The medial prefrontal cortex (mPFC) has been implicated in the processing of emotionally significant stimuli, particularly the inhibition of inappropriate responses. We examined the role of the mPFC in regulation of fear responses using a differential fear conditioning procedure in which the excitatory conditioned stimulus (CS+) was paired with an aversive footshock and intermixed with the inhibitory conditioned stimulus (CS-). In the first experiment, using rats as subjects, muscimol, a gamma-amino-butyric acid type A (GABAA) receptor agonist, or artificial cerebrospinal fluid (aCSF) was infused intracranially into the mPFC across three conditioning sessions. Twenty-four hours after the last conditioning session, freezing response of the rats was tested in a drug-free state. Neither the muscimol nor the aCSF infusion had any effect on differential responding. In the second experiment, the same experimental procedure was used except that the infusion was made before the testing session rather than the conditioning sessions. The results showed that muscimol infusion impaired differential responding: the level of freezing to CS- was indiscriminable from that to CS+. Taken together, these results suggest that the mPFC is responsible for the regulation of fear response by inhibiting inappropriate fear expressions.
Animals ; Freezing ; Muscimol ; Prefrontal Cortex ; Rats

Induced activation of the gamma-aminobutyric acidA (GABA(A)) receptor in the retina of goldfish caused the fish to rotate in the opposite direction to that of the spinning pattern during an optomotor response (OMR) measurement. Muscimol, a GABA(A) receptor agonist, modified OMR in a concentration-dependent manner. The GABA(B) receptor agonist baclofen and GABA(C) receptor agonist CACA did not affect OMR. The observed modifications in OMR included decreased anterograde rotation (0.01~0.03 micrometer), coexistence of retrograde rotation and decreased anterograde rotation (0.1~30 micrometer) and only retrograde rotation (100 micrometer~1 mM). In contrast, the GABA(A) receptor antagonist bicuculline blocked muscimolinduced retrograde rotation. Based on these results, we inferred that the coding inducing retrograde movement of the goldfish retina is essentially associated with the GABA(A) receptor-related visual pathway. Furthermore, from our novel approach using observations of goldfish behavior the induced discrete snapshot duration was approximately 573 ms when the fish were under the influence of muscimol.
Baclofen ; Bicuculline ; Clinical Coding ; Cytarabine ; Goldfish ; Injections, Intraocular ; Muscimol ; Receptors, GABA ; Receptors, GABA-A ; Retina ; Visual Pathways

PURPOSE: This study was aimed to investigate the modulatory effect of ammonium carbonate on the GABAA receptor. METHODS: The effects of ammonium carbonate on the binding of radioligands to components of the GABAA receptor complex were observed. RESULTS: [3H]Flunitrazepam binding to the benzodiazepine receptor was enhanced by ammonium (<800 micrometer). Further increasing ammonium carbonate concentrations decreased [3H]flunitrazepam binding to control levels. Furthermore, GABA and muscimol increased the potency of ammonium carbonate in enhancing [3H]flunitrazepam binding. Ammonium carbonate also increased, then decreased the binding of 10nM [3H]muscimol binding to the GABAA receptor in a concentration-dependent manner. More importantly, the presence of ammonia along with a benzodiazepine receptor agonist synergistically enhanced [3H]muscimol binding to the GABA receptor. CONCLUSION: These suggest that ammonia may enhance GABAergic neurotransmission at concentrations commonly encountered in hepatic failure, then suppress the inhibitory neuronal function observed at higher (>1mM) ammonia concentrations. This increase in GABAergic neurotransmission is consistent with the clinical picture of lethargy, ataxia and cognitive deficits associated with liver failure and congenital hyperammonemia.
Ammonia ; Ammonium Compounds* ; Ataxia ; Carbon* ; gamma-Aminobutyric Acid ; Hyperammonemia ; Lethargy ; Liver Failure ; Muscimol ; Neurons ; Receptors, GABA ; Receptors, GABA-A ; Synaptic Transmission

Pregnolone[5beta-pregnan-3alpha-ol-one(5beta3alpha)] and allopregnanolone [(5alpha-pregnan-3alpha-ol-20-one(5alpha3alpha))] are neuroactive steroids that are reduced metabolites of progesterone. It was reported that Neuroactive steroids may have anxiolytic and anticonvulsant action similar to benzodiazepines and barbiturates. Therefore, the present study was designed to assess the interaction of steroids with GABAA-benzodiazepine receptor complex. The effect of steroids on the ligands binding to GABAA receptor complex was investigated using rat cortices. 5beta3alpha and 5alpha3alpha enhanced the binding of [3H] flunitrazepam to GABAA receptor, but testosterone, progesterone and dexamethasone did not. GABA also showed the enhancement of [3H] flunitrazepam binding, but did not show the additive effect. Unlike to GABA, 5beta3alpha and 5alpha3alpha did not affect on the [3H] muscimol binding to rat cortices. From these findings, it can be concluded that Neuroactive steroids are potent positive modulators of the GABA A receptor, and do not act at GABA binding site.
Animals ; Barbiturates ; Benzodiazepines ; Binding Sites ; Dexamethasone ; Flunitrazepam ; gamma-Aminobutyric Acid ; Ligands ; Muscimol ; Pregnanolone ; Progesterone ; Rats ; Receptors, GABA-A ; Steroids* ; Testosterone

In the previous experiments, we reported that ethanol extract of Gastrodiae Rhizoma, the dried tuber of Gastrodia ElataBlume (Orchidaceae) increased pentobarbital-induced sleeping behaviors. These experiments were undertaken to know whether 4-hydroxybenzaldehyde (4-HBD), is one of the major compounds of Gastrodiae Rhizoma increases pentobarbital-induced sleeping behaviors and changes sleep architectures via activating GABA(A)-ergic systems in rodents. 4-HBD decreased locomotor activity in mice. 4-HBD increased total sleep time, and decreased of sleep onset by pentobarbital (28 mg/kg and 40 mg/kg). 4-HBD showed synergistic effects with muscimol (a GABA(A) receptor agonist), shortening sleep onset and enhancing sleep time on pentobarbital-induced sleeping behaviors. On the other hand, 4-HBD (200 mg/kg, p.o.) itself significantly inhibited the counts of sleep-wake cycles, and prolonged total sleep time and non-rapid eye movement (NREM) in rats. Moreover, 4-HBD increased intracellular Cl- levels in the primary cultured cerebellar cells. The protein levels of glutamic acid decarboxylase (GAD) and GABA(A) receptors subunits were over-expressed by 4-HBD. Consequently, these results demonstrate that 4-HBD increased NREM sleep as well as sleeping behaviors via the activation of GABA(A)-ergic systems in rodents.
Animals ; Ethanol ; Eye Movements* ; Gastrodia* ; Glutamate Decarboxylase ; Hand ; Mice ; Motor Activity ; Muscimol ; Pentobarbital ; Rats ; Receptors, GABA-A ; Rodentia*

In this study, we examined the morphine-induced modulation of the nociceptive spinal dorsal horn neuronal activities before and after formalin-induced inflammatory pain. Intradermal injection of formalin induced time-dependent changes in the spontaneous activity of nociceptive dorsal horn neurons. In naive cats before the injection of formalin, iontophoretically applied morphine attenuated the naturally and electrically evoked neuronal responses of dorsal horn neurons. However, neuronal responses after the formalin-induced inflammation were significantly increased by morphine. Bicuculline, GABAA antagonist, increased the naturally and electrically evoked neuronal responses of dorsal horn neurons. This increase in neuronal responses due to bicuculline after the formalin-induced inflammation was larger than that in the naive state, suggesting that basal GABAA tone increased after the formalin injection. Muscimol, GABAA agonist, reduced the neuronal responses before the treatment with formalin, but not after formalin treatment, again indicating an increase in the GABAergic basal tone after the formalin injection which saturated the neuronal responses to GABA agonist. Morphine-induced increase in the spinal nociceptive responses after formalin treatment was inhibited by co-application of muscimol. These data suggest that formalin-induced inflammation increases GABAA basal tone and the inhibition of this augmented GABAA basal tone by morphine results in a paradoxical morphine- induced increase in the spinal nociceptive neuronal responses after the formalin-induced inflammation.
Animals ; Bicuculline ; Cats ; Formaldehyde ; GABA Agonists ; Inflammation ; Injections, Intradermal ; Morphine ; Muscimol ; Neurons ; Nociceptors ; Posterior Horn Cells* ; Spinal Cord

gamma-Aminobutyric acid (GABA) has been reported to enhance exocrine secretion evoked not only by secretagogues but also by intrinsic neuronal excitation in the pancreas. The pancreas contains cholinergic neurons abundantly that exert a stimulatory role in exocrine secretion. This study was undertaken to examine effects of GABA on an action of cholinergic neurons in exocrine secretion of the pancreas. Intrinsic neurons were excited by electrical field stimulation (EFS; 15 V, 2 msec, 8 Hz, 45 min) in the isolated, perfused rat pancreas. Tetrodotoxin or atropine was used to block neuronal or cholinergic action. Acetylcholine was infused to mimic cholinergic excitation. GABA (30microM) and muscimol (10microM), given intra-arterially, did not change spontaneous secretion but enhanced cholecystokinin (CCK; 10 pM) -induced secretions of fluid and amylase. GABA (3, 10, 30microM) further elevated EFS-evoked secretions of fluid and amylase dose-dependently. GABA (10, 30, 100microM) also further increased acetylcholine (5microM) -induced secretions of fluid and amylase in a dose-dependent manner. Bicuculline (10microM) effectively blocked the enhancing effects of GABA (30microM) on the pancreatic secretions evoked by either EFS or CCK. Both atropine (2microM) and tetrodotoxin (1microM) markedly reduced the GABA (10microM) -enhanced EFS- or CCK-induced pancreatic secretions. The results indicate that GABA enhances intrinsic cholinergic neuronal action on exocrine secretion via the GABAA receptors in the rat pancreas.
Acetylcholine ; Amylases ; Animals ; Atropine ; Bicuculline ; Cholecystokinin ; Cholinergic Neurons ; gamma-Aminobutyric Acid* ; Muscimol ; Neurons ; Pancreas* ; Rats* ; Receptors, GABA ; Tetrodotoxin

Glutamate Is the predominant excitatory neurotransmitter in the mammalian CNS. To elucidate the influence of glutamate on the noradrenergic neurotransmission in rat cortex, we examined the effects of agents that act in several steps of neurotransmission on [3H]norepinephrine ([3H])NE) release evoked by glutamate. Glutamate (1 mM) evoked significant release of [3H]NE from rat cortex slices in the absence of Mg2+in the incubation media. This effect was attenuated by cromakalime (10 nM) and lemakalime (10 nM), and the inhibitory effect of cromakalime was abolished by glipizide. Inhibitory effect of muscimol (30 uM) and baclofen (3 uM, 30 uM) was antagonized by biccuculine (3 uM), respectively. Nipecotic acid(10 uM), DABA(300 uM), and beta-alanine(100 uM) attenuated the glutamate-induced release of [3H]NE. Dihydrokinate (300 uM) PDC (100 nM) increased the glutamate-induced release of [3H]NE. Ifenprodile (10 nM) and arcaine (1 uN), blockers of polyamine site, attenuated the release of ("H)NE. The stimulatory effect of spermine was abolished by arcaine. CPA(100 nM) and CPCA(100 nM), EHNA(30 uN) and NBTI(1 uN) attenuated the release of ("H)NE. Verapamil(S uN), nitredipine(10 uN), u- conotoxin (100 nM) and flunarizine (5 uM) attenuated the release of (3H)NE. Dantrolene(30 uM), KT-362(3 uM), and ryanodine(10 nM), attenuated the glutamate-induced release of [3H]NE. Glycine (10 uM) increased the release of [3H]NE. DCQX (30 uN) attenuated the release of [3H]NE. These results suggest that glutamate-evoked release of norepinephrine can be modulated by GABAergic, adenosinergic neurotransmitters, and by various drugs which modulate ion channel activities in rat cortex.
Animals ; Baclofen ; Cerebral Cortex ; Conotoxins ; Cromakalim ; Flunarizine ; Glipizide ; Glutamic Acid ; Glycine ; Ion Channels ; Muscimol ; Neurotransmitter Agents ; Norepinephrine* ; Rats* ; Spermine ; Synaptic Transmission

BACKGROUND: The intrathecal (IT) administration of glycine or GABAA receptor antagonist result in a touch evoked allodynia through disinhibition in the spinal cord. Glycine is an inhibitory neurotransmitter that appears to be important in sensory processing in the spinal cord. This study was aimed to evaluate the effect of glycine-related amino acids on antagonizing the effects of IT strychnine (STR) or bicuculline (BIC) when each amino acid was administered in combination with STR or BIC. METHODS: A total of 174 male ICR mice were randomized to receive an IT injection of equimolar dose of glycine, betaine, beta-alanine, or taurine in combination with STR or BIC. Agitation in response to innocuous stimulation with a von Frey filament after IT injection was assessed. The pain index in hot-plate test were observed after it injection. The effect of it muscimol in combination with str or bic were also observed. RESULTS: The allodynia induced by STR was relieved by high dose of glycine or betaine. But, allodynia induced by BIC was not relieved by any amino acid. Whereas the STR-induced thermal hyperalgesia was only relieved by high dose of taurine at 120 min after IT injection, the BIC-induced one was relieved by not only high dose of taurine at 120 min but also low dose of glycine or betaine at 60 min after IT injection. The BIC-induced allodynia and thermal hyperalgesia was relieved by IT muscimol. CONCLUSIONS: This study suggests that IT glycine and related amino acids can reduce the allodynic and hyperalgesic action of STR or BIC in mice.
Amino Acids ; Animals ; beta-Alanine ; Betaine ; Bicuculline ; Dihydroergotamine ; Glycine ; Humans ; Hyperalgesia ; Male ; Mice ; Mice, Inbred ICR ; Muscimol ; Neurotransmitter Agents ; Nitrogen Mustard Compounds ; Spinal Cord ; Strychnine ; Taurine

BACKGROUND AND PURPOSE: Valproic acid (2-propylpentanoic acid) which enhances GABA synthesis and blocks it's degradation has been useful treatment of migraine and may activate GABA receptors to modulate trigeminal nociceptive neurons innervating the meninges. But the mechanism and action of sodium valproate in headache is not clear. To investigate the mechanism of valproic acid action in headache model, we compared the change of dural plasma protein extravasation in both substance-P neurogenic inflammation rats with valproic acid pretreatment and without valproic acid pretreatment. METHOD: Sprague-Dawely rats were pretreated with valproate 30 minutes prior to substance-P administration in order to test the effects of sodium valproate on dural plasma protein extravasation by detecting the amount of extravasated Evans blue in the dura matter. To examine the abilities of either bicuculine (GABAA antagonist) and phaclofen (GABAB antagonist) to reverse the effect of valproate, they were administered 5 min before valproate administration. After then we also test the effect of muscimol (GABAA agonist) and bicuculine (GABAA antagonist) in substance-P induced neurogenic inflammation rats. RESULTS: Intraperitoneal injection of sodium valproate and muscimol reduced dural plasma protein extravasation after intravenous substance-P administration. The GABAA antagonist bicuculine completely reversed the effect of valproate and muscimol on plasma extravasation following substance-P administration, whereas the GABAB receptor antagonist, phaclofen, did not. CONCLUSION: We concluded that the attenuation of dural plasma protein extravasation by valproate and muscimol is mediated by via GABAA receptors within the meninges. Agonists and modulators at the GABAA receptor may become useful for the development of selective therapeutic agents for migraine headache.
Animals ; Evans Blue ; gamma-Aminobutyric Acid ; Headache* ; Injections, Intraperitoneal ; Meninges ; Migraine Disorders ; Muscimol ; Neurogenic Inflammation ; Nociceptors ; Plasma ; Rats* ; Receptors, GABA ; Sodium* ; Valproic Acid*