The first choice group of psychotropic agents in schizophrenia is neuroleptics. However, this treatment is not effective in all patients and with every symptom. We summarize papers published on the role of antiepileptic drugs in treatment-resistant schizophrenia. We have searched the computer database system MEDLINE for relevant articles including reviews, reports of drug studies and case histories. Antiepileptic drugs can change symptoms of schizophrenia by their action on GABA-ergic neurotransmission or via anti-glutamatergic mechanisms. High doses of adjunctive benzodiazepines reduce positive symptoms, anxiety, and agitation. Carbamazepine is effective in affective symptoms of schizophrenia and influences violent behavior in psychotic patients. Its anti-kindling action may represent a promising treatment strategy for some patients with chronic course of schizophrenia. Valproate treatment leads to a decrease in positive symptoms as well as hostility. Lamotrigine is expected to influence the positive, negative, affective, and cognitive symptoms of schizophrenia. New antiepileptics (e.g., gabapentin, oxcarbazepine, topiramate, vigabatrin) present a promise as potential adjuncts to neuroleptic treatment in resistant symptoms of schizophrenia.

Peroxidase-anti-peroxidase immunocytochemistry, applied on serial semithin epoxy resin sections, was used to examine the localization of endogenous GABA in horizontal cells in the retina of a marine teleost, the dragonet (Callionymus lyra L.). The immunostaining shows that not only the external H1 cone horizontal cells label with antibodies against GABA, but also the H2 and H3 cone horizontal cells in the inner nuclear layer. The distribution of the H1 cells corresponds to that of the single cones. They are square-patterned and in the dorsal retina their density equals 20,000 cells/mm2. The estimated density of the immunostained H2 and the H3 cells in the dorsal retina is 9500 and 1300 cells/mm2, respectively. The H2 and H3 cells are not geometrically arranged, but nearest-neighbor analysis shows that these horizontal cell types do have a very regular disposition. We suggest that GABA is the likely neurotransmitter substance used by all cone horizontal cell types in teleost retina.

A subpopulation of cells developing in dissociated neuronal cultures prepared from 8-day-old embryonic chick retinae can be identified as putative in vitro counterparts of GABAergic amacrine cells by immunocytochemical and autoradiographic markers and by their electrophysiological responses to transmitter agonists. In the present study, transmitter-gated conductances expressed by these neurons were examined using the whole-cell patch-clamp technique. At negative holding potentials, the excitatory amino acid agonists N-methyl-D-aspartate (NMDA), kainate quisqualate, and glutamate induced inward currents with reversal potentials close to 0 mV in most of the cells selected for recording. NMDA-evoked responses were selectively blocked by the noncompetitive inhibitor MK 801 and by Mg2+ (in a voltage-dependent manner) and were potentiated in the presence of submicromolar concentrations of glycine. Glutamate apparently interacted with both NMDA and non-NMDA type receptors. All cells tested responded to the inhibitory transmitters GABA and glycine. Both inhibitory agonists could be shown to activate chloride conductances. Responses to GABA and glycine were specifically inhibited in the presence of bicuculline and strychnine, respectively. Thus, GABAergic neurons in retinal cultures express at least two different excitatory amino acid receptors–NMDA and non-NMDA–and two different inhibitory amino acid receptors–the GABAA and the glycine receptor. The results demonstrate the ability of the cultured neurons to develop an apparently mature phenotype and contribute to the understanding of the functional properties of GABAergic amacrine cells in the vertebrate retina.

The inhibitory amino-acid neurotransmitter, gamma-aminobutyric acid (GABA), was localized in the pure cone retina of the lizard Anolis carolinensis by autoradiographic and immunocytochemical techniques. Uptake of [3H]-GABA labeled horizontal cells, amacrine cells, numerous cells in the ganglion cell layer, both plexiform layers, and the nerve fiber layer. Label in the inner plexiform layer showed distinct lamination.

The pattern of GABA immunoreactivity was similar to the pattern of [3H]-GABA uptake, although some differences, particularly in labeling of amacrine and ganglion cells, were observed. Immunocytochemistry revealed endogenous stores of GABA in a set of horizontal cells, amacrine cells, and cells in the ganglion cell layer. Both plexiform layers were labeled by the GABA antisera. Labeling in the inner plexiform layer (IPL) was highly stratified and GABA-immunoreactive strata were present in both sublaminae a and b. Six subtypes of conventionally placed GABA-immunoreactive amacrine cells and one displaced amacrine cell subtype were identified. Three of the six conventional amacrine cell subtypes were of pyriform morphology and three subtypes were of multipolar morphology. GABA-immunoreactive interstitial cells also were observed.

Under certain conditions the GABA antiserum labeled the cones. Etching the resin eliminated cone labeling, suggesting that GABA in the cones is present in a labile pool, unlike GABA in horizontal or amacrine cells, or the observed labeling was not due to endogenous GABA. Cones did not demonstrate [3H]-GABA uptake.

The distribution patterns of GABA immunoreactive (+) and immunonegative (−) amacrine cell synapses and profiles in the inner plexiform layer (IPL) were analyzed in three macaque monkey retinas using postembedding electron-microscopic (EM) immunogold cytochemistry. Synapses and profiles were counted at 5% intervals throughout the IPL depth in three EM montages (total area = 6509 μm2), with 0% depth at the inner nuclear layer/IPL border. Nearly 70% of all amacrine synapses were GABA+, and they contacted all major classes of neurons that arborize in the IPL: bipolars (45%), ganglion cells (25%), and GABA+ (20%) and GABA− (10%) amacrines. A major relationship was seen between GABA+ amacrine processes and bipolar terminals: 76% of all amacrine-to-bipolar synapses were GABA+, and 82% of bipolar output dyads contained at least one GABA+ amacrine.

GABA+ amacrine profiles (N = 2455) were concentrated in three wide bands at IPL depths of 0–25%, 40–60%, and 75–100%, corresponding to the dense bands seen with light-microscopic immunocytochemistry. In contrast, GABA+ amacrine synapses (N = 1081) were distributed evenly throughout the IPL depth, rather than being confined to the three dense bands. GABA− amacrine synapses (N = 516) were concentrated at 40% and 60% depths.

Each category of amacrine output synapses had a characteristic pattern of stratification in the IPL. GABA+amacrine-to-bipolar synapses occurred throughout the IPL but were most frequent at 20% and 80% IPL depths, where the dendrites of midget cone bipolars arborize (Polyak, 1941). In contrast, GABA+amacrine-to-ganglion cell synapses were concentrated at 30% and 70% IPL depths, near the dendritic arborizations of parasol ganglion cells (Watanabe & Rodieck, 1989). GABA+ synapses onto bipolars and amacrines were also concentrated at the level of rod bipolar terminals. GABA+ amacrines must play significant but different roles in ON and OFF midget and parasol pathways as well as the rod pathway.

In the retina of the African clawed frog (Xenopus laevis), endogenous dopamine release increases in light and decreases in darkness. Exogenous melatonin and several chemical analogs of melatonin suppressed light-evoked dopamine release from frog retina in a concentration-dependent manner. The rank order of potency for inhibition of light-evoked dopamine release was melatonin » 5-methoxytryptamine ≥ N-acetylserotonin > 5-methoxytryptophol ⋙ serotonin. Melatonin did not suppress dopamine release below levels seen in darkness. The putative melatonin receptor antagonist luzindole inhibited the effect of melatonin. Luzindole enhanced dopamine release in darkness but had little effect in light. These data suggest a role for endogenous melatonin in dark-induced suppression of retinal dopamine.

Picrotoxin and bicuculline, GABA-A receptor antagonists, blocked melatonin-induced suppression of dopamine release. In the presence of melatonin, bicuculline was significantly less potent in stimulating dopamine release. These results suggest that melatonin enhances GABAergic inhibition of light-evoked dopamine release. This mechanism may underlie the light/dark difference in dopamine release in vertebrate retina.

Endogenous dopamine release in the retina of the African clawed frog (Xenopus laevis) increases in light and decreases in darkness. The roles of the inhibitory amino acid transmitters gamma-aminobutyric acid (GABA) and glycine in regulating this light/dark difference in dopamine release were explored in the present study. Exogenous GABA, the GABA-A receptor agonist muscimol, the GABA-B receptor agonist baclofen, and the GABA-C receptor agonist cis-aminocrotonic acid (CACA) suppressed light-evoked dopamine overflow from eyecups. The effects of GABA-A and -B receptor agonists were selectively reversed by their respective receptor-specific antagonists, whereas the effect of CACA was reversed by the competitive GABA-A receptor antagonist bicuculline. The benzodiazepine diazepam enhanced the effect of muscimol on light-evoked dopamine release. Both GABA-A and -B receptor antagonists stimulated dopamine release in light or darkness. Bicuculline was more potent in light than in darkness. These data suggest that retinal dopaminergic neurons are inhibited by GABA-A and -B receptor activation in both light and darkness but that GABA-mediated inhibitory tone may be greater in darkness than in light.

Exogenous glycine inhibited light-stimulated dopamine release in a concentration-dependent and strychnine-sensitive manner. However, strychnine alone did not increase dopamine release in light or darkness, nor did it augment bicuculline-stimulated release in darkness. Additionally, both strychnine and 7-chlorokynurenate, an antagonist of the strychnine-insensitive glycine-binding site of the N-methyl-D-aspartate subtype of glutamate receptor, suppressed light-evoked dopamine release. Thus, the role of endogenous glycine in the regulation of dopamine release remains unclear.

In an immunocytochemical study, using an antiserum and a monoclonal antibody specific for the amino acid, γ-aminobutyric acid (GABA), GABA-like immunoreactivity (GLIR) has been demonstrated for the first time in parasitic flatworms. In Moniezia expansa (Cestoda), GLIR was seen in nerve nets which were closely associated with the body wall musculature and in the longitudinal nerve cords. In the liver fluke Fasciola hepatica (Trematoda), the GLIR occurred in the longitudinal nerve cords and lateral nerves in the posterior half of the worm. GLIR was also detected in subtegumental fibres in F. hepatica. The presence of GABA was verified, using high-pressure liquid chromatography coupled with fluorescence detection. The concentration of GABA (mean ± S.D.) in M. expansa anterior region was 124·8 ± 15·3 picomole/mg wet weight, while in F. hepatica it was 16·8 ± 4·9 picomole/mg. Since several insecticides and anti-nematodal drugs are thought to interfere with GABA-receptors, the findings indicate that GABAergic neurotransmission may be a potential target for chemotherapy in flatworms too.

A growing body of experimental evidence suggests that anaesthetics, by influencing GABAergic and glutaminergic neural signalling, can have adverse effects on the developing central nervous system. The biological foundation for this is that gamma-aminobutyric acid and glutamate could act non-synaptically, in addition to their role in neurotransmission in the adult brain, in the regulation of neuronal development in the central nervous system. These neurotransmitters and their receptors are expressed from very early stages of central nervous system development and appear to influence neural progenitor proliferation, cell migration and neuronal differentiation. During the synaptogenetic period, pharmacological blockade of N-methyl-d-aspartate (NMDA)-type glutamate receptors as well as stimulation of GABAA receptors has been reported to be associated with increased apoptosis in the developing brain. Importantly, recent data suggest that even low, non-apoptogenic concentrations of anaesthetics can perturb neuronal dendritic development and thus could potentially lead to impairment of developing neuronal networks. The extrapolation of these experimental observations to clinical practice is of course very difficult and requires extreme caution as differences in drug concentrations and exposure times as well as interspecies variations are all important confounding variables. While clinicians should clearly not withhold anaesthesia based on current animal studies, these observations should urge more laboratory and clinical research to further elucidate this issue.

Gamma hydroxybutyric acid, a central inhibitory neurotransmitter and a cerebral metabolite of gamma-aminobutyric acid, is present in high concentrations in the mammalian hypothalamus and basal ganglia. Its sodium salt gamma hydroxybutyrate has been effectively used as an intravenous anaesthetic agent, and as an oral sedative, and in the management of the alcohol withdrawal syndrome. In an animal model, using 72 Wistar strain rats allocated to one of six groups of 12 animals each, with implanted lumbar intrathecal catheters, we examined whether gamma hydroxybutyrate, 20% 40 μL (32 mg kg−1) administered alone or combined with fentanyl, gamma hydroxybutyrate 20% 20 μL (16 mg kg−1), fentanyl 0.005% 20 μL (4 mg kg−1) as an intrathecal bolus, provides intra-operative anaesthesia, comparable with that produced by intrathecal lignocaine. We demonstrated that gamma hydroxybutyrate, given by an intrathecal bolus in the rat model, produced reversible segmental antinociception, together with muscular relaxation of the abdominal wall and rear limbs. This is accompanied by moderate sedation without haemodynamic or respiratory depression. This agent may thus be promising for use as a spinal anaesthetic drug.