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PubMed1991

Characterization of tiagabine (NO-328), a new potent and selective GABA uptake inhibitor.

Tiagabine (NO-328) (R(-)-N-[4,4-bis(3-methylthien-2-yl)but-3-enyl]nipecotic acid, hydrochloride) is a new centrally acting GABA uptake inhibitor. The anticonvulsant activity of tiagabine was evaluated against seizures induced by methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), pentylenetetrazol, bicuculline, maximal electrostimulation (MES), or high intensity sound. The sedative actions of tiagabine were evaluated in tests for traction, rotarod performance and exploratory behavior. Finally, interoceptive properties of tiagabine were assessed using diazepam-, CGS 9896-, pentylenetetrazol-, or amphetamine-discriminating rats. Tiagabine was an effective anticonvulsant in doses which did not produce sedation or motor debilitation, although it was not potent against MES. In a manner similar to other anti-epileptic drugs, tiagabine potentiated dopaminergic function (methylphenidate-induced gnawing in mice) although it did not substitute for amphetamine in amphetamine-trained animals. Furthermore, although tiagabine antagonized DMCM-induced convulsions, it exhibited neither CGS 9896 or diazepam-like interoceptive effects, nor did it block (or potentiate) pentylenetetrazol-discrimination. Thus, GABA uptake inhibition represents a novel rationale for a valproate-like anticonvulsant drug therapy.

Animals↗
PubMed1991

Biochemical and behavioral studies following subchronic administration of GABA uptake inhibitors in mice.

N-(4,4-Diphenyl-3-butenyl) nipecotic acid (SKF(R)-89976A) and N-(4,4-diphenyl-3-butenyl) guvacine (SKF 100330A) are potent inhibitors of the uptake of GABA and have anticonvulsant properties. In the present study, the effects of these compounds on several behavioral and biochemical measures were determined, following subchronic administration. Administration of SKF(R)-89976A (8.9 mg/kg) for 14 days caused a small but significant reduction in its potency to protect against pentylenetetrazole-induced seizures, whereas treatment with SKF 100330A (13.6 mg/kg) had no significant effect. The percentage of animals rendered cataleptic by administration of either GABA uptake inhibitor was reduced by treatment for as few as 4 days and treatment with SKF(R)-89976A for 14 days resulted in a 4-fold increase in the CD50 for induction of catalepsy. The binding of [3H]GABAA and [3H]GABAB in membranes from the forebrain of the mouse were not influenced by treatment with drug nor was synaptosomal uptake of [3H]GABA. Likewise, the binding of [3H]sulpiride in striatal membranes of the mouse was unaffected by repeated exposures to SKF(R)-89976A. These results demonstrate that prolonged administration of GABA uptake inhibitors produced only a small reduction in anticonvulsant potency, whereas liability to side-effects, as demonstrated by the reduction in catalepsy, was substantially reduced.

Animals↗
PubMed1983

Use of gamma-aminobutyric acid (GABA)-transaminase inhibitors and a GABA uptake inhibitor to investigate the influence of GABA neurons on dopamine-containing amacrine cells of the rat retina.

The effects of inhibiting gamma-aminobutyric acid-transaminase (GABA-T) with aminooxyacetic acid or with gabaculine and inhibiting GABA uptake with nipecotic acid on dopamine (DA) synthesis in the retina of light-exposed rats were studied. 3,4-Dihydroxyphenylalanine (Dopa) accumulation after the inhibition of L-aromatic amino acid decarboxylase with NSD-1015 was used as an index of DA synthesis. The GABA-T inhibitors significantly increased GABA levels in the retina but had no effect on retinal Dopa accumulation in the light. Dopa accumulation was significantly inhibited at a high dosage by nipecotic acid alone and by low dosages of nipecotic acid in rats pretreated with either aminooxyacetic acid or gabaculine. The dosages of nipecotic acid which inhibited Dopa accumulation in the light also inhibited [3H]GABA uptake in the retina. The inhibitory effects of gabaculine and nipecotic acid on Dopa accumulation appeared to occur at least partially via GABA receptors because their action was significantly reversed by the GABA antagonist bicuculline methiodide. These experiments thus suggest that endogenous GABA can suppress the light-evoked increase in DA synthesis in the rat retina and support previous studies which concluded that an inhibitory GABA input may at least partially regulate the activity of the DA neurons in the retina of rats.

4-Aminobutyrate Transaminase↗
PubMed1991

Involvement of GABA in acoustically-evoked inhibition in inferior colliculus neurons.

Most criteria for establishing GABA as an inhibitory neurotransmitter in the central nucleus of inferior colliculus (ICc) have been satisfied, but the role of GABA in acoustic coding in ICc is not established. The present study examined this issue by evaluating the effects of iontophoretic application of agents that alter activity at GABA receptors on potential forms of acoustically-evoked inhibition in ICc neurons. Application of the GABAA antagonist, bicuculline, selectively blocked the firing reduction at high intensities observed during non-monotonic rate-intensity functions in ICc neurons. Binaural inhibition was selectively blocked by bicuculline and increased by nipecotic acid. Application of GABA, nipecotic acid (GABA uptake inhibitor) and a benzodiazepine (flurazepam), which enhances the action of GABA, increased the duration and intensity of ipsilateral inhibition and response pause, while bicuculline blocked these acoustically-evoked inhibitory events. Offset inhibition was increased by nipecotic acid application and reduced by bicuculline with the appearance of an offset peak. The present data support an important role for GABA as a neurotransmitter, mediating, in part, non-monotonicity, binaural inhibition, response pause and offset inhibition in ICc neurons. Alterations of these GABA-mediated inhibitory phenomena may occur in auditory dysfunctions observed with aging and audiogenic seizures.

Acoustic Stimulation↗
PubMed1985

Gamma-aminobutyric acid uptake and the termination of inhibitory synaptic potentials in the rat hippocampal slice.

Intracellular recordings were made from CA1 pyramidal cells in the rat hippocampal slice to study the processes that influence the time course of inhibitory post-synaptic potentials (i.p.s.p.s) mediated by gamma-aminobutyric acid (GABA), and conductance changes evoked by ionophoretically applied GABA. The GABA-uptake inhibitors, nipecotic acid and cis-4-OH-nipecotic acid (1 mM), greatly prolonged conductance increases associated with both hyperpolarizing and depolarizing responses to ionophoretically applied GABA. In contrast to their effects on GABA-evoked conductances, uptake inhibitors only slightly prolonged antidromically evoked i.p.s.p.s. Their primary effect occurred after the i.p.s.p. had decayed to 5-30% of its peak. 4-OH-isonipecotic acid, a nipecotic acid analogue that does not inhibit GABA uptake, did not prolong i.p.s.p.s or ionophoretically evoked conductance changes. Sodium pentobarbitone (100 microM), a drug that prolongs the open time of GABA-activated chloride channels, potentiated both i.p.s.p.s and responses to ionophoretically applied GABA. Whereas pentobarbitone also prolonged i.p.s.p.s, it did not prolong responses to ionophoretically applied GABA. The prolongation of i.p.s.p.s by pentobarbitone occurred equally in both the early and late phases of the i.p.s.p., in contrast to the effects of GABA-uptake inhibitors. I.p.s.p.s did not usually decay exponentially. The observation that uptake inhibitors prolonged the late but not the early decay phase of the i.p.s.p., together with the previous finding that the conductance change persists for the duration of the i.p.s.p., indicate that GABA is present in the synapse throughout much of the i.p.s.p. These data suggest that diffusion of GABA out of the synapse, a non-exponential process, is an important determinant of the i.p.s.p. decay time course. Increasing the extracellular potassium concentration from 3.5 to 8.5 mM resulted in spontaneously occurring, synchronous burst firing of pyramidal cells. Cis-4-OH-nipecotic acid significantly reduced the number and amplitude of extracellularly recorded population spikes within each burst. We conclude that diffusion, channel open time and GABA uptake all influence the time course of GABA-mediated i.p.s.p.s. The time course of a single, brief i.p.s.p. is determined predominantly by post-synaptic channel kinetics and diffusion of GABA out of the synapse, whereas the inhibition produced by prolonged synaptic bursts or relatively long application of exogenous GABA can be markedly influenced by GABA uptake.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed1995

GABA concentrations in the striatum following repetitive cerebral ischemia.

GABAergic neurons in the striatum are very sensitive to the effects of ischemia. The progressive decline in striatal GABA following transient forebrain ischemia in gerbils may be secondary to either a decreased production or an increase in reuptake mechanisms or both. The current experiment was designed to evaluate release of GABA by stimulation with K+ or inhibition of its uptake with nipecotic acid or their combination (K+ nipecotic) after repetitive forebrain ischemia in gerbils by in-vivo microdialysis on Days 1, 3, 5, and 14 following the insult. Infusion of nipecotic acid or potassium chloride, resulted in a significant increase in extracellular GABA. This response was significantly decreased in the post-ischemic animals. The synergistic effect of increased GABA concentrations by the infusion of nipecotic acid + potassium chloride seem in the controls was not evident in the post-ischemic animals. In conclusion, though there is a reduction in the extracellular GABA concentrations in the first week following an ischemic insult, restorative mechanisms are operative in the second week as seen by the increasing GABA concentrations.

Animals↗
PubMed1982

Comparative assay of anticonvulsant and toxic potencies of sixteen GABAmimetic drugs.

The relative ability of 16 direct and indirect GABAmimetic drugs to elevate the threshold for electroconvulsions and pentetrazole seizures was studied in mice. The following drugs were tested: GABA and its pro drug cetyl GABA, the GABA agonists muscimol, THIP and progabide, the inhibitors of the high affinity GABA uptake (-)- and (+)-nipecotic acid ethyl ester, (+/-)-nipecotic acid methyl ester, (+/-)-cis-4-hydroxynipecotic acid methyl ester and guvacine methyl ester, and the inhibitors of GABA degradation aminooxyacetic acid, gabaculine, gamma-acetylenic GABA, gamma-vinyl GABA and ethanolamine-O-sulphate. Valproic acid was induced as a reference standard. All drugs were administered intraperitoneally and their anticonvulsant potencies were compared at the previously established time of peak drug effect. All GABAmimetics gave rise to significant, dose-dependent threshold elevations. Most potent were muscimol, THIP and Cetyl GABA, and least potent were gamma-vinyl GABA and ethanolamine-O-sulphate. Determination of minimal neurotoxicity by means of the chimney test indicated that the anticonvulsant effect of most GABAmimetics was impaired by a narrow margin of safety. Only cetyl GABA, aminooxyacetic acid and progabide exhibited satisfactory margins of safety similar to those of valproic acid in any particular test. Based on the present data, cetyl GABA and progabide appear to be the most interesting compounds examined besides valproic acid and both GABAmimetics may be interesting as potential antiepileptic drugs.

Animals↗
PubMed1983

Anticonvulsant activity of GABA uptake inhibitors and their prodrugs following central or systemic administration.

The activity of compounds inhibiting neuronal or glial GABA uptake has been assessed following intracerebroventricular (i.c.v.) or intraperitoneal (i.p.) administration in DBA/2 mice (sound-induced seizures) or Swiss S mice (pentylenetetrazol-induced seizures). Sound-induced seizures are suppressed by the i.c.v. injection of (+/-)-nipecotic acid, 3.2 mumol, or (+/-)-cis-4-hydroxynipecotic acid, 2 mumol, but not by i.p. injection of (+/-)-nipecotic acid, 3.2 mmol/kg or (+/-)-cis-4-hydroxynipecotic acid 4 mmol/kg. Pentylenetetrazol-induced seizures are not suppressed by i.c.v. injection of (+/-)-nipecotic acid 1-4 mumol, or (+/-)-cis-4-hydroxynipecotic acid, 2-4 mumol. THPO (4,5,6,7-tetrahydroisoxazolo[4.5-c]pyridin-3-ol), 1-5 mumol i.c.v. or 1-4 mmol/kg i.p., protects against sound-induced seizures. There is no protection against pentylenetetrazol seizures after i.c.v. THPO injection, but THPO, 2-8 mmol/kg i.p., is protective. Among prodrugs, (+/-)-nipecotic acid pivaloyloxymethyl ester protects against sound-induced seizures, when given i.c.v. (3.2 mumol) or i.p. (1.6-3.2 mmol/kg) and against pentylenetetrazol seizures when given i.p. (0.5-4 mmol/kg). (+/-)-cis-4-hydroxynipecotic acid methyl ester protects against sound-induced seizures when given i.p. (3.2 mmol/kg), but is only partially protective against pentylenetetrazol seizures, when given i.p. (4 mmol/kg). Some prodrugs induce myoclonus following either i.c.v. or i.p. administration.

Acoustic Stimulation↗
PubMed1979

Convulsant and anticonvulsant actions in DBA/2 mice of compounds blocking the reuptake of GABA.

Compounds blocking the uptake of GABA into neurons or glia have been injected intracerebroventricularly (icv) or intraperitoneally (ip) in DBA/2 mice, age 21-28 days. Protection against audiogenic seizures was seen 30 min after the icv injection of (+)-2,4-diaminobutyric acid (0.5-2.0 mumoles), (+/-)-nipecotic acid (1.6-3.2 mumoles), (+)-ethyl nipecotate (0.4-0.8 mumoles), (-)-piperazic acid (4 mumoles) and putrescine (2 mumoles) or the ip injection of (+)-2,4-diaminobutyric acid (4-8 mmoles/kg and (+)-ethyl nipecotate (0.24-0.32 mmoles/kg). Of these ethyl nipecotate and nipecotic acid were the most effective anticonvulsants icv, but nipecotic acid was ineffective ip. Limb myoclonus and other epileptic manifestations (rearing, wild running, tonic clonic seizures) occurred in the absence of auditory stimulation after (+)-2,4-diaminobutyric acid (0.5-2.0 mumoles), (+/-)-cis-3-aminocyclohexane carboxylic acid (3.2-6.4 mumoles) and putrescine (2 mumoles). beta-Alanine (2-4 mumoles, icv) depressed respiration but did not protect against audiogenic seizures or induce myoclonus.

Alanine↗
PubMed1995

The gamma-aminobutyric acid uptake inhibitor, tiagabine, is anticonvulsant in two animal models of reflex epilepsy.

The effects of i.p. administration of the gamma-aminobutyric acid (GABA) uptake inhibitors R(-)N-(4,4-di(3-methylthien-2-yl)-but-3-enyl) nipecotic acid hydrochloride (tiagabine; molecular weight 412.0), (1-(2-(((diphenylmethylene)-amino)oxy)ethyl)-1,2,5,6-tetrahydro-3- pyridinecarboxylic acid hydrochloride (NNC-711; molecular weight 386.9), and (+/-)-nipecotic acid (molecular weight 128.2) are compared with those of carbamazepine (molecular weight 236.3) on sound-induced seizures and locomotor performance in genetically epilepsy-prone (GEP) rats. The ED50 value against clonic seizures (in mumol kg-1 at the time of maximal anticonvulsant effect) for tiagabine was 23 (0.5 h), and for NNC-711 was 72 (1 h), and for carbamazepine was 98 (2 h). (+/-)-Nipecotic acid (0.4-15.6 mmol kg-1) was not anticonvulsant. High doses of NNC-711 (207-310 mumol kg-1) and of (+/-)-nipecotic acid (39-78 mmol kg-1) induced ataxia and myoclonic seizures 0.25-1 h. Tiagabine and carbamazepine did not induce myoclonic seizures and had similar therapeutic indices (locomotor deficit ED50/anticonvulsant ED50) ranging from 0.4 to 1.9. In Papio papio, we observed a reduction in photically induced myoclonic seizures with tiagabine (2.4 mumol kg-1 i.v.) accompanied with neurological impairment. Tiagabine has comparable anticonvulsant action to carbamazepine in rats and has anticonvulsant effects in non-human primates supporting the potential use of inhibitors of GABA uptake as therapy for epilepsy.

Acoustic Stimulation↗
PubMed1988

Enhanced pressor response to GABA in the nucleus tractus solitarii of the spontaneously hypertensive rat.

A previous study from this laboratory demonstrated that ongoing GABAergic neurotransmission in the nucleus tractus solitarii (NTS) functions to maintain baseline arterial pressure (AP). In that study, bilateral microinjection of nipecotic acid into the NTS was observed to elevate AP. Since nipecotic acid is a selective GABA uptake blocker, changes in GABA release should be reflected by changes in the response to nipecotic acid. The present study utilized this approach to assess endogenous GABA activity within the NTS of the spontaneously hypertensive rat (SHR). Male SHR, 16-20 weeks of age, were anesthetized with chloralose, paralyzed and ventilated. Age-matched Wistar-Kyoto (WKY) rats were studied as controls. Bilateral microinjection of nipecotic acid (10 nmol in 100 nl; a maximally effective dose) into the NTS elicited a pressor response which was significantly greater in the SHR than the response observed in the WKY rats. Similarly, direct stimulation of GABAB receptors in the NTS with (-)-baclofen 40 pmol, a maximally effective dose) elicited an increase in AP which was significantly greater in the SHR. In contrast, bilateral microinjection of the direct acting GABAA agonist muscimol (160 pmol, a maximally effective dose) resulted in a similar elevation of AP in both the SHR and WKY rats. These results suggest that the enhanced pressor response caused by endogenous GABA in the NTS of the SHR is due to a greater response evoked by stimulation of GABAB receptors. Thus, enhanced GABAB receptor-mediated neural transmission in the NTS may contribute to the expression or maintenance of hypertension in this genetic model of hypertension.

Animals↗
PubMed1980

Inhibitors of the GABA uptake systems.

This review describes a novel class of heterocyclic GABA uptake inhibitor with no affinity for the GABA receptors. The parent compound nipecotic acid is a potent inhibitor of neuronal and glial GABA uptake, and nipecotic acid is a substrate for the transport carriers concerned. The structurally related cyclic amino acids guvacine and cis-4-hydroxynipecotic acid are also potent inhibitors of both GABA transport systems. Even minor structural alterations of these compounds result in considerable or complete loss of activity. Whereas homonipecotic acid is a weak but selective inhibitor of glial GABA uptake, homoguvacine is virtually inactive. Similarly the lower homologues of nipecotic acid and guvacine, beta-proline and 3-pyrroline-3-carboxylic acid, respectively, show some selectivity with respect to inhibition of glial GABA uptake, but these compounds are much weaker than the parent compounds. The bicyclic compounds THPO and THAO, in which the carboxyl groups of nipecotic acid and homonipecotic acid have been replaced by 3-isoxazolol units are moderately potent and practically specific inhibitors of glial GABA uptake. cis-4-Mercaptonipecotic acid is considerably weaker than the closely related analogue cis-4-hydroxynipecotic acid, but the former compound may interact irreversibly with the GABA transport carriers. The results demonstrate a pronounced substrate specificity of the glial and in particular the neuronal GABA transport system. It is evident that the GABA molecule is transported in a conformation different from that, in which it activates its receptors. These findings are of importance for the development of drugs for selective pharmacological regulation of the functions of central GABA-mediated synapses in certain neurological diseases.

Animals↗
PubMed1990

Endogenous GABA acts on GABAB receptors in nucleus tractus solitarius to increase blood pressure.

Previous studies found that injection of the GABA uptake inhibitor nipecotic acid into the nucleus tractus solitarius (NTS) increases arterial pressure. This effect of nipecotic acid was not antagonized by the selective GABAA receptor blocking agent bicuculline, suggesting that the action of nipecotic acid was mediated through an action of GABA on GABAB receptors in the NTS. The present studies examined this issue using a newly described GABAB antagonist, phaclofen. Injection of phaclofen (4 nmol in 100 nl artificial CSF) into the NTS of chloralose-anesthetized rats produced a slight decrease in arterial pressure (-8 +/- 2 mmHg) lasting less than 1 min. Smaller doses had no effect. Phaclofen antagonized in a dose-dependent (0.5-4 nmol) manner the increase in arterial pressure produced by injection into the NTS of the GABAB agonist baclofen (5-100 pmol). In contrast, phaclofen had no effect on the pressor response elicited by injection into the NTS of the GABAA agonist muscimol. Phaclofen (4 nmol) injected into the NTS totally reversed the increase in blood pressure elicited by injection into the NTS of a maximally effective dose of nipecotic acid (10 nmol). Phaclofen also inhibited the pressor response elicited by injection into the NTS of another indirectly acting GABA agonist, gamma-vinylGABA (GVG). Although GVG is an effective inhibitor of GABA transaminase, the enzyme involved in the metabolism of GABA, the time course of inhibition of GABA transaminase evoked by GVG was not consistent with the pressor response being produced by this mechanism. However, the pressor response elicited by GVG is consistent with its reported ability to inhibit GABA uptake.(ABSTRACT TRUNCATED AT 250 WORDS)

4-Aminobutyrate Transaminase↗
PubMed1991

gamma-Aminobutyric acid (GABA) stimulates somatostatin release following activation of a GABA uptake carrier located on somatostatin nerve endings of rat cerebral cortex.

The effect of gamma-aminobutyric acid (GABA) on the release of somatostatin-like immunoreactivity (SRIF-LI) was studied in synaptosomes prepared from rat cerebral cortex and exposed in superfusion to the amino acid. GABA (1-300 microM) increased the spontaneous outflow of SRIF-LI in a concentration-dependent manner. The effect of GABA was not prevented by the GABAA receptor antagonists bicuculline or picrotoxin. The GABAA receptor agonist muscimol (10-100 microM) did not affect SRIF-LI release. Similarly ineffective was the GABAB receptor agonist (-)-baclofen (100 microM). The GABA-induced SRIF-LI release was counteracted by the GABA uptake inhibitors N-(4,4-diphenyl-3-butenyl)-nipecotic acid (SK&F 89976A) and nipecotic acid. When used as a GABA carrier substrate, nipecotic acid mimicked GABA and increased SRIF-LI release; its effect was antagonized by SK&F 89976A. The mechanism involved appears to be selective for GABA inasmuch as neutral amino acids such as leucine, alpha-aminobutyric acid or valine, tested at 100 microM, had little or no effect on the release of SRIF-LI. Neither GABA (100 microM) nor nipecotic acid (300 microM) enhanced the release of cholecystokinin-like immunoreactivity. The GABA-evoked somatostatin release was calcium-dependent and tetrodotoxin-insensitive. It is concluded that a carrier for the uptake of GABA exists on somatostatin-releasing terminals of rat cerebral cortex and that GABA uptake may regulate somatostatin release. This conclusion would be compatible with the reported coexistence of GABA and somatostatin in cerebrocortical neurons.

Amino Acids↗
PubMed1967

A method for the degradation of radioactive nicotinic acid.

A chemical degradation scheme is reported, which permits the measurement of the radioactivity of each carbon atom of nicotinic acid. Nicotinic acid is decarboxylated by heating with copper chromite to give carbon dioxide (C-7) and pyridine. The pyridine is converted into 4-nitropyridine 1-oxide, which is heated with aqueous calcium hypobromite to give tribromonitromethane. Combustion of the latter gives carbon dioxide derived from C-4 of the nicotinic acid. Nicotinic acid is also reduced to nipecotic acid, which is oxidized to succinic acid by acidic potassium permanganate. Stepwise degradation of the succinic acid by standard procedures gives two samples of carbon dioxide, which correspond to C-3, C-6 and C-4, C-5 of the nicotinic acid. Benzoylation of the nipecotic acid, followed by oxidation with permanganate at pH7, gives 5-amino-4-carboxyvaleric acid; this is converted into 2-methyleneglutaric acid by the action of nitrous acid. Hydrogenation of the 2-methyleneglutaric acid over rhodium in methanol gives 2-methylglutaric acid, which is oxidized with dilute chromic acid to acetic acid. Stepwise degradation of the acetic acid by standard procedures gives two samples of carbon dioxide, which correspond to C-2 and C-3 of the nicotinic acid. Thus the radioactivities of C-2, C-3, C-4 and C-7 are determined directly and those of C-5 and C-6 by difference. The method was shown to be isotopically valid for [2,3,7-(14)C]-, [4,6-(14)C(2)]- and [5-(14)C]-nicotinic acid.

Carbon Dioxide↗
PubMed1987

Uptake inhibitors potentiate gamma-aminobutyric acid-induced contractile responses in the isolated ileum of the guinea-pig.

The gamma-aminobutyric acid (GABA)-induced contractile responses in the guinea-pig isolated ileum, maintained in Krebs-bicarbonate solution (pH 7.4, 37 degrees C), were significantly potentiated by inhibitors of GABA uptake, with a greater potentiation of the responses in the presence of (+/-)-cis-3-aminocyclohexane-carboxylic acid (ACHC) greater than L-2,4-diaminobutyric acid (DABA) greater than (+/-)-nipecotic acid greater than beta-alanine, whilst simultaneous addition of DABA with beta-alanine caused a greater potentiation of the GABA-induced responses than did nipecotic acid with beta-alanine, or any of the uptake blockers applied alone. The concentration-response curves for the GABA-induced ileal contraction were shifted to the left in the presence of the uptake inhibitors, this shift being more prominent over the lower concentration range of GABA (1-20 microM). By contrast, contractile responses to muscimol or 3-amino-1-propanesulphonic acid (3APS) were not potentiated by the uptake blockers, neither were their concentration-response curves altered. Bicuculline methochloride shifted the GABA concentration-response curve to the right, whilst picrotoxinin both shifted the concentration-response curve for GABA to the right and depressed the maximum response. In the presence of the uptake inhibitors, the rightward shift of the concentration-response curves for GABA induced by bicuculline was less than that induced by bicuculline alone. The rightward shift with picrotoxinin was similarly reduced in the presence of the uptake inhibitors, without altering the depression of the maximum by picrotoxinin. Bicuculline caused a rightward shift of the concentration-response curves for 3APS and muscimol, with the curve for 3APS most affected. Picrotoxinin similarly shifted the concentration-response curves for 3APS and muscimol but depressed the maximum, with the curve for 3APS again being most affected. None of the inhibitors of GABA uptake influenced the concentration-response curves for 3APS or muscimol in the presence of bicuculline or picrotoxinin. 5. In conclusion, a saturable GABA uptake system is present in the enteric nervous system of the guinea-pig intestine, where neuronal GABA uptake appears to predominate over glial uptake.

Animals↗
PubMed1980

Influence of cellular transport on the interaction of amino acids with gamma-aminobutyric acid (GABA)-receptors in the isolated olfactory cortex of the guinea-pig.

1 Freshly cut guniea-pig olfactory cortex slices contained 2.2 mmol gamma-aminobutyric acid (GABA)/kg tissue weight. This declined during in vitro incubation at 25 degrees C in the absence of exogenous GABA, but increased to 6.95 mmol/kg after 1.5 h incubation in 1 mM GABA. 2 Uptake of [3H]-GABA (1 microM) was inhibited by 1 mM (+/-)-nipecotic acid (-83%), beta-amino-n-butyric acid (BABA) (-59%), L-2,4-diaminobutyric acid (DABA) (-63%), (+/-)cis-3-aminocyclohexane carboxylic acid (ACHC) (-53%), and 3-aminopropanesulphonic acid (3-APS) (-26%), but was increased by beta-alanine (BALA) (+23%). 3 Autoradiographs showed steep concentration gradients of radioactivity across slices incubated for short periods in [3H]-GABA. 4 Efflux of [3H]-GABA from pre-loaded slices was accelerated strongly by nipecotic acid, BABA, DABA and ACHC but weakly or not all by BALA or 3-APS. 5 Nipecotic acid (1 mM) potentiated the surface-depolarization of the slice produced by GABA but not that produced by 3-APS. 6 The depolarizing actions of DABA, BABA, nipecotic acid and ACHC, but not that of 3-APS or BALA, were potentiated when the endogenous GABA content of slices was raised. 7 It is concluded that: (a) the depolarizing action of exogenous GABA is limited by cellular uptake; (b) surface-depolarizations produced by nipecotic acid, DABA, BABA and ACHC may be mediated by the release of GABA; and (c) neuronal, rather than glial, transport systems are responsible for these effects.

Amino Acids↗
PubMed1982

Carnosine-synthetase inhibition of beta-alanine analogues.

A number of beta-alanine analogues were tested for their ability to inhibit carnosine-synthetase from rat and chick skeletal muscle. Of the analogues tested, 3-aminopropane-sulfonic acid (APS) was the most effective inhibitor of enzyme from either source. 5-Aminovaleric acid (5-AV) also inhibited the enzyme from rat, but did not inhibit the enzyme from chick. 2-Aminoethylphosphonic acid and o-phosphoethanolamine had a small amount of inhibitory activity on both rat and chick enzymes, while 3-aminopropanephosphonic acid, aminooxyacetic acid and nipecotic acid had a small amount of inhibitory activity on the rat enzyme only. None of the analogues tested acted as substrates for either enzyme under our conditions. Kinetic data indicated that the inhibition by APS was competitive with respect to beta-alanine for both rat and chick enzymes. Inhibition of the rat enzyme by 5-AV was non-competitive with respect to beta-alanine for both rat and chick enzymes. Inhibition of the rat enzyme by 5-AV was noncompetitive with respect to beta-alanine. APS and 5-AV were also shown to inhibit carnosine-synthetase from rat brain and heart. Chronic injections of either APS or 5-AV failed to produce significant changes in carnosine levels in rat skeletal muscle or brain; however preliminary results indicate that APS injections may produce a lowering of carnosine levels in rat heart.

Alanine↗