Intravenous GABA Research Articles

Modulation of brain function by targeted delivery of GABA through the disrupted blood-brain barrier

The technology of transcranial focused ultrasound (FUS) enables a novel approach to neuromodulation, a tool for selective manipulation of brain function to be used in neurobiology research and with potential applications in clinical treatment. The method uses transcranial focused ultrasound to non-invasively open the blood-brain barrier (BBB) in a localized region such that a systemically injected neurotransmitter chemical can be delivered to the targeted brain site. The approach modulates the chemical signaling that occurs in and between neurons, making it complimentary to most other neuromodulation techniques that affect the electrical properties of neuronal activity. Here, we report delivering the inhibitory neurotransmitter GABA to the right somatosensory cortex of the rat brain during bilateral hind paw electrical stimulation and measure the inhibition of activation using functional MRI (fMRI). In a 2 × 2 factorial design, we evaluated conditions of BBB Closed vs BBB Open and No GABA vs GABA. Results from fMRI measurements of the blood oxygen level-dependent (BOLD) signal show: 1) intravenous GABA injection without FUS-mediated BBB opening does not have an effect on the BOLD response; 2) FUS-mediated BBB opening alone significantly alters the BOLD signal response to the stimulus, both in amplitude and shape of the time course; 3) the combination of FUS-mediated BBB opening and GABA injection further reduces the peak amplitude and spatial extent of the BOLD signal response to the stimulus. The data support the thesis that FUS-mediated opening of the BBB can be used to achieve non-invasive delivery of neuroactive substances for targeted manipulation of brain function.

GABA inhibits excitatory neurotransmission in rat pelvic ganglia.

Intravenous GABA inhibited, in a bicuculline-sensitive manner, contractions of the urinary bladder induced by preganglionic nerve stimulation in urethane anaesthetized rats, while it had no significant effect on contractions produced by postganglionic nerve stimulation. In addition, intravenous GABA strongly inhibited DMPP-induced bladder contractions; this effect was also prevented by bicuculline. These experiments suggest that GABA inhibits excitatory neurotransmission in rat pelvic ganglia through a mechanism involving, at least in part, the activation of postsynaptic GABA A receptors.

Chronic Intrathecal Baclofen Administration for the Treatment of Severe Generalized Tetanus via a Synchromed Infusion Pump

Centers for Disease Control (CDC) data indicate that the incidence of tetanus in the United States is highest among the elderly. Conventional therapies for the control of accompanying generalized muscle spasms include large doses of oral or intravenous GABA agonists as antispasticity agents. We describe a case of an elderly patient with severe symptoms of tetanus who developed a prolonged encephalopathy and ventilatory insufficiency with oral baclofen and benzodiazepine therapy. Intrathecal baclofen adequately controlled her severe extensor spasms, facilitated her ventilatory management, and did not compromise her mental status during her extended convalescence. Accordingly, we report the first placement of a permanent implanted infusion pump for this disease. This modality offers advantage for continuous long-term titration of medication for spasms or rigidity control without the systemic sedative effects of conventional therapy.

Prejunctional GABA-B inhibition of cholinergic, neurally-mediated airway contractions in guinea-pigs

GABA is a known inhibitory neurotransmitter in the CNS. Recent studies have also demonstrated the presence of GABA in peripheral tissue, including lung. To delineate a role for GABA in lung, the effect of GABA and selective GABA agonists and antagonists on neuronally-induced airway contractions in guinea pigs were studied. In vitro, tracheal contractions induced by electrical field stimulation (EFS) were inhibited by tetrodotoxin and atropine indicating that the contractions were mediated by neuronal release of acetylcholine. The contractions caused by EFS, but not those by exogenous acetylcholine, were inhibited by GABA (EC 50 = 4.5 μM) and the selective GABA-B agonist baclofen (EC 50 = 9 μM), but not by the GABA-A agonist, muscimol. The inhibitory effect of baclofen was not affected by the GABA-A antagonist, bicuculline, but was significantly reversed with the GABA-B antagonists, 3-aminopropylphosphonic acid (3-APPA) (pA 2 = 4.5) and 2-hydroxysaclofen (pA 2 = 4.1). In vivo, vagal nerve stimulation (5 V, 20 Hz, 0.5 ms, 5 s) in anesthetized, mechanically ventilated guinea-pigs caused cholinergic-dependent bronchospasms that were inhibited by intravenous GABA (3 and 10 mg/kg) and baclofen (1–10 mg/kg), but not by muscimol. The inhibitory effects of GABA and baclofen against vagal bronchospasm were blocked by 3-APPA (5 mg/kg, iv), but not by bicuculline. Responses to the GABA-B agonists were unaltered after the treatment of animals with phentolamine or propranolol to block α-adrenergic and β-adrenergic receptors, respectively. Bronchospasm due to intravenous methacholine was also unchanged by GABA and baclofen. These results demonstrate that GABA inhibits cholinergic bronchoconstriction in guinea-pigs and does so by a mechanism involving inhibitory prejunctional GABA-B receptors.

P-401 - Intravenous GABA produces not only bradycardia with hypotension but also pressor and tachycardic responses in unanesthetized and unrestrained dogs.

P-401 - Intravenous GABA produces not only bradycardia with hypotension but also pressor and tachycardic responses in unanesthetized and unrestrained dogs.

Inhibitory Effect of Intravenous GABA Antagonists on Gastric Acid Secretion Stimulated by Secretagogues in Rats

Effect of intravenous administration of GABA antagonists on gastric acid secretion in perfused stomachs was studied in rats anesthetized with urethane. Bethanechol (BeCh)-stimulated acid secretion was definitely inhibited by bicucul-line, a GABA antagonist, and strychnine, a glycine antagonist, but not by picrotoxin and pentylenetetrazol, GABA antagonists. The inhibitory effect of bicuculline and strychnine was accompanied by vigorous convulsions. Only the bicuculline-induced inhibition was still seen in d-tubocurarine paralyzed rats, and it was abolished in spinal rats. 2-Deoxy-D-glucose (2-DG)-stimulated acid secretion was apparently depressed by all the GABA antagonists of bicuculline, picrotoxin and pentylenetetrazol. The inhibitory effect of picrotoxin, but not bicuculline, on the 2-DG stimulation was still elicited in spinal rats. Inhibition of acid secretion stimulated by pentobarbital, a centrally acting secretagogue, was produced by picrotoxin and pentylenetetrazol in spinal rats. These findings suggest that bicuculline acts centrally to inhibit acid secretion stimulated both peripherally by BeCh and centrally by 2-DG, besides nonspecific mechanisms due to convulsions, and the action would be directed to centers which are implicated in stimulation of the sympatho-adrenomedullary system; picrotoxin and pentylenetetrazol also act centrally to inhibit 2-DG- or pentobarbital-stimulated acid secretion through depression of the central vagal tone which leads to inhibition of gastric acid secretion.

Inhibitory effect of intravenous GABA antagonists on gastric acid secretion stimulated by secretagogues in rats.

Effect of intravenous administration of GABA antagonists on gastric acid secretion in perfused stomachs was studied in rats anesthetized with urethane. Bethanechol (BeCh)-stimulated acid secretion was definitely inhibited by bicuculline, a GABA antagonist, and strychnine, a glycine antagonist, but not by picrotoxin and pentylenetetrazol, GABA antagonists. The inhibitory effect of bicuculline and strychnine was accompanied by vigorous convulsions. Only the bicuculline-induced inhibition was still seen in d-tubocurarine paralyzed rats, and it was abolished in spinal rats. 2-Deoxy-D-glucose (2-DG)-stimulated acid secretion was apparently depressed by all the GABA antagonists of bicuculline, picrotoxin and pentylenetetrazol. The inhibitory effect of picrotoxin, but not bicuculline, on the 2-DG stimulation was still elicited in spinal rats. Inhibition of acid secretion stimulated by pentobarbital, a centrally acting secretagogue, was produced by picrotoxin and pentylenetetrazol in spinal rats. These findings suggest that bicuculline acts centrally to inhibit acid secretion stimulated both peripherally by BeCh and centrally by 2-DG, besides nonspecific mechanisms due to convulsions, and the action would be directed to centers which are implicated in stimulation of the sympatho-adrenomedullary system; picrotoxin and pentylenetetrazol also act centrally to inhibit 2-DG- or pentobarbital-stimulated acid secretion through depression of the central vagal tone which leads to inhibition of gastric acid secretion.

Intravenous GABA administration is anxiogenic in man

Seven persons (three normal volunteers and four euthymic bipolar patients) received one to four doses of γ-aminobutyric acid (GABA) intravenously. All subjects reported dysphoria, and their mood disturbance scores on the Profile of Mood States were significantly increased in a dose-related fashion. Placebo infusions did not produce similar responses. Mood disturbance was accompanied by a dose-related increase in pulse and blood pressure.

GABA a receptor mediated neurogenic inhibition of motility in the small intestine of urethane-anaesthetized rats

1. 1. Intravenous GABA (0.1-3 mg/kg) induced transient relaxation of the duodenum in urethane anaesthetized rats. The effect of GABA was mimicked by homotaurine and antagonized by bicuculline, suggesting the involvement of GABA A receptors in this type of response. 2. 2. Duodenal relaxation induced by GABA was unaffected by i.v. hexamethonium, phentolamine propranolol or 6-hydroxydopamine but was prevented in preparations pretreated with topical tetrodotoxin thus indicating its neurogenic origin. 3. 3. The ability of GABA to induce neurogenic relaxation decreased rapidly when increasing the distance from the duodenum while relaxations induced by DMPP or noradrenaline were observed throughout the whole rat small intestine.

The effect of peripherally administered GABA on spontaneous contractions of rat urinary bladder in vivo

1. 1. Intravenous GABA suppresses the spontaneous contractions of rat urinary bladder produced by saline loading (micturition reflex) without possessing any significant inhibitory effect on spontaneous and stimulated (neuro-hormones and field stimulation) contraction of rat detrusor strips in vitro. 2. 2. The in vivo effects of GABA, in view of the results obtained with atropine, hexamethonium and tetrodotoxin in the same experimental conditions, are likely to be ascribable to an action at pelvic ganglia level.

The effect of intravenous administration of GABA and brain extracts on blood pressure in the rat.

1. A rat bioassay was used to study pressor substances in brain extracts. 2. A compound with pressor activity in pentolinium-treated rats was extracted from brain, purified using Dowex, Sephadex electrophoresis and identified as gamma-aminobutyric acid (GABA) by HPLC and mass spectrometry. 3. Intravenous GABA (1-5 microgram) or brain extracts caused a dose dependent decrease in blood pressure in pentobarbitone-anaesthetized rats. 4. After ganglion blockade with pentolinium (2 mg/kg subcutaneously), GABA or brain extracts cause a dose dependent increase in rat blood pressure. 5. This pressor effect is reduced by alpha- and beta-blockers (intravenous phentolamine, 0.5 mg/kg and propranolol, 0.05 mg/kg). 6. It is concluded that GABA causes a fall in blood pressure by a central mechanism and ganglion blockade unmasks a pressor effect.

PROCEEDINGS OF THE AUSTRALIAN SOCIETY FOR MEDICAL RESEARCH

PROCEEDINGS OF THE AUSTRALIAN SOCIETY FOR MEDICAL RESEARCH

Intravenous GABA agonist administration stimulates firing of A 10 dopaminergic neurons

Increasing intravenous doses of two γ-aminobutyric acid (GABA) agonists, muscimol and 4,5,6,7-tetrahydro-isoxazolo-[5,4-c]pyridin-3-ol (THIP), caused dose-related increases in extracellular, single unit activity of A 10 dopaminergic neurons of the ventral tegmental area. Muscimol, the more potent of the two compounds, stimulated firing at doses approximately 15–20 times lower than the doses of THIP required to elicit equivalent excitatory effects. The maximum stimulation achieved was approximately 150 and 140% of the baseline firing rate for muscimol and THIP, respectively.

Synaptic effects of systemic gamma-amino butyric acid in cortical regions of increased vascular permeability.

ConclusionUnder ordinary circumstances systemically administered γ-amino butyric acid does not produce electrophysiological effects. Following destruction of the blood-brain barrier the synaptic actions are similar to those produced by topical application. In regions of increased barrier-permeability, intravenous GABA abolishes or reduces the frequency of spontaneous paroxysmal discharges arising from such areas. Therefore systemically administered GABA produces no synaptic effects because of failure to penetrate the blood-brain barrier. By permitting rapid exchanges of GABA between blood and brain during electrophysiological studies following barrier lesions, information was obtained relating to the role of γ-amino butyric acid in the central nervous system not attainable by the method of topical application. Production of experimental, localized regions of blood-brain barrier loss may have applications for the study of substances that are otherwise denied access to the cells of the central nervous system.