Increased GABA Levels Research Articles

Discovery of N1-(6-Chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)tryptamine as a Potent, Selective, and Orally Active 5-HT6Receptor Agonist

N1-Arylsulfonyltryptamines have been identified as 5-HT6 receptor ligands. In particular, N1-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)tryptamine (11q) is a high affinity, potent full agonist (5-HT6 Ki = 2 nM, EC50 = 6.5 nM, Emax = 95.5%). Compound 11q is selective in a panel of over 40 receptors and ion channels, has good pharmacokinetic profile, has been shown to increase GABA levels in the rat frontal cortex, and is active in the schedule-induced polydipsia model for obsessive compulsive disorders.

Increased γ-Aminobutyric Acid Levels in Mouse Brain Induce Loss of Righting Reflex, but Not Immobility, in Response to Noxious Stimulation

The general anesthetic state comprises behavioral and perceptual components, including amnesia, unconsciousness, and immobility. gamma-Aminobutyric acidergic (GABAergic) inhibitory neurotransmission is an important target for anesthetic action at the in vitro cellular level. In vivo, however, the functional relevance of enhancing GABAergic neurotransmission in mediating essential components of the general anesthetic state is unknown. Gabaculine is a GABA-transaminase inhibitor that inhibits degradation of released GABA, and consequently increases endogenous GABA in the central nervous system. Here, we examined, behaviorally, the ability of increased GABA levels to produce components of the general anesthetic state. All drugs were administered systemically in adult male ddY mice. To assess the general anesthetic components, two end-points were used. One was loss of righting reflex (LORR; as a measure of unconsciousness); the other was loss of movement in response to tail-clamp stimulation (as a measure of immobility). Gabaculine induced LORR in a dose-dependent fashion with a 50% effective dose of 100 (75-134; 95% confidence limits) mg/kg. The behavioral and microdialysis studies revealed that the endogenous GABA-induced LORR occurred in a brain concentration-dependent manner. However, even larger doses of gabaculine (285-400 mg/kg) produced no loss of tail-clamp response. In contrast, all the tested volatile anesthetics concentration-dependently abolished both righting and tail-clamp response, supporting the evidence that volatile anesthetics act on a variety of molecular targets. These findings indicate that LORR is associated with enhanced GABAergic neurotransmission, but that immobility in response to noxious stimulation is not, suggesting that LORR and immobility are mediated through different neuronal pathways and/or regions in the central nervous system.

Yoga Asana Sessions Increase Brain GABA Levels: A Pilot Study

The aim of this study was to compare changes in brain gamma-aminobutyric (GABA) levels associated with an acute yoga session versus a reading session. It was hypothesized that an individual yoga session would be associated with an increase in brain GABA levels. This is a parallel-groups design. Screenings, scan acquisitions, and interventions took place at medical school-affiliated centers. The sample comprised 8 yoga practitioners and 11 comparison subjects. Yoga practitioners completed a 60-minute yoga session and comparison subjects completed a 60-minute reading session. GABA-to-creatine ratios were measured in a 2-cm axial slab using magnetic resonance spectroscopic imaging immediately prior to and immediately after interventions. There was a 27% increase in GABA levels in the yoga practitioner group after the yoga session (0.20 mmol/kg) but no change in the comparison subject group after the reading session ( -0.001 mmol/kg) (t = -2.99, df = 7.87, p = 0.018). These findings demonstrate that in experienced yoga practitioners, brain GABA levels increase after a session of yoga. This suggests that the practice of yoga should be explored as a treatment for disorders with low GABA levels such as depression and anxiety disorders. Future studies should compare yoga to other forms of exercise to help determine whether yoga or exercise alone can alter GABA levels.

Attenuation of cocaine-seeking by GABA B receptor agonists baclofen and CGP44532 but not the GABA reuptake inhibitor tiagabine in baboons

The current study evaluated the effects of drugs that increase GABA levels by activation of GABA B receptors (baclofen and CGP44532) or by inhibition of GABA reuptake (tiagabine) on the reinstatement of extinguished lever responding produced by priming doses of cocaine in baboons (i.e., cocaine-seeking). Cocaine self-injection was established and maintained under a fixed ratio (FR10) schedule of reinforcement during daily 2 h sessions. Lever responding was extinguished by substituting vehicle (saline) for cocaine until the number of self-injections decreased to 10 or less per session for two consecutive sessions (defined as extinction). Once extinction occurred, priming doses of cocaine (0.1–3.2 mg/kg, i.v.) were administered during extinction conditions. Administration of priming doses of cocaine significantly increased cocaine-seeking in a dose-dependent manner. Cocaine-seeking produced by priming doses of cocaine were attenuated by pretreatment with baclofen ( N = 5) or CGP44532 ( N = 5) but not tiagabine ( N = 3). The doses of baclofen (0.32 mg/kg), and CGP445532 (0.32 mg/kg) that reduced cocaine-seeking produced by cocaine priming doses did not reinstate cocaine-seeking and did not produce overt effects when administered alone. These data indicate that GABA B agonists may reduce relapse to cocaine taking.

Subthalamic Stimulation-Induced Forelimb Dyskinesias Are Linked to an Increase in Glutamate Levels in the Substantia Nigra Pars Reticulata

The neurobiological mechanisms by which high-frequency stimulation of the subthalamic nucleus (STN-HFS) alleviates the motor symptoms of Parkinson's disease (PD) remain unclear. In this study, we analyzed the effects of STN-HFS on motor behavior in intact or hemiparkinsonian rats (6-hydroxydopamine lesion of the substantia nigra pars compacta) and investigated the correlation between these effects and extracellular glutamate (Glu) and GABA levels, assessed by intracerebral microdialysis in the substantia nigra pars reticulata (SNr). STN-HFS at an intensity corresponding to the threshold inducing contralateral forelimb dyskinesia, increased Glu levels in the SNr of both intact and hemiparkinsonian rats. In contrast, STN-HFS at half this intensity did not affect Glu levels in the SNr in intact or hemiparkinsonian rats but increased GABA levels in hemiparkinsonian rats only. STN-HFS-induced forelimb dyskinesia was blocked by microinjection of the Glu receptor antagonist kynurenate into the SNr and facilitated by microinjection of a mixture of the Glu receptor agonists AMPA and NMDA into the SNr. These new neurochemical data suggest that STN-HFS-induced forelimb dyskinesia is mediated by glutamate, probably via the direct activation of STN axons, shedding light on the mechanisms of STN-HFS in PD.

Subchronic administration of l-DOPA to adult rats with a unilateral 6-hydroxydopamine lesion of dopamine neurons results in a sensitization of enhanced GABA release in the substantia nigra, pars reticulata

l-DOPA is the most effective pharmacological agent used for the symptomatic treatment of Parkinson's disease but long-term l-DOPA treatment induces involuntary abnormal movements such as dyskinesias. The present study, using in vivo microdialysis, investigated the effects of a single or subchronic administration of l-DOPA to adult rats with a unilateral 6-OHDA lesion of dopamine neurons on GABA release in the substantia nigra, pars reticulata (SNr). The results indicate that a challenge injection of l-DOPA (50 mg/kg, i.p.) significantly increases GABA levels in the SNr of rats treated with a daily repeated administration of l-DOPA (50 mg/kg, i.p.). Further statistical analysis between groups also showed that extracellular GABA levels were significantly higher in the subchronic l-DOPA group than in the group receiving only one injection of l-DOPA. These results show that the subchronic administration of l-DOPA results in a sensitization of enhanced extracellular GABA levels in the SNr.

Further potential of the GABA receptor in the treatment of insomnia

The benzodiazepine binding site on the GABA A receptor is the target for the majority of hypnotics, including the nonbenzodiazepine ‘Z drugs’ (zaleplon, zolpidem, zopiclone and eszopiclone). Concerns still exist over long-term benzodiazepine use, and efforts are, therefore, being made to search for new hypnotic agents and alternative receptor target sites, with novel mechanisms of action. Clinically useful compounds, including GABA mimetics and GABA-uptake inhibitors, have been found by developing structurally rigid analogs of GABA. The GABA-site agonist 4,5,6,7-tetra hydroisoxazolo[5,4-c]pyridin-3-ol (THIP) shows high potency for extrasynaptic GABA A receptor subtypes, which are not primary targets for classical benzodiazepines or the Z drugs. Hence, THIP targets a novel set of GABA A receptors. The antiepileptic drug, tiagabine, is a specific blocker of the GAT-1 GABA-transporter, increasing GABA levels following synaptic GABA release. It is proposed that this promotes extrasynaptic GABA A receptor activity. In contrast, two other GABA analogs, pregabalin and gabapentin, are not GABA mimetics but appear to act at calcium channels responsible for neurotransmitter release, rather than at the GABA receptors. All of these GABA analogs modify sleep behaviors and so are potentially effective hypnotic drugs that provide an alternative to the benzodiazepine binding site of the GABA A receptor.

Prefrontal GABA levels in cocaine-dependent subjects increase with pramipexole and venlafaxine treatment

There is evidence that prefrontal lobe GABA levels are low in cocaine-dependent (CD) individuals, and treatment with GABA agonists decreases cocaine self-administration. The aim of the study is to measure changes in GABA levels in CD subjects at baseline and after 8 weeks of treatment with pramipexole, venlafaxine, or placebo. CD subjects enrolled in a treatment trial for cocaine dependence were recruited for this proton (1H) magnetic resonance spectroscopy (MRS) study. GABA levels in the prefrontal lobe were measured before and after treatment. Mean percentage changes in GABA levels were as follows: pramipexole +17.0+/-28.0%, venlafaxine +13.0+/-11.0%, and placebo -2.1+/-19.5%. Pramipexole-treated subjects had significantly increased brain GABA levels compared to placebo (p=0.031). Venlafaxine treatment was nonsignificantly associated with increased GABA levels compared to placebo (p=0.16). The overall statistical model for the effect of drug treatment vs placebo on brain GABA levels, including adjustment for baseline levels, was highly significant (p=0.002). Despite significant changes in GABA levels, there were no significant differences in the number of urine samples positive for cocaine metabolites. This study demonstrates that 1H MRS can measure changes in GABA levels following pharmacologic treatment. The increase in GABA levels, although significant, is modest compared to other MRS studies of depression or epilepsy associated with clinical improvements. The failure to see larger increases in GABA levels and an associated reduction in cocaine consumption may reflect the relatively low doses of medication used.

GABAergic Modulation of the Expression of Genes Involved in GABA Synaptic Transmission and Stress in the Hypothalamus and Telencephalon of the Female Goldfish (Carassius auratus)

GABA is one of the most abundant neurotransmitters in the vertebrate central nervous system and is involved in neuroendocrine processes such as development, reproduction, feeding and stress. To examine the effect of GABA on gene expression in the brain, we used a cDNA macroarray containing 26 genes involved in GABA synaptic transmission (GABA receptor subunits, GABA transporters), reproduction (gonadotrophin-releasing hormone isoforms and oestrogen receptor alpha), feeding (neuropeptide Y and cholecystokinin), and stress [corticotrophin-releasing factor (CRF)]. To elevate GABA levels in the brain, we injected female goldfish with gamma-vinyl GABA (300 microg/g of body weight) (24 h), an irreversible inhibitor of the enzyme GABA transaminase (GABA-T). We found that increased levels of GABA in the hypothalamus resulted in a 2.2-fold down-regulation of GABA(A) receptor beta4 subunit mRNA. In the telencephalon, we found that increased GABA levels resulted in a 1.5-fold increase of CRF mRNA and a 1.8-fold decrease of GABA(A) receptor beta2 subunit mRNA. Increasing GABA in the hypothalamus and telencephalon of the goldfish did not significantly affect the mRNA abundance of genes involved in GABA synthesis (glutamic acid decarboxylase isoforms) and degradation (GABA-T), feeding, or reproduction. Our preliminary study suggests that the regulation of GABA receptor subunit mRNA expression by GABA may be a conserved evolutionary mechanism in vertebrates to modulate GABAergic synaptic transmission.

GABAergic Modulation of the Activity of Globus Pallidus Neurons in Primates: In Vivo Analysis of the Functions of GABA Receptors and GABA Transporters

Neurons in the external and internal segment of the globus pallidus (GPe and GPi, respectively) receive substantial GABAergic inputs from the striatum and through axon collaterals of neighboring pallidal neurons. The effects of GABA on pallidal activity depend on the synaptic localization of GABA receptors and the distribution and activity of GABA transporters (GATs). To explore the contribution of GABA receptors and transporters to pallidal function, we recorded the activity of single neurons in GPe or GPi before, during, and after local microinjections of GABAergic compounds in awake rhesus monkeys. Activation of GABA(A) or GABA(B) receptors with muscimol or baclofen, respectively, inhibited pallidal activity. These effects were reversed by concomitant infusion of the respective GABA receptor antagonists, gabazine and CGP-55845. Given alone, the antagonists were without consistent effect. Application of the selective GAT-1 inhibitor, SKF-89976A, and the semiselective GAT-3 blocker, SNAP-5114, decreased pallidal activity. Both GAT inhibitors increased GABA levels in the pallidum, as measured by microdialysis. Electron microscopic observations revealed that these transporters are located on glial processes and unmyelinated axonal segments, but rarely on terminals. Our results indicate that activation of GABA(A) and GABA(B) receptors inhibits neuronal activity in both segments of the pallidum. GAT-1 and GAT-3 are involved in the modulation of endogenous GABA levels and may be important in regulating the extrasynaptic levels of GABA. Together with previous evidence that a considerable proportion of pallidal GABA receptors are located outside the synaptic cleft, our experiments strongly support the importance of extrasynaptic GABAergic transmission in the primate pallidum.

Neurotensin Activates GABAergic Interneurons in the Prefrontal Cortex

Converging data suggest a dysfunction of prefrontal cortical GABAergic interneurons in schizophrenia. Morphological and physiological studies indicate that cortical GABA cells are modulated by a variety of afferents. The peptide transmitter neurotensin may be one such modulator of interneurons. In the rat prefrontal cortex (PFC), neurotensin is exclusively localized to dopamine axons and has been suggested to be decreased in schizophrenia. However, the effects of neurotensin on cortical interneurons are poorly understood. We used in vivo microdialysis in freely moving rats to assess whether neurotensin regulates PFC GABAergic interneurons. Intra-PFC administration of neurotensin concentration-dependently increased extracellular GABA levels; this effect was impulse dependent, being blocked by treatment with tetrodotoxin. The ability of neurotensin to increase GABA levels in the PFC was also blocked by pretreatment with 2-[1-(7-chloro-4-quinolinyl)-5-(2,6-dimethoxyphenyl)pyrazole-3-yl)carbonylamino]tricyclo(3.3.1.1 [EC] .3.7)decan-2-carboxylic acid (SR48692), a high-affinity neurotensin receptor 1 (NTR1) antagonist. This finding is consistent with our observation that NTR1 was localized to GABAergic interneurons in the PFC, particularly parvalbumin-containing interneurons. Because neurotensin is exclusively localized to dopamine axons in the PFC, we also determined whether neurotensin plays a role in the ability of dopamine agonists to increase extracellular GABA levels. We found that D2 agonist-elicited increases in PFC GABA levels were blocked by pretreatment with SR48692, consistent with data indicating that D2 autoreceptor agonists increase neurotensin release from dopamine-neurotensin axons in the PFC. These findings suggest that neurotensin plays an important role in regulating prefrontal cortical interneurons and that it may be useful to consider neurotensin agonists as an adjunct in the treatment of schizophrenia.

Valproate modifies spontaneous excitation and inhibition at cortical synapses in vitro

The anticonvulsant, valproic acid (VPA), has a very wide spectrum of clinical activity and has conventionally been considered to act by enhancing inhibitory GABAergic activity, either by increasing GABA levels and its subsequent release or by enhancing postsynaptic GABA responses. However, the pharmacology of VPA is complex and other mechanisms may well contribute. In the present study, we examined the effect of the drug on the release of GABA and glutamate at synapses in the rat entorhinal cortex, using the whole-cell patch clamp technique to record spontaneous excitatory (sEPSCs) and inhibitory postsynaptic currents (sIPSCs). VPA reduced the frequency but not the amplitude of both spontaneous sEPSCs and sIPSCs, with a more pronounced effect on the former. However, VPA had no effect on miniature, monoquantal events recorded in the presence of TTX, suggesting that the reduction in release occurred via blockade of Na +-channels in the presynaptic neurones. In addition, VPA also prolonged the decay time of sIPSCs, and this effect was occluded by a benzodiazepine agonist, zolpidem. These data suggest that in addition to presynaptic effects on release, VPA can potentiate postsynaptic responses, possibly by interaction with the benzodiazepine regulatory site of the GABA A receptor.

Estrogen-induced neurochemical and electrophysiological changes in the parabrachial nucleus of the male rat

Estrogen has previously been shown to significantly change sympathetic and parasympathetic system output via an action within the central nuclei responsible for regulating autonomic tone. These estrogen-induced changes were observed within 30 min of systemic administration and could be blocked by the direct microinjection of the estrogen receptor antagonist, ICI 182780, into the parabrachial nucleus (PBN) of the pons. In the present investigation, we sought to determine the possible mechanism(s) by which estrogen produced these rapid changes in autonomic tone by determining if estrogen modulates neuronal excitability within the PBN. Male Sprague–Dawley rats were anaesthetized with Inactin (sodium thiobutabarbitol, 100 mg/kg) and instrumented for the intravenous injection of estrogen and placed in a stereotaxic frame for the insertion of a microdialysis probe or glass recording electrode into the PBN. In the first experiment, we sought to determine the local concentration of estrogen in the cerebrospinal fluid in the PBN following systemic injection of estrogen. In the second experiment, we sought to determine the functional significance of systemic estrogen injection on neuronal activity and amino acid neurotransmitter levels in the PBN. Systemic estrogen injection resulted in a significant increase in local estrogen concentration in the PBN which corresponded to a decrease in neuronal excitability and extracellular glutamate levels while increasing GABA levels in the PBN. These results suggest that estrogen decreases neuronal excitability in the PBN by modulating synaptic transmission via an increased release of GABA and a decreased release of glutamate.

Lower in vivo brain extracellular GABA concentration in diabetic rats during forced swimming

Diabetic rats are more immobile during the forced-swimming test (FST) and GABAergic drugs reverse this behavior. We investigated if there is in vivo changes of GABA levels of diabetic rats during the FST. In vivo basal striatal GABA levels of streptozotocin diabetic rats are similar to non-diabetic rats. Non-diabetic rats presented a significant increase in GABA levels after the FST while the increase was delayed and lower in diabetic rats. These results suggest that diabetes may change GABA homeostasis and modify behavioral responses in an animal model of depression.

Corticotropin releasing-factor (CRF) increases extracellular GABA levels in the rat hypothalamus

We investigated the effect of the perfusion of corticotropin releasing-factor (CRF) on the extracellular levels of γ-aminobutyric acid (GABA) in the hypothalamic paraventricular nucleus in the rat using a microdialysis technique. Local perfusion of CRF (3 μM, 10 μM and 30 μM) caused significant increases in extracellular GABA levels in a dose dependent manner. Increases in GABA levels in this region caused by CRF were significantly reduced by the presence of [D-Phe12, Nle21,38, α-Me-Leu37]-CRF (12-41) (D-Phe CRF12-41, 1 μM), a CRF receptor antagonist. These findings suggest that CRF activates GABAergic neurons in the rat hypothalamic paraventricular nucleus via CRF receptors, which might be related to regulation of ACTH secretion in the anterior lobe of the pituitary.

Evidence that nitric oxide production increases γ-amino butyric acid permeability of blood-brain barrier

Blood-brain barrier permeability (BBB) to the inhibitory neurotransmitter γ-amino butyric acid (GABA) was studied in rats following intraperitoneal (i.p) injections of GABA alone and in combination with L-Arginine (L-Arg). Administration of GABA (600 mg/kg body weight [b. wt.]) alone increased brain GABA concentration (33%, p < 0.01), when compared to untreated rats and administration of L-Arg (2000 mg/kg b. wt.) alone also increased GABA concentration (65%, p < 0.01) in the brain. Moreover, GABA + L-Arg treated brains showed a fourfold increase in GABA level (383.3%, p < 0.01) when compared to controls. Dose-dependent increase in nitric oxide production was observed 10 min after i.p injections of L-Arg (400, 800, 1000, and 2000 mg/kg b. wt.) and a peak nitric oxide (NO) production was observed at the dose level of 2000 mg/kg b. wt. On the other hand, administration of GABA failed to increase NO production in the brain. Rats pretreated (10 min) with a nonspecific nitric oxide synthase (NOS) inhibitor N ω-nitro-L-Arginine methyl ester (L-NAME, 50 mg/kg b. wt.) completely blocked the production of NO induced by L-Arg. In addition, L-NAME attenuated GABA entry into the brain after the administration of GABA alone or in combination with L-Arg. We conclude that high NO concentrations in the brain following L-Arg administration may increase the permeability of BBB to peripheral GABA.

Identification of a sensitive period of prenatal cocaine exposure that alters the development of the anterior cingulate cortex.

Administration of cocaine to pregnant rabbits produces robust and long-lasting anatomical, neurochemical and behavioral alterations in their offspring. For example, exposure to cocaine following implantation [embryonic day (E) 8] through gestation (E29) produces increased length and decreased bundling of layer III and V pyramidal neuron dendrites, increased parvalbumin expression in the dendrites of interneurons, and increased GABA levels in the anterior cingulate cortex (ACC) and other dopamine-rich cortical areas. We have investigated the presence of a sensitive period of in utero exposure during specific developmental epochs prior to and during the onset of cortical development that might be capable of producing such effects. Cocaine (3 mg/kg i.v., twice daily) or saline was administered during embryonic days E16-E25 (onset and peak of corticogenesis), E8-E15 (prior to cortical plate formation), E8-E25 or E8-E29 as in earlier studies. Examination of the ACC in offspring exposed from E8 to E25 and from E16 to E25 were found to induce alterations in the development of pyramidal neurons and interneurons that are nearly identical to those induced by the complete exposure (E8-E29) paradigm. No alterations were observed following the E8-E15 cocaine exposure. These data suggest that exposure to cocaine during E16-E25, the time of peak corticogenesis, appearance of cortical monoamines and onset of D(1) dopamine receptor expression, is necessary and sufficient to produce long-term effects on the organization of excitatory pyramidal neurons and inhibitory interneurons in the ACC.

Gamma-vinyl GABA reduces paired pulse inhibition in the rat dentate gyrus in vivo and in vitro

Gamma vinyl GABA (GVG), an irreversible GABA transaminase inhibitor, has anticonvulsant effects. GVG increases GABA levels in the brain by blocking its degradation, and is presumed to enhance GABAergic inhibition, however, in some cases it exacerbates seizures. We investigated the effects of GVG in vivo and in vitro on paired pulse inhibition (PPI) recorded in the rat dentate gyrus (DG) evoked by perforant path stimulation. At 2.5 h and 24 h after administration of GVG (1 g/kg, i.p.), there was a loss of PPI at both 15- and 25-ms interpulse intervals (IPI). Activation of presynaptic GABA B autoreceptors could explain this in vivo effect. We therefore further investigated the effects of co-application of GVG with the GABA B antagonists 2-OH saclofen (saclofen) or CGP 35348 (CGP) on PPI in hippocampal slices by in vitro study. Bath application of GVG (400 and 500 μM) not only resulted in a loss of perforant path evoked PPI at a 15-ms IPI, but produced facilitation of the second population spike relative to the first. Co-application of saclofen (250 μM) with GVG (500 μM) prevented facilitation of the second response of a paired-pulse. The facilitation of the second stimulation response produced by GVG (400 μM) was converted to inhibition by bath application of CGP 35348 (400 μM). These results suggest that activation of presynaptic GABA B receptors by increased extracellular GABA may be one of the contributing factors to the apparent paradoxical effect of GVG on PPI in the DG.

A possible interaction between CCKergic and GABAergic systems in the rat brain

Cholecystokinin sulfated octapeptide (CCK-8S) was given to rats i.p. at single doses of 10 and 100 nmol/kg, respectively. It produced a modification in GABA levels in several areas of the rat brain. After 30 min of injection, the lower dose (10 nmol/kg) increased GABA levels in striatum by 31% ( P<0.05). The higher dose (100 nmol/kg) enhanced GABA levels either in hippocampus by 78% ( P<0.05) or in frontal cerebral cortex by 81% ( P<0.05) and decreased in olfactory bulbs by 57% ( P<0.01). Thus, these results show that systemic injection of CCK-8S, produced regional specific changes on GABA levels in brain, and these effects were dose-dependent. Systemic pretreatment with the CCK B receptor antagonist, PD 135,158, 1 mg/kg i.p., on the endogenous levels of GABA in certain regions was also studied. The selective CCK B receptor antagonist, PD 135,158, did not have an effect per se on the endogenous levels of GABA but prevents the action induced by the neuropeptide. We suggest that the action of CCK may be mediated via a selective action on the CCK B receptor subtypes.

Effects of acute and chronic Triazolam treatments on brain GABA levels in albino rats

The present study investigated the effects of acute and chronic intraperitoneal administration of Triazolam on g-aminobutyric acid (GAB A) levels in different brain areas of albino rats. Three experiments were conducted. In the first, five groups of rats were acutely treated with different doses of Triazolam (0.25 mg/kg-4.0 mg/kg), In the second experiment, rats were treated chronically with a single daily dose of Triazolam (started with 0.25 mg/kg and increased by time to 1.0 mg/kg) for 5 weeks, simulating clinical use. In the third, rats were treated chronically with three daily doses of Triazolam (started with 0.25 mg/kg and increased by time to 0.5 mg/kg) for 20 days, representing a form of drug abuse. Brain levels of GABA and plasma levels of Triazolam were measured using high performance liquid chromatography (HPLC). The acute Triazolam administration produced an increase in GABA levels in all brain areas studied. The chronic administration of single daily dose of Triazolam produced normal GABA levels in all brain areas except brain stem where the levels were significantly decreased; this indicates the development of tolerance to Triazolam action on increasing GABA content. The chronic administration of three daily doses of Triazolam produced a decrease in GABA levels in all brain regions studied. In conclusion, chronic single daily dose treatment (representing normal use) produces tolerance to Triazolam effects on brain GABA levels, while chronic three daily doses administration (akin to drug abuse) causes a fall in GABA levels.