Pharmacology of Intracisternal or Intrathecal Glycine, Muscimol, and Baclofen in Strychnine-induced Thermal Hyperalgesia of Mice

Glycine and gamma-aminobutyric acid (GABA) are localized and released by the same interneurons in the spinal cord. Although the effects of glycine and GABA on analgesia are well known, little is known about the effect of GABA in strychnine-induced hyperalgesia. To investigate the effect of GABA and the role of the glycine receptor in thermal hyperalgesia, we designed an experiment involving the injection of muscimol (a GABAA receptor agonist), baclofen (a GABAB receptor agonist) or glycine with strychnine (strychnine sensitive glycine receptor antagonist). Glycine, muscimol, or baclofen with strychnine was injected into the cisterna magna or lumbar subarachnoidal spaces of mice. The effects of treatment on strychnine-induced heat hyperalgesia were observed using the pain threshold index via the hot plate test. The dosages of experimental drugs and strychnine we chose had no effects on motor behavior in conscious mice. Intracisternal or intrathecal administration of strychnine produced thermal hyperalgesia in mice. Glycine antagonize the effects of strychnine, whereas, muscimol or baclofen does not. Our results indicate that glycine has anti-thermal hyperalgesic properties in vivo; and GABA receptor agonists may lack the binding abilities of glycine receptor antagonists with their sites in the central nervous system.

GABA in the central amygdaloid nucleus modulates the electrolyte excretion and hormonal responses to blood volume expansion in rats

We investigated the involvement of GABAergic mechanisms of the central amygdaloid nucleus (CeA) in unanesthetized rats subjected to acute isotonic or hypertonic blood volume expansion (BVE). Male Wistar rats bearing cannulas unilaterally implanted in the CeA were treated with vehicle, muscimol (0.2 nmol/0.2 µL) or bicuculline (1.6 nmol/0.2 µL) in the CeA, followed by isotonic or hypertonic BVE (0.15 or 0.3 M NaCl, 2 mL/100 g body weight over 1 min). The vehicle-treated group showed an increase in sodium excretion, urinary volume, plasma oxytocin (OT), and atrial natriuretic peptide (ANP) levels compared to control rats. Muscimol reduced the effects of BVE on sodium excretion (isotonic: 2.4 ± 0.3 vs vehicle: 4.8 ± 0.2 and hypertonic: 4.0 ± 0.7 vs vehicle: 8.7 ± 0.6 µEq·100 g-1·40 min-1); urinary volume after hypertonic BVE (83.8 ± 10 vs vehicle: 255.6 ± 16.5 µL·100 g-1·40 min-1); plasma OT levels (isotonic: 15.3 ± 0.6 vs vehicle: 19.3 ± 1 and hypertonic: 26.5 ± 2.6 vs vehicle: 48 ± 3 pg/mL), and ANP levels (isotonic: 97 ± 12.8 vs vehicle: 258.3 ± 28.1 and hypertonic: 160 ± 14.6 vs vehicle: 318 ± 16.3 pg/mL). Bicuculline reduced the effects of isotonic or hypertonic BVE on urinary volume and ANP levels compared to vehicle-treated rats. However, bicuculline enhanced the effects of hypertonic BVE on plasma OT levels. These data suggest that CeA GABAergic mechanisms are involved in the control of ANP and OT secretion, as well as in sodium and water excretion in response to isotonic or hypertonic blood volume expansion.

Agonistic-like responses from the torus semicircularis dorsalis elicited by GABA A blockade in the weakly electric fish Gymnotus carapo

Findings by our group have shown that the dorsolateral telencephalon of Gymnotus carapo sends efferents to the mesencephalic torus semicircularis dorsalis (TSd) and that presumably this connection is involved in the changes in electric organ discharge (EOD) and in skeletomotor responses observed following microinjections of GABA A antagonist bicuculline into this telencephalic region. Other studies have implicated the TSd or its mammalian homologue, the inferior colliculus, in defensive responses. In the present study, we explore the possible involvement of the TSd and of the GABA-ergic system in the modulation of the electric and skeletomotor displays. For this purpose, different doses of bicuculline (0.98, 0.49, 0.245, and 0.015 mM) and muscimol (15.35 mM) were microinjected (0.1 æL) in the TSd of the awake G. carapo. Microinjection of bicuculline induced dose-dependent interruptions of EOD and increased skeletomotor activity resembling defense displays. The effects of the two highest doses showed maximum values at 5 min (4.3 ± 2.7 and 3.8 ± 2.0 Hz, P < 0.05) and persisted until 10 min (11 ± 5.7 and 8.7 ± 5.2 Hz, P < 0.05). Microinjections of muscimol were ineffective. During the interruptions of EOD, the novelty response (increased frequency in response to sensory novelties) induced by an electric stimulus delivered by a pair of electrodes placed in the water of the experimental cuvette was reduced or abolished. These data suggest that the GABA-ergic mechanisms of the TSd inhibit the neural substrate of the defense reaction at this midbrain level.

The inactivation of the basolateral nucleus of the rat amygdala has an anxiolytic effect in the elevated T-maze and light/dark transition tests

Pharmacological evidence indicates that the basolateral nucleus of the amygdala (BLA) is involved in the mediation of inhibitory avoidance but not of escape behavior in the elevated T-maze test. These defensive responses have been associated with generalized anxiety disorder (GAD) and panic disorder, respectively. In the present study, we determined whether the BLA plays a differential role in the control of inhibitory avoidance and escape responses in the elevated T-maze. Male Wistar rats (250-280 g, N = 9-10 in each treatment group) were pre-exposed to one of the open arms of the maze for 30 min and 24 h later tested in the model after inactivation of the BLA by a local injection of the GABA A receptor agonist muscimol (8 nmol in 0.2 æL). It has been shown that a prior forced exposure to one of the open arms of the maze, by shortening latencies to withdrawal from the open arm during the test, improves the escape task as a behavioral index of panic. The effects of muscimol in the elevated T-maze were compared to those caused by this GABA agonist in the avoidance reaction generated in the light/dark transition test. This defensive behavior has also been associated with GAD. In the elevated T-maze, intra-BLA injection of muscimol impaired inhibitory avoidance (control: 187.70 ± 14.90 s, muscimol: 37.10 ± 2.63 s), indicating an anxiolytic effect, without interfering with escape performance. The drug also showed an anxiolytic effect in the light/dark transition test as indicated by the increase in the time spent in the lighted compartment (control: 23.50 ± 2.45 s, muscimol: 47.30 ± 4.48 s). The present findings point to involvement of the BLA in the modulation of defensive responses that have been associated with GAD.

Efectos de la administración central de agonistas GABAérgicos sobre la microestructura de la conducta alimenticia. Estudio experimental en ratas / Response to central administration of GABAergic agents on the microestructure of feeding behaviour. Experimental trial in rats

Debido a la administración de muscimol en el HVM (hipotálamo ventromedial) la ingesta de carbohidratos y la ingesta total se incrementaron; conductualmente este aumento de la ingesta de alimento se caracterizó por el aumento del tiempo total, asociado a un incremento en la duración de los episodios alimentarios. La administración de baclofén en el HVM incrementó la ingesta de carbohidratos y la ingesta total, este aumento se caracterizó por episodios alimentarios menos frecuentes pero más largos. Se confirma que la estimulación de los receptores GABAA y GABAB en el HVM inducen la alimentación y se concluye que el sistema GABAérgico está involucrado en el control de la conducta alimenticia.

Role of the amygdala, hippocampus and entorhinal cortex in memory consolidation and expression

1. Experiments using localized microinfusions of specific agonists and antagonists of neurotransmitter receptors have shown that the amygdala, hippocampus, medial septum and entorhinal cortex are involved in memory consolidation, storage and expression. The data are consistent with observations derived from lesion studies suggesting a role for these structures in memory processes, but permit many additional conclusions concerning the mechanisms involved and their timing. 2. Memories are initially processed by glutamatergic N-methyl-D-aspartate (NMDA) receptors in amygdala, hippocampus and medial septum, which are sensitive to amino-phosphono valerate (AP5). Memory of inhibitory avoidance is processed by the three structures; memory of habituation to a novel environment is processed only by the hippocampus. At the time of consolidation, immediately after training, gamma-aminobutyrate type A (GABA-A) receptors, modulated by endogenous benzodiazepines, play an inhibitory role, and cholinergic muscarinic and beta-noradrenergic transmission play a modulatory role. 3. From 90 to 180 min after training, memories are blocked by cyano-nitro-quinoxalinedione (CNQX) given into the amygdala, septum and hippocampus. CNQX blocks non-NMDA glutamatergic receptors. Also between 90 and 180 min after training, memory of the habituation and inhibitory avoidance tasks is blocked by the infusion of AP5 or of the GABA-A agonist, muscimol, into the entorhinal cortex. This late post-training intervention of the entorhinal cortex is essential for the integration of successively acquired memories, and occurs in response to the simultaneous activation of CNQX-sensitive synapses in amygdala and hippocampus. 4. The expression of memory is blocked by the infusion of CNQX, at the time of testing, into the amygdala and hippocampus (inhibitory avoidance), into the hippocampus but not the amygdala (habituation), or into the entorhinal cortex (for the two tasks). Since consolidation is blocked by AP5 infused into these structures (see above), the data agree with the hypothesis that memories are mediated by (or actually consist of) long-term potentiation (LTP) in these areas of the brain. LTP induction is blocked by AP5 and LTP expression is blocked by CNQX. It is possible that, at the time of memory expression, the entorhinal cortex is an output of the amygdala and hippocampus

Changes in succinate dehydrogenase activity of rats after intraventricular injections of GABA, muscimol and picrotoxin.

Effects of intraventricular injections of GABA, and a GABA agonist, muscimol and an antagonist, picrotoxin on succinate dehydrogenase (SDH) enzyme activity in plasma and a few hypothalamic nuclei of brain of rats have been investigated using biochemical, histochemical and cytophotometric techniques. Results show that SDH decreased by GABA and muscimol treatment, and increased after picrotoxin injection. From the above findings, it is apparent that GABA, muscimol and picrotoxin influence SDH activity of plasma and hypothalamic nuclei.

Effect of GABA, muscimol and picrotoxin given in third ventricle on serum cholinesterases and monoamine oxidase and on plasma succinic dehydrogenase in rats.

Effect of injection in third ventricle of GABA, the GABA agonist muscimol, and the GABA antagonist picrotoxin on the activities of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and monoamine oxidase (MAO) in serum and succinic dehydrogenase (SDH) in plasma has been studied. Surprisingly, the AChE, BuChE, MAO and SDH enzymes activity were inhibited by GABA and muscimol, while they were enhanced by picrotoxin.