latency to the onset of this perturbation was as short as 12 ms. 4. Injection of the gamma-aminobutyric acid (GABA) antagonist bicuculline into the rostral pole of the SC, which decreases normal GABA inhibition and increases cell activity, increased the latency of saccades to both visual and remembered targets. 5. Injection of the GABA agonist muscimol into the rostral SC, which increases normal GABA inhibition and decreases activity, reduced the latency for saccades to visual targets. The monkey also had difficulty maintaining visual fixation and suppressing unwanted saccades. 6. After muscimol injections, monkeys frequently made very short-latency saccades forming a peak in the saccade latency histogram at < 100 ms. These saccades are similar to express saccades made by normal monkeys. This finding suggests that the fixation cells in the rostral SC are critical for controlling the frequency of express saccades. 7. These results support the hypothesis that fixation cells in the rostral SC inhibit the generation of saccadic eye movements and that they form part of a system of oculomotor control, that of visual fixation.

Genes required for GABA function in Caenorhabditis elegans

Abstract: gamma-Aminobutyric acid (GABA) neurotransmission is widespread in vertebrate and invertebrate nervous systems. Here we use a genetic approach to identify molecules specific to GABA function. On the basis of the known in vivo roles of GABAergic neurons in controlling behaviour of the nematode Caenorhabditis elegans, we identified mutants defective in GABA-mediated behaviours. Five genes are necessary either for GABAergic neuronal differentiation or for pre- or postsynaptic GABAergic function. The gene unc-30 is required for the differentiation of a specific type of GABAergic neuron, the type-D inhibitory motor neuron. The gene unc-25 is necessary for GABA expression and probably encodes the GABA biosynthetic enzyme glutamic acid decarboxylase. The genes unc-46 and unc-47 seem to be required for normal GABA release. Finally, the gene unc-49 is apparently necessary postsynaptically for the inhibitory effect of GABA on the body muscles and might encode a protein needed for the function of a GABAA-like receptor. Some of these genes are likely to encode previously unidentified proteins required for GABA function.

Postsynaptic targets of GABAergic hippocampal neurons in the medial septum-diagonal band of broca complex

Abstract: The termination pattern of hippocamposeptal nonpyramidal cells was investigated by injecting Phaseolus vulgaris leucoagglutinin (PHAL) into stratum oriens of the CA1 region. Electron microscopic analysis showed that the majority of the anterogradely labeled boutons formed symmetric synapses with dendrites and occasionally with cell bodies located in the medial septum-diagonal band of Broca complex. We have demonstrated with postembedding GABA immunocytochemistry that the majority of PHAL-labeled axon terminals were GABAergic. The neurochemical character of the postsynaptic target cells was also investigated using immunocytochemical double staining. Our data showed that the majority of the labeled hippocamposeptal axons innervated parvalbumin-immunoreactive cells representing GABAergic projection neurons, and a smaller number of contacts were found on ChAT-positive neurons. Septohippocampal neurons identified by retrograde HRP transport were also shown to reactive direct hippocamposeptal input. According to recent results, the lateral septum is unlikely to relay the hippocampal feedback to the medial septum; therefore, the direct hippocampal projection to the medial septum, arising from GABAergic nonpyramidal cells, seems to be the only feedback pathway to the area containing septohippocampal neurons. A novel circuit diagram, based on our recent morphological-immunocytochemical findings, is shown for the synaptic organization of the septo-hippocampo-septal loop. We suggest that the GABAergic hippocamposeptal feedback controls the activity of septal (mostly GABAergic) projection neurons as a function of hippocampal synchrony. The newly discovered reciprocal interactions may give a better insight into septohippocampal physiology.

Evidence for "preterminal" nicotinic receptors on GABAergic axons in the rat interpeduncular nucleus

Abstract: Presynaptic nicotinic ACh receptors (nAChRs) are abundant in the nervous system, where they are thought to regulate the release of various neurotransmitters. Whole-cell recordings performed on rat interpeduncular nucleus neurons using the thin-slice technique showed that nicotine dramatically increased the frequency of postsynaptic GABAergic currents. This effect was observed at low micromolar concentration of agonist; it was mimicked by cytisine, dimethylphenylpiperazinium, and ACh in the presence of eserine. It was blocked by hexamethonium, dihydro-beta-erythroidine, and mecamylamine. The presynaptic action was suppressed in the presence of TTX. A comparable effect of nicotine was found using a preparation of acutely isolated neurons that had retained synaptic terminals attached to their cell body as evidenced by immunoreactivity to synaptophysin and presence of spontaneous GABAergic and glutamatergic synaptic activity. Nicotinic agonists increased the frequency of GABAergic postsynaptic currents, an effect blocked by curare and mecamylamine. This action was also suppressed in the presence of TTX. These data suggest the presence of nAChRs at a preterminal level on axons of intrinsic GABAergic neurons. We propose that, in contrast to presynaptic nAChRs, activation of these "preterminal" nAChRs can trigger a spike discharge and thus have a generalized action on the GABAergic afferent.

The striopallidal neuron : a main locus for adenosine-dopamine interactions in the brain

Abstract: Recent pharmacological data suggest that a receptor-receptor interaction between adenosine A2 and dopamine D2 receptors in the brain underlies the behavioral effects of adenosine agonists and adenosine antagonists, such as caffeine and theophylline. According to this interaction, stimulation of A2 receptors inhibits and their blockade potentiates the effects of D2 receptor stimulation. Furthermore, both A2 and D2 receptors are selectively colocalized on GABAergic striopallidal neurons. In this microdialysis investigation the effect of intrastriatal infusion of adenosine and dopamine agonists and antagonists alone or in combination was studied on the release of GABA from the terminals of the striopallidal neuron in awake, freely moving rats. We report that the GABAergic striopallidal neuron, which is a key component of the indirect striatal efferent pathway, is a main locus for A2-D2 interactions in the brain and possibly a main target for the central actions of adenosine agonists and antagonists.

GABAergic circuits of the striatum.

Abstract: Publisher Summary The neostriatum contains a large number of neurons and terminals that contain y-aminobutyric acid (GABA), an inhibitory transmitter. GABAergic inhibition has been thought to play a major role in regulating the neuronal activities of the striatum. This chapter discusses the studies on the GABAergic circuits and their functions in the striatum. First, it describes the anatomical organizations and then discusses the functional implications of GABAergic elements. The neostriatum contains many GABAergic neurons and GABAergic synaptic terminals, which are considered to be major elements in regulating the neuronal activities of the striatum. Anatomical and physiological studies indicate that GABAergic interneurons play a major role in the regulation of the firing activity of the spiny projection neurons through their feedforward connection. It is also suggested by anatomical studies that cholinergic and dopaminergic inputs affect the activity of GABAergic interneurons.

Regulation of neuropeptide expression in cultured cerebral cortical neurons by brain-derived neurotrophic factor.

Abstract: The neuropeptide-inducing activity of neurotrophic factors was tested in cultured cerebral cortical neurons. Brain-derived neurotrophic factor (BDNF) specifically increased contents of the neuropeptides somatostatin (SOM) and neuropeptide Y (NPY), but its effect on contents of cholecystokinin octapeptide and GABA was much less significant. The maximal induction of NPY content (15-fold increase) was achieved by 20 ng/ml of BDNF. These changes were also reproduced at the mRNA level. In contrast, neurotrophin-3 was much less potent at increasing NPY and SOM contents, and nerve growth factor had no effect on them. The expression of mRNA for NPY and SOM was fully dependent on the presence of BDNF in culture but irrelevant to the survival-promoting activity of BDNF, which has been reported previously. Most of the NPY immunoreactivity induced by BDNF was colocalized with glutamate decarboxylase immunoreactivity in cultured cortical neurons. These results suggest that BDNF regulates the peptidergic expression of GABAergic neurons in the cerebral cortex.

Coexistence of NADPH diaphorase with GABA, glycine, and acetylcholine in rat spinal cord.

Abstract: The enzyme NADPH diaphorase is present in many spinal neurons, and is thought to correspond to nitric oxide synthase. In order to determine which types of neuron in the spinal cord contain this enzyme, we have carried out a combined enzyme histochemical and immunocytochemical study with antibodies to GABA, glycine, and choline acetyltransferase. Two hundred and twenty-four NADPH diaphorase-positive neurons in midlumbar spinal cord from four rats were tested for GABA- and glycine-like immunoreactivity. The majority of these neurons (207/224) were GABA-immunoreactive and 139 were also glycine-immunoreactive. NADPH diaphorase-positive neurons in laminae I and II generally showed both types of immunoreactivity, while those in deeper laminae of the dorsal horn and around the central canal either showed both types or else were only GABA-immunoreactive. Since GABA and acetylcholine are thought to coexist in spinal neurons, NADPH diaphorase staining was combined with immunostaining for choline acetyltransferase. Immunoreactive neurons in laminae III and IV were all NADPH diaphorase-positive, while only some of those around the central canal and in the deeper laminae of the dorsal horn were positive. Choline acetyltransferase-immunoreactive neurons in the intermediolateral cell column (presumed sympathetic preganglionic neurons) were often NADPH diaphorase-positive, whereas those in the ventral horn (presumed motorneurons) were not. NADPH diaphorase-positive cells in the intermediolateral cell column were not immunoreactive with GABA or glycine antibodies. These results suggest that NADPH diaphorase is largely restricted to GABAergic neurons in the lumbar spinal cord, and that it is mainly present in those neurons in which GABA coexists with glycine or acetylcholine. Since nitric oxide has been implicated in pain processing and hyperalgesia, while GABA, glycine, and acetylcholine are thought to be involved in analgesia and prevention of hyperalgesia, it is likely that nitric oxide synthase-containing GABAergic neurons in dorsal horn have dual actions in transmission of nociceptive information. © 1993 Wiley-Liss, Inc.

Neostriatal GABAergic interneurones contain NOS, calretinin or parvalbumin.

Abstract: To reveal functional heterogeneity among GABAergic interneurones in rat neostriatum, we investigated: (1) whether nitric oxide synthase (NOS)- and calretinin-immunoreactive cells, like parvalbumin-immunoreactive cells, were also immunoreactive for 67 kD glutamic acid decarboxylase (GAD67) and GABA; (2) whether NOS cells, calretinin cells and parvalbumin cells belonged to separate populations or not. NOS cells, calretinin cells and parvalbumin cells all showed immunoreactivity for GAD67 in colchicine-treated rats. Calretinin cells and parvalbumin cells were also immunoreactive for GABA. Only a few cells (0-3%) showed immunoreactivity for two antigens. These results suggest that the neostriatum has at least three GABAergic interneuronal systems.

Cholinergic modulation of synaptic inhibition in the guinea pig hippocampus in vitro: excitation of GABAergic interneurons and inhibition of GABA-release.

Abstract: 1. The effect of cholinergic receptor activation on gamma-aminobutyric acid (GABA)-mediated inhibitory synaptic transmission was investigated in voltage-clamped CA1 pyramidal neurons (HPNs) in the guinea pig hippocampal slice preparation. 2. The cholinergic agonist carbachol (1-10 microM) induced a prominent and sustained increase in the frequency and amplitudes of spontaneous inhibitory postsynaptic currents (IPSCs) in Cl(-)-loaded HPNs. The potentiation of spontaneous IPSCs was not dependent on excitatory synaptic transmission but was blocked by atropine (1 microM). 3. Monosynaptically evoked IPSCs were reversibly depressed by carbachol (10 microM). 4. The frequency of miniature IPSCs recorded in the presence of tetrodotoxin (0.6 or 1.2 microM) was reduced by carbachol (10 or 20 microM) in an atropine-sensitive manner. 5. We conclude that, while cholinergic receptor activation directly excites hippocampal GABAergic interneurons, it has, in addition, a suppressant effect on the synaptic release mechanism at GABAergic terminals. This dual modulatory pattern could explain the suppression of evoked IPSCs despite enhanced spontaneous transmission.

Network of GABAergic large basket cells in cat visual cortex (area 18): Implication for lateral disinhibition

Abstract: Anatomical and immunohistochemical data indicate that, in addition to pyramidal neurons, nonpyramidal cells are exposed to perisomatic inhibition mediated by γ-aminobutyric acid (GABA)-containing terminals. However, no direct information is available as yet for the origin of GABAergic inputs to morphologically identified GABAergic neurons. In the present paper, we studied the topographical and synaptic relationship between identified GABAergic large basket cells and their immunohistochemically characterized target neurons revealed by parvalbumin-(PV) and GABA immunostaining in the same material. Extracellularly applied biocytin labelled a total of 36 and 9 large basket cells in layers III and V, respectively. Of these, the axonal arborizations of two basket cells, BC1 and BC2, were reconstructed. The axon of BC1 occupied an area of about 2.3 × 2.2 mm2 in layer III, providing a total of 2,755 terminals. The axon of BC2 showed an overall extent of 3.8 × 1.7 mm2 in layer V elongated in the anteroposterior direction, and gave off 1,599 terminals. Immunostaining for PV was carried out to reveal putative nonpyramidal targets for BC1 and BC2. It was found that in addition to immunonegative cells, they established an average of 4–6 perisomatic contacts onto each of 58 (BC1) and 33 (BC2) PV-immunopositive neurons. For electron microscopic verification, 23 terminals apposing the somata of 12 PV-immunopositive neurons were selected. Each terminal was found to establish symmetrical (type II) contacts with its targeted cell. Furthermore, the distribution of soma area of the targeted PV-immunopositive cells and of identified large basket cells showed remarkable similarity, implying that the two populations were actually the same. In addition, the average horizontal distance between neighbouring PV-immunopositive target cells was found to be about 100 μm both in layers III and V. The results suggest that in area 18 the same large basket cell provides direct inhibition to certain pyramidal cells and facilitation to other pyramidal neurons, by inhibiting their presynaptic large basket cells at regular intervals. 1993 Wiley-Liss, Inc.

Immunocytochemical localization of the amino acid neurotransmitters in the chicken retina

Abstract: Postembedding immunocytochemistry was used to determine the cellular localization of the amino acid neurotransmitters glutamate, aspartate, gamma-aminobutyric acid (GABA), and glycine in the avian retina. The through retinal pathway was glutamatergic, with all photoreceptors, bipolar cells, and ganglion cells being immunoreactive for glutamate. Bipolar cells displayed the highest level of glutamate immunoreactivity, with the cell bodies terminating just below the middle of the inner nuclear layer. All lateral elements, horizontal cells, amacrine cells, and interplexiform cells were immunoreactive for glycine or GABA. The GABAergic neurons consisted of two classes of horizontal cells and amacrine cells located in the lower part of the inner nuclear layer. GABA was also localized in displaced amacrine cells in the ganglion cell layer, and a population of ganglion cells that co-localize glutamate and GABA. Both the horizontal cells and GABAergic amacrine cells had high levels of glutamate immunoreactivity, which probably reflects a metabolic pool. At least two types of horizontal cells in the avian retina could be discriminated on the basis of the presence of aspartate immunoreactivity in the H2 horizontal cells. Glycine was contained in a subclass of amacrine cells, with their cell bodies located between the bipolar cells and GABAergic amacrine cells, two subclasses of bipolar cells, displaced amacrine cells in the ganglion cell layer, and ganglion cells that colocalize glutamate and glycine. Glycinergic amacrine cells had low levels of glutamate. We have also identified a new class of glycinergic interplexiform cell, with its stellate cell body located in the middle of the inner nuclear layer among the cell bodies of bipolar cells. Neurochemical signatures obtained by analyzing data from serial sections allowed the classification of subclasses of horizontal cells, bipolar cells, amacrine cells, and ganglion cells. © 1993 Wiley-Liss, Inc.

Adenosine A2a receptor modulation of electrically evoked endogenous GABA release from slices of rat globus pallidus.

Abstract: Adenosine A2a receptors have been localized to GABAergic striatopallidal neurons, but their functional role is unknown. To address this question, the modulation of endogenous GABA release by adenosine A2a receptors was examined in slices of rat globus pallidus. The selective adenosine A2a receptor agonist CGS-21680 (3.0-10 nM) significantly increased electrically stimulated release (overflow) of GABA, with 10 nM CGS-21680 resulting in a 44% increase compared with the control. Both the nonselective adenosine receptor antagonist 8-phenyltheophylline (10 microM) and the selective A2a receptor antagonist KF-17837 (100 nM) abolished the CGS-21680-induced increase in GABA overflow. Higher concentrations of CGS-21680 (0.10-1.0 microM) decreased GABA overflow by approximately 25%. 8-Phenyltheophylline (10 microM) antagonized these effects, whereas KF-17837 (100 nM) did not, suggesting actions of CGS-21680 on other adenosine receptors at these concentrations. These results demonstrate that activation of adenosine A2a receptors augments electrically stimulated release of GABA from globus pallidus slices and suggest a mechanism by which adenosine may modulate GABAergic output from the striatopallidal efferent system.

Neurochemical substrates of rigidity and chorea in Huntington's disease

Abstract: SUMMARY Huntington's disease is a progressive degenerative neurological disorder which produces a characteristic movement disorder termed chorea. Although chorea is associated with dysfunction of the basal ganglia, the underlying mechanisms by which dyskinesias such as chorea are produced, are poorly understood. Recent studies in primates have led to experimental models of chorea with postulated involvement of specific neural pathways. In the present study we attempted to determine the validity of the experimental models by measuring concentrations of γaminobutyric acid (GABA), glutamate, substance P and met-enkephalin in the basal ganglia of Huntington's disease patients who manifested either chorea or rigidity/bradykinesia within 6 months of death. We also characterized changes in the Huntington's disease patients according to pathological grade, since this may be a confounding factor. We analysed post-mortern brain tissue from 12 controls, and 11 grade 3 and 12 grade 4 Huntington's disease patients. The grade 3 and 4 cases consisted of eight adult-onset choreic, nine adult-onset rigid and six juvenile-onset rigid patients. We also analysed the putamen and globus pallidus from 11 grade 2 adult onset choreic Huntington's disease patients. A model of chorea based on experimental studies in primates proposes that a loss of striatal GABAergic inhibitory projections to the globus pallidus externa leads to increased activity of the inhibitory globus pallidus externa GABAergic neurons which project to the subthalamic nucleus. It is believed that the loss of GABAergic inputs to the globus pallidus externa precedes a loss of GABAergic input to the globus pallidus interna, which occurs later in the disease and is associated with the development of rigidity and bradykinesia. In the choreic Huntington's disease patients whom we studied, there was a greater loss of GABA in the globus pallidus externa than in the globus pallidus interna, and the globus pallidus interna: globus pallidus externa GABA ratio was significantly increased compared with rigid patients. There were also increases in GABA in the subthalamic nucleus in the choreic patients, although this did not reach significance. A differential loss of met-enkephalin in the globus pallidus externa compared with substance P loss in the globus pallidus interna was not observed in either the choreic patients with advanced disease or the grade II patients. There was a significant increase in GABA concentrations in the ventroanterior nucleus of the thalamus in the choreic patients compared with rigid/bradykinetic patients. These results are in accord with major tenets of proposed models of dyskinesia in experimental animals; however, the finding of increased GABA in the thalamus requires modification of current theories.

Cellular localizations of AMPA glutamate receptors within the basal forebrain magnocellular complex of rat and monkey

Abstract: The cellular distributions of alpha-amino-3-hydroxy-5-methyl-4- isoxazole propionic acid (AMPA) receptors within the rodent and nonhuman primate basal forebrain magnocellular complex (BFMC) were demonstrated immunocytochemically using anti-peptide antibodies that recognize glutamate receptor (GluR) subunit proteins (i.e., GluR1, GluR4, and a conserved region of GluR2, GluR3, and GluR4c). In both species, many large GluR1-positive neuronal perikarya and aspiny dendrites are present within the medial septal nucleus, the nucleus of the diagonal band of Broca, and the nucleus basalis of Meynert. In this population of neurons in rat and monkey, GluR2/3/4c and GluR4 immunoreactivities are less abundant than GluR1 immunoreactivity. In rat, GluR1 does not colocalize with ChAT, but, within many neurons, GluR1 does colocalize with GABA, glutamic acid decarboxylase (GAD), and parvalbumin immunoreactivities. GluR1- and GABA/GAD-positive neurons intermingle extensively with ChAT-positive neurons. In monkey, however, most GluR1-immunoreactive neurons express ChAT and calbindin-D28 immunoreactivities. The results reveal that noncholinergic GABAergic neurons, within the BFMC of rat, express AMPA receptors, whereas cholinergic neurons in the BFMC of monkey express AMPA receptors. Thus, the cellular localizations of the AMPA subtype of GluR are different within the BFMC of rat and monkey, suggesting that excitatory synaptic regulation of distinct subsets of BFMC neurons may differ among species. We conclude that, in the rodent, BFMC GABAergic neurons receive glutamatergic inputs, whereas cholinergic neurons either do not receive glutamatergic synapses or utilize GluR subtypes other than AMPA receptors. In contrast, in primate, basal forebrain cholinergic neurons are innervated directly by glutamatergic afferents and utilize AMPA receptors.

Bidirectional effects of GABAergic agonists and antagonists on maintenance of voluntary ethanol intake in rats

Abstract: The effects of THIP (GABAA agonist) and picrotoxin (GABA antagonist) on the maintenance of voluntary ethanol ingestion were examined. Thirty-three male Long-Evans rats were initially exposed to a screening procedure in which increasing concentrations of ethanol (from 2% to 9%) were presented in a free choice with water, on an alternate day schedule. Following the screening procedure, the rats were exposed to five ethanol presentations at a concentration of 9%, which constituted the baseline period, and five additional ethanol presentations during which the effects of the GABAergic manipulations were determined (test period). During the test period, the animals received IP injections of either 16 mg/kg of THIP, 2 mg/kg of picrotoxin or saline. The results suggested that the differential GABA manipulations resulted in bidirectional effects on the consumption of ethanol. More specifically, the GABAA agonist THIP increased the intake of ethanol as compared to baseline measures, while the GABA antagonist picrotoxin decreased ethanol intake. Similarly, the administration of THIP increased ethanol preference. In contrast, preference for ethanol over water was decreased following the administration of picrotoxin. It appears that the effects of these GABAergic manipulations are specific to ethanol, since total fluid intake was not influenced by the administration of either drug (i.e., THIP or picrotoxin). In light of the literature suggesting that THIP and picrotoxin are active at different sites within the GABAA chloride-ionophore receptor complex, the present findings would suggest that the GABAA receptor may play a role in regulating the voluntary intake of ethanol.

Dopamnine‐Immunoreactive axon varicosities form nonrandom contacts with GABA‐immunoreactive neurons of rat medial prefrontal cortex

Abstract: Recent postmortem studies have suggested that reduced γ-aminobutyric acid (GABA)ergic activity in limbic cortex may be one component to the pathophysiology of schizophrenia. This hypothesis has underscored the importance of knowing whether midbrain dopamine afferents interact extensively enough with inhibitory interneurons to suggest a direct functional relationship. Toward this end, a double immunofluorescence approach combined with confocal laser scanning microscopy has been used to localize dopamine and GABA simultaneously in rat medial prefrontal cortex. The results confirm studies from other laboratories showing a rich network of dopamine-immunoreactive fibers forming a gradient across the cortical laminae, with deeper layers having the highest density. When viewed with oil immersion optics, dopamine-immunoreactive fibers were frequently found to be in close apposition with GABA-immunoreactive cell bodies. The percentage of GABA-containing neurons showing such contacts was highest in layer VI (65%) and progressively decreased toward layer I (9%). Varicose regions of the dopamine fibers were typically present at the point of contact with a GABA-immunoreactive cell body. Using an immunoperoxidase technique to localize dopamine fibers and cresyl violet staining to visualize neurons simultaneously, two separate statistical analyses were performed to assess whether the frequency of contacts between dopamine fibers and cell bodies in general may be due to random effects. In layer VI, a high percentage of both pyramidal and nonpyramidal neurons were found to be in contact with dopamine varicosities (71% and 76%, respectively), but these were not significantly different from that observed for GABA-containing cells (65%) in double-immunofluorescence specimens. A Chi-square statistical test was used to compare the observed and predicted number of varicosities forming cell body contacts. This analysis indicated that the percentage of dopamine varicosities (30%) that form appositions with cell bodies is much greater than would be expected if these appositions were due to random effects (15%). Moreover, using an estimate of intensity for a stationary Poisson process, it was again found that random effects can not account for these interactions (P = 0.01). Taken together with earlier electron microscopic studies from other laboratories, the present findings support the idea that GABAergic interneurons have extensive interactions with dopamine varicosities. While these interactions are not unique to GABAergic cell bodies, they suggest that inhibitory interneurons can play a direct role in mediating the effects of midbrain dopamine afferents in rat medial prefrontal cortex. © 1993 Wiley-Liss, Inc.

The spinal GABA system modulates burst frequency and intersegmental coordination in the lamprey: differential effects of GABAA and GABAB receptors

Abstract: 1. The effect of spinal GABAergic neurons on the segmental neuronal network generating locomotion has been analyzed in the lamprey spinal cord in vitro. It is shown that gamma-aminobutyric acid (GABA)A- and GABAB-mediated effects influence the burst frequency and the intersegmental coordination and that the GABA system is active during normal locomotor activity. 2. Fictive locomotor activity was induced by superfusing the spinal cord with a Ringer solution containing N-methyl-D-aspartate (NMDA, 150 microM). The efferent locomotor activity was recorded by suction electrodes from the ventral roots or intracellularly from interneurons or motoneurons. If a GABA uptake blocker was added to the perfusate, the burst rate decreased. This effect was counteracted by GABAB receptor blockade by phaclofen or 2-(OH)-saclofen. If instead a GABAB receptor agonist (baclofen) was added during fictive locomotion, a depression of the burst rate occurred. It was concluded that a GABAB receptor activation due to an endogenous release of GABA caused a depression of the burst activity with a maintained well-coordinated locomotor activity. 3. If a GABAA receptor antagonist (bicuculline) is applied during fictive locomotion elicited by NMDA, a certain increase of the burst rate occurred. Conversely, if a selective GABAA agonist (muscimol) was administered, the burst rate decreased. Similarly, if the GABAA receptor activity was potentiated by activation of a benzodiazepine site by diazepam, the burst rate was reduced. If, however the GABAergic effect was first enhanced by an uptake blocker (nipecotic acid), an administration of a GABAA antagonist (bicuculline) increased the burst rate, but in addition, the burst pattern became less regular with recurrent shorter periods without clear reciprocal burst activity. The GABAA receptor activity appears important for the rate control and for permitting a regular burst pattern. 4. The intersegmental coordination in the lamprey is characterized by a rostrocaudal constant phase lag of approximately 1% of the cycle duration between the activation of consecutive segments during forward swimming. This rostrocaudal phase lag can be reversed during backward swimming, which can be induced also experimentally in the isolated spinal cord by providing a higher excitability to the caudal segments. In a split-bath configuration, a GABA uptake blocker or a GABAB agonist was administered to the rostral part of the spinal cord, which caused a reversal of the phase lag as during backward swimming. If GABAA receptors were blocked under similar conditions, the intersegmental coordination became irregular. It is concluded that an increased GABA activity in a spinal cord region can modify the intersegmental coordination.(ABSTRACT TRUNCATED AT 400 WORDS)