Doses Of Muscimol Research Articles

Possible involvement of GABAergic system on central amygdala Mediated anxiolytic effect of agmatine in rats

Objectives To study the pharmacological interactions between agmatine and gamma aminobutyric acid (GABA) modulatory agents in the regulation of anxiety-like behavior in rats. Materials and methods Male Wistar rats were treated drugs per se or in combination and 15 min after last injection were subjected to elevated plus-maze (EPM) test. Anxiety-like behavior was evaluated by measuring behavioral conventional readout, open arm activity (duration and/or entries) for 5-minute duration. Results Acute intra-central amygdala (CeA) injection of agmatine (0.1-0.6 μmol/site/rat), muscimol (0.25-1 nmol/site/rat), diazepam (5-20 μg/site/rat) and allopregnanolone (2-8 μg/site/rat) increased open arm entries of the rats in EPM suggesting anxiolytic effect in dose dependent manner. Moreover, the anxiolytic effect at subeffective dose of agmatine (0.1 μmol/site/rat) was potentiated by subeffective dose of muscimol (0.25 nmol/site/rat), diazepam (5 μg/site/rat) and allopregnanolone (4 μg/site/rat). Whereas, pretreatment with GABAA receptor antagonist, bicuculline (10 ng/site/rat) blocked the anxiolytic effect of agmatine and its synergistic effect of agmatine plus muscimol. Similarly, benzodiazepine (BZD) receptor antagonist, flumazenil (15 μg/site/rat) and GABA allosteric modulator antagonist, RO 15-45 13 (10 μg/site/rat) reduced the anxiolytic effect of agmatine, given alone and with diazepam and allopregnanolone, respectively. Conclusion These results indicated that anxiolytic effect of agmatine is medicated via GABAergic mechanisms, probably conciliated by the GABAA receptor subtypes. Modulation of interplay between agmatine and GABAA receptor activity might be a pertinent solution for the regulation of anxiety.

Additive effect of histamine and muscimol upon induction of antinociceptive and antidepressant effects in mice.

We investigated the effects of histamine and GABA A receptor agents on pain and depression-like behaviors and their interaction using a tail-flick test and the forced swimming test (FST) in male mice. Our data revealed that intraperitoneal administration of muscimol (0.12 and 0.25 mg/kg) increased the percentage of maximum possible effect (%MPE) and area under the curve (AUC) of %MPE, indicating an antinociceptive response. Intraperitoneal injection of bicuculline (0.5 and 1 mg/kg) decreased %MPE and AUC of %MPE, suggesting hyperalgesia. Moreover, muscimol by reducing the immobility time of the FST elicited an antidepressant-like response but bicuculline by enhancing the immobility time of the FST caused a depressant-like response. Intracerebroventricular (i.c.v.) microinjection of histamine (5 µg/mouse) enhanced %MPE and AUC of %MPE. i.c.v. infusion of histamine (2.5 and 5 µg/mouse) decreased immobility time in the FST. Co-administration of different doses of histamine along with a sub-threshold dose of muscimol potentiated antinociceptive and antidepressant-like responses produced by histamine. Cotreatment of different doses of histamine plus a noneffective dose of bicuculline reversed antinociception and antidepressant-like effects elicited by histamine. Cotreatment of histamine, muscimol, and bicuculline reversed antinociceptive and antidepressant-like behaviors induced by the drugs. The results demonstrated additive antinociceptive and antidepressant-like effects between histamine and muscimol in mice. In conclusion, our results indicated an interaction between the histaminergic and GABAergic systems in the modulation of pain and depression-like behaviors.

Delayed but not immediate effects of estrogen curtail gamma-aminobutyric acid-mediated feeding responses elicited from the nucleus accumbens shell.

The present study investigated immediate versus delayed effects of estrogen replacement in ovariectomized (OVX) rats on hyperphagia elicited by gamma-aminobutyric acid (GABA)-A-agonist (muscimol) infusions into the nucleus accumbens shell (AcbSh). First, because intra-AcbSh muscimol-induced feeding has never been explored in OVX rats, a dose-effect curve was generated and compared to sham-operated males, the current point of reference in the literature. Muscimol (5, 10, 25, and 50 ng) increased food intake in both sexes, and both sexes reached the same asymptotic level of intake. Nevertheless, slopes of the linearized dose-effect functions for males and OVX females differed significantly, with females starting at a lower baseline and exhibiting a steeper slope. Next, the behavioral profiles of a behaviorally active, but nonmaximal intra-AcbSh muscimol dose (25 ng), were examined in a separate group of OVX females at two time-points: immediately after injecting 17β-estradiol 3-benzoate (EB) subcutaneously (5 μg), and 24 hr post-EB. Delayed, but not immediate, EB pretreatment suppressed, but did not eliminate, muscimol-driven food intake. However, EB did not change nonfood-directed behaviors such as locomotion or rearing. These results demonstrate that feeding mediated by intra-AcbSh GABA-A receptors is delimited by delayed, but not rapid, effects of estradiol. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

GABA-ergic agents modulated the effects of histamine on the behaviour of male mice in the elevated plus maze test.

What is the central question of this study? Is there an interaction between histamine and the GABAergic system in modulation of anxiety in mice? What is the main finding and its importance? There is a synergistic anxiogenic effect between histamine and bicuculline in mice. This effect may be due to a direct or an indirect effect of the histaminergic system on the GABAergic system. It has been documented that both histaminergic and GABAergic systems participate in the neurobiology of anxiety behaviour. In the current research, we investigated the effects of the histaminergic system and GABAA receptor agents on anxiety-related behaviours and their interaction using the elevated plus maze test in mice. Intraperitoneal (i.p.) administration of muscimol (0.12 and 0.25mg/kg) increased the open arm time (OAT) (P<0.001) without affecting the open arm entries (OAE) and locomotor activity, showing an anxiolytic effect. i.p. injection of bicuculline (0.5 and 1mg/kg) decreased OAT (P<0.001) but not OAE and locomotor activity, suggesting an anxiogenic behaviour. Intracerebroventricular (i.c.v.) microinjection of histamine (2.5 and 5μg/mouse) resulted in a decline in OAT (P<0.001) but not OAE and locomotor activity, indicating an anxiogenic response. Co-administration of histamine with GABAergic agents, muscimol (0.06mg/kg; i.p.) and bicuculline (0.25mg/kg; i.p.), decreased (P<0.001) and increased (P<0.05), respectively, the anxiogenic-like response to the effective dose (5μg/mouse; i.c.v.) of histamine. In addition, co-treatment of effective doses of histamine (2.5 and 5μg/mouse;i.c.v.) with an effective dose of muscimol (0.12mg/kg; i.p.) and a non-effective dose of bicuculline (0.25mg/kg; i.p.) significantly decreased OAT (P<0.001), suggesting a likely interaction between the histaminergic and GABAergic systems in the regulation of anxiety. The results demonstrated a synergistic anxiogenic-like effect between histamine and bicuculline in mice. In conclusion, our results present an interaction between the histaminergic and GABAergic systems in anxiolytic/anxiogenic-like behaviours in the elevated plus maze test.

Harmaline potentiates morphine-induced antinociception via affecting the ventral hippocampal GABA-A receptors in mice

Morphine is one of the most effective medications for treatment of pain, but its side effects limit its use. Therefore, identification of new strategies that can enhance morphine-induced antinociception and/or reduce its side effects will help to develop therapeutic approaches for pain relief. Considering antinociceptive efficacy of harmaline and also highlighted the important role of GABA-A receptors in the pain perception, this research aimed to determine whether the ventral hippocampal (vHip) GABA-A receptors are involved in the possible harmaline-induced enhancement of morphine antinociception. To achieve this, vHip regions of adult male mice were bilaterally cannulated and pain sensitivity was measured in a tail-flick apparatus. Intraperitoneally administration of morphine (0, 2, 4 and 6 mg/kg) or harmaline (0, 1.25, 5 and 10 mg/kg) increased the percentage of maximal possible effect (%MPE) and induced antinociception. Interestingly, co-administration of sub-effective doses of harmaline (5 mg/kg) and morphine (2 mg/kg) induced antinociception. Intra-vHip microinjection of muscimol (0, 200 and 300 ng/mice), a GABA-A receptor agonist, enhanced the anti-nociceptive effects of harmaline (2.5 mg/kg)+morphine (2 mg/kg) combination. Microinjection of the same doses of muscimol into the vHip by itself did not alter tail-flick latency. Intra-vHip microinjection of bicuculline (100 ng/mouse), a GABA-A receptor antagonist, did not cause a significant change in MPE%. Bicuculline (60 and 100 ng/mouse, intra-vHip) was administered with the harmaline (5 mg/kg)+morphine (2 mg/kg), and inhibited the potentiating effect of harmaline on morphine response. These findings favor the notion that GABAergic mechanisms in the vHip facilitate harmaline-induced potentiation of morphine response in the tail-flick test in part through GABA-A receptors. These findings shall provide insights and strategies into the development of pain suppressing drugs.

GABAergic Transmission in the Basolateral Amygdala Differentially Modulates Plasticity in the Dentate Gyrus and the CA1 Areas.

The term “metaplasticity” is used to describe changes in synaptic plasticity sensitivity following an electrical, biochemical, or behavioral priming stimulus. For example, priming the basolateral amygdala (BLA) enhances long-term potentiation (LTP) in the dentate gyrus (DG) but decreases LTP in the CA1. However, the mechanisms underlying these metaplastic effects are only partly understood. Here, we examined whether the mechanism underlying these effects of BLA priming involves intra-BLA GABAergic neurotransmission. Low doses of muscimol, a GABAA receptor (GABAAR) agonist, were microinfused into the rat BLA before or after BLA priming. Our findings show that BLA GABAAR activation via muscimol mimicked the previously reported effects of electrical BLA priming on LTP in the perforant path and the ventral hippocampal commissure-CA1 pathways, decreasing CA1 LTP and increasing DG LTP. Furthermore, muscimol application before or after tetanic stimulation of the ventral hippocampal commissure-CA1 pathways attenuated the BLA priming-induced decrease in CA1 LTP. In contrast, muscimol application after tetanic stimulation of the perforant path attenuated the BLA priming-induced increase in DG LTP. The data indicate that GABAAR activation mediates metaplastic effects of the BLA on plasticity in the CA1 and the DG, but that the same GABAAR activation induces an intra-BLA form of metaplasticity, which alters the way BLA priming may modulate plasticity in other brain regions. These results emphasize the need for developing a dynamic model of BLA modulation of plasticity, a model that may better capture processes underlying memory alterations associated with emotional arousing or stressful events.

Manipulations of inhibition in cortical circuitry differentially affect spectral and temporal features of Bengalese finch song.

The interplay between inhibition and excitation can regulate behavioral expression and control, including the expression of communicative behaviors like birdsong. Computational models postulate varying degrees to which inhibition within vocal motor circuitry influences birdsong, but few studies have tested these models by manipulating inhibition. Here we enhanced and attenuated inhibition in the cortical nucleus HVC (used as proper name) of Bengalese finches (Lonchura striata var. domestica). Enhancement of inhibition (with muscimol) in HVC dose-dependently reduced the amount of song produced. Infusions of higher concentrations of muscimol caused some birds to produce spectrally degraded songs, whereas infusions of lower doses of muscimol led to the production of relatively normal (nondegraded) songs. However, the spectral and temporal structures of these nondegraded songs were significantly different from songs produced under control conditions. In particular, muscimol infusions decreased the frequency and amplitude of syllables, increased various measures of acoustic entropy, and increased the variability of syllable structure. Muscimol also increased sequence durations and the variability of syllable timing and syllable sequencing. Attenuation of inhibition (with bicuculline) in HVC led to changes to song distinct from and often opposite to enhancing inhibition. For example, in contrast to muscimol, bicuculline infusions increased syllable amplitude, frequency, and duration and decreased the variability of acoustic features. However, like muscimol, bicuculline increased the variability of syllable sequencing. These data highlight the importance of inhibition to the production of stereotyped vocalizations and demonstrate that changes to neural dynamics within cortical circuitry can differentially affect spectral and temporal features of song.NEW & NOTEWORTHY We reveal that manipulations of inhibition in the cortical nucleus HVC affect the structure, timing, and sequencing of syllables in Bengalese finch song. Enhancing and blocking inhibition led to opposite changes to the acoustic structure and timing of vocalizations, but both caused similar changes to vocal sequencing. These data provide support for computational models of song control but also motivate refinement of existing models to account for differential effects on syllable structure, timing, and sequencing.

GABA-cannabinoid interplays in the dorsal hippocampus and basolateral amygdala mediate morphine-induced amnesia

The aim of the current study was to investigate the involvement of GABA neurotransmission in the CA1 region and endocannabinoid system in the basolateral amygdala (BLA) on morphine-induced memory impairment. We hypothesized that possible functional interaction between the GABAergic and cannabinoid systems in these brain regions would modulate morphine response in memory processing. Step-through type inhibitory avoidance paradigm was used for evaluating memory consolidation in adult male Wistar rats. Our results indicated that post-training systemic injection of morphine (3 and 5 mg/kg, i.p.) impaired memory retrieval. The microinjection of a GABA-A receptor agonist, muscimol (0.01-0.03 μg/rat) into the CA1 region increased the response of an ineffective dose of morphine (0.5 mg/kg, i.p.) and induced memory impairment, suggesting a synergistic interaction between morphine and muscimol. Interestingly, the activation of the BLA CB1 receptors by the microinjection of WIN55,212-2 (0.05-0.1 μg/rat) increased the effect of ineffective doses of muscimol (0.01 μg/rat; intra-CA1) and morphine (0.5 mg/kg, i.p.), inducing amnesia. The obtained results also showed that microinjection of AM251, a cannabinoid CB1 receptor antagonist, (1−2 μg/rat) into the BLA reversed the synergistic effect of muscimol and morphine, improving memory consolidation. It should be noted that the intra-CA1 microinjection of muscimol, intra-BLA microinjection of WIN55,212-2 or AM251 alone could not affect memory consolidation. Accordingly, it can be concluded that there may be a synergistic interaction between the CA1 GABAergic system and the BLA endocannabinoid neurotransmission with respect to the modulation of morphine-induced memory impairment.

Convection-Enhanced Delivery of Muscimol Into the Bilateral Subthalamic Nuclei of Nonhuman Primates.

Muscimol is a gamma-aminobutyric acid receptor agonist that selectively and temporarily inhibits neurons. Local bolus injection of muscimol has been used experimentally to inhibit neuronal populations within discrete anatomical structures and discern their physiological function. To determine the safety and behavioral effects of convection-enhanced delivery of muscimol into the bilateral subthalamic nuclei (STN) of nonhuman primate rhesus macaques (NHPs). Six awake NHPs underwent co-infusion of gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA), a surrogate magnetic resonance imaging (MRI) tracer, with increasing concentrations of muscimol for behavioral and histological assessment. Three other NHPs were co-infused with Gd-DTPA and 3H-muscimol into the STN to determine muscimol distribution by MRI and autoradiography. Two NHPs underwent microcatheter implantation without muscimol infusion for control comparison. MRI revealed selective and complete perfusion of the bilateral STN in animals infused with Gd-DTPA and muscimol. No abnormal movements occurred at 0.125 mM. Muscimol doses between 0.25 and 4.4 mM resulted in transient, dose-dependent hyperkinesia. Muscimol (8.8 mM) resulted in severe bilateral dyskinesias, ballistic movements, and sedation. An 88.8 mM dose produced unresponsiveness in 1 animal. Infusion-related pathological abnormities or toxicity was not present on histological examination. MRI distribution of co-infused Gd-DTPA was similar to autoradiographic distribution of 3H-muscimol (Vd; R=0.94). Mean Vd of infused animals was 37.9 mm3±11.7 mm3 and mean Vd: Vi 7.6±2.3. Bilateral convection-enhanced delivery of muscimol into the primate STN resulted in dose-related hyperkinetic movements that resolved after stopping the infusion. Muscimol was not toxic to brain tissue. Gd-DTPA accurately tracked muscimol distribution.

Taurine potentiates the anticonvulsive effect of the GABAA agonist muscimol and pentobarbital in the immature mouse hippocampus.

The high incidence of epileptic seizures in neonates and their frequent refractoriness to pharmacologic therapies require identification of new therapeutical options. Therefore, we investigated whether the modulatory effect of taurine on γ-aminobutyric acid (GABA)A receptors can enhance the anticonvulsive potential of the GABAA receptor agonist muscimol and of the barbiturate pentobarbital. We performed field potential recordings in in toto hippocampus preparations of immature (postnatal days 4-7) C57Bl/6 mouse pups. Spontaneous epileptiform activity was induced by the continuous presence of the potassium channel blocker 4-aminopyridine and the glycinergic antagonist strychnine in Mg2+ -free solutions. Bath application of 0.1μmol/L muscimol increases the occurrence of recurrent epileptiform discharges, whereas they are significantly attenuated in a dose-dependent manner by muscimol in concentrations between 0.5 and 5μmol/L. Taurine at concentrations between 0.1 and 0.5mmol/L induces a proconvulsive effect, but upon coapplication, it significantly augments the anticonvulsive effect of moderate muscimol doses (0.5-1μmol/L). In addition, the anticonvulsive effect of 100 and 200μmol/L pentobarbital is increased significantly in the presence of 0.5μmol/L taurine. These observations demonstrate that taurine can indeed enhance the anticonvulsive effects of muscimol and pentobarbital, suggesting that taurine may act as a positive modulator on GABAA receptors. Thus, interfering with the modulatory taurine binding site of GABAA receptors or the interstitial taurine concentration may provide new therapeutical options for anticonvulsive therapies in neonates.

Involvement of CA1 GABAA Receptors in Ketamine-Induced Impairment of Spatial and Non-Spatial Novelty Detection in Mice

Inhibitory GABAergic and excitatory glutamatergic neurons from multiple brain areas, send fibers to the hippocampal CA1 region. NMDA receptors have been identified as important compoents of the brain system underlying memory formation, which that through an increase in glutamate-mediated neurotransmission. Ketamine and other NMDA receptor antagonists produce deficits in cognitive tasks, including both spatial and non-spatial memory. In the current study, we tested whether the activation or inhibition of GABAA receptors in CA1 hippocampal of mice has an impact on ketamine (NMDA antagonist) induced spatial and non-spatial novelty detection deficits. Adult male mice weighing between 25–30 g were used. The open-field method was used to evaluate spatial and non-spatial memory information. Data obtained from the present study revealed that an intra-CA1 injection with a sub-threshold dose the GABAA receptor antagonist bicuculline (0.0625 µg mouse) disrupted spatial memory but restored non-spatial memory induced by lower and higher doses of ketamine (0.05 and 0.01 mg/kg) respectively. Meanwhile, the co-administration of the intra-CA1 injection with a sub-threshold dose of muscimol (GABAA receptor agonist at 0.25 µg/mouse) and a lower dose of ketamine could only impair the ability of non-spatial change detection but could not alter spatial novelty. In conclusion, ketamine (which contributes to the impairment of memory trace stored in the hippocampus) may be generated from GABAA receptors of CA1 neurons and their blockade could prevent these effects.

Neuroscience: Memory Encoding in the Absence of Cell Firing

New research suggests that rats can learn new spatial information in the absence of cell firing. A small enhancement of GABAergic inhibition with a low dose of muscimol blocked cell firing but left long-term potentiation induction intact, while behaviorally it blocked memory retrieval but left memory encoding intact.

Determining differential access to midwifery caseload in Queensland: A comparison of public health maternity models for women with complex pregnancy using demographic profile and matched population data

In this article, caspase activation in identifiable reticulospinal neurons of lampreys was inhibited after a complete spinal cord injury using a specific agonist of the GABAA receptor (muscimol). The data presented in this article are quantifications of fluorescent labelling of identifiable descending neurons of larval lampreys after a complete spinal cord injury using fluorochrome-labelled inhibitors of caspases (FLICA) and the corresponding statistical analysis. A single dose of muscimol decreased the intensity of FLICA labelling in giant identifiable reticulospinal neurons following spinal cord injury in lampreys.

Migration et communication médicale. Les difficultés de compréhension dans les consultations centrées sur les douleurs chroniques, O. Weber. Éditions Lambert-Lucas, Limoges (2017). Préface par Celia Roberts (Kings College). 308 p.

To investigate the interaction between hippocampal γ-aminobutyric acid GABAA receptor (GABAAR) or GABAB receptor (GABABR) and N-methyl-D-aspartate receptor (NMDAR) in the acquisition of passive avoidance memory in rats, we used GABAA or GABAB agents, D-AP5 (as a NMDAR antagonist), and a combination of the mentioned drugs in a step-through task. All agents were microinjected into the intra-CA1 regions at a volume of 1 µl/rat, prior to training. GABAAR agonist muscimol (0.2 µg/rat), selective GABABR agonist baclofen (0.5 µg/rat) or NMDAR antagonist D-AP5 (0.25 µg/rat) decreased step-through latency, indicating a memory retention impairment. Neither GABAAR antagonist bicuculline (0.0625–0.25 µg/rat) nor GABABR antagonist phaclofen (0.1–0.5 µg/rat) altered memory retrieval by itself. Moreover, the lower dose of muscimol (0.05 µg/rat) decreased D-AP5 (0.125 µg/rat) response on memory acquisition, but bicuculline did not alter the D-AP5 response. Furthermore, baclofen and phaclofen at the dose of 0.1 µg/rat potentiated D-AP5 response at the doses of 0.0625 and 0.125 µg/rat, but abolished memory impairment induced by D-AP5 at the higher dose (0.25 µg/rat). The results suggest that the microinjection of GABAA and GABAB agents into the CA1 region differently affects memory acquisition deficit induced by D-AP5. The activation of GABAARs increased the impairment effect of D-AP5 on passive avoidance memory, but their blockade did not have an effect. Also, the activation or blockade of GABABRs induced a similar and dual effect.

ToxGPS, a solution guiding read-across workflow based on chemoinformatics and safety assessment

In this article, caspase activation in identifiable reticulospinal neurons of lampreys was inhibited after a complete spinal cord injury using a specific agonist of the GABAA receptor (muscimol). The data presented in this article are quantifications of fluorescent labelling of identifiable descending neurons of larval lampreys after a complete spinal cord injury using fluorochrome-labelled inhibitors of caspases (FLICA) and the corresponding statistical analysis. A single dose of muscimol decreased the intensity of FLICA labelling in giant identifiable reticulospinal neurons following spinal cord injury in lampreys.

GABAA receptor in the Pedunculopontine tegmental (PPT) nucleus: Effects on cardiovascular system.

The pedunculopontine tegmental (PPT) nucleus is a heterogeneous nucleus with several functions including cardiovascular regulation. The presence of GABAA receptor has been shown in the PPT. Therefore, the cardiovascular effects of this receptor were examined. Rats were divided into: Control; Muscimol; Bicuculline (BMI); Hexamethonium (Hexa)+BMI and Atropine+BMI groups. The femoral vein and artery were cannulated for drug administration and recording of cardiovascular parameters, respectively. Muscimol (a GABAA agonist; 1.5 and 2.5nmol), BMI (a GABAA antagonist; 0.1 and 0.2nmol) were stereotaxically microinjected into the PPT. To evaluate the peripheral cardiovascular mechanisms of GABAA receptors, Hexa (a ganglionic blocker; 10mg/kg) and atropine (a muscarinic receptor antagonist; 1mg/kg) were intravenously (iv) injected before BMI (0.2nmol). The average changes of mean arterial pressure (ΔMAP), systolic blood pressure (ΔSBP) and heart rate (ΔHR) in different intervals were calculated and compared both within and between case group and control group (repeated measures ANOVA). The peak changes in each group were also calculated and compared with those of the control group (independent sample t-test). Both doses of BMI significantly increased ΔMAP, ΔSBP and ΔHR compared to control, while the only higher dose of muscimol significantly decreased ΔSBP. Iv injection of Hexa significantly attenuated ΔMAP, ΔSBP and ΔHR responses induced by BMI but atropine did not affect. Our results demonstrate that GABAA receptor of the PPT has a tonic inhibitory effect on the cardiovascular system and its peripheral effect mostly is mediated by sympathetic system.

Dorsal hippocampal cannabinergic and GABAergic systems modulate memory consolidation in passive avoidance task

In the present research, we examined the possible interaction between the hippocampal CB2 and GABAA receptors on modulation of memory consolidation. In this research, step-down passive a .voidance task was used to evaluate memory consolidation in adult male NMRI mice. The results showed that post-training intra-CA1 administration of muscimol (0.05 and 0.1 μg/mouse) impaired memory consolidation as evidenced by a decrease in step-down latency on the test day, which was suggestive of drug-produced amnesia. However co-administration of different doses of muscimol (0.01, 0.05 and 0.1 μg/mouse) along with a not-effect dose of AM630 (1 μg/mouse) or GP1a (1 μg/mouse) had no significant effect on impairment of memory consolidation induced by muscimol. Although post-training intra-CA1 administration of the cannabinoid CB2 receptor antagonist, AM630 (1, 10 and 100 μg/mouse) alone had no effect, its co-administration with an effective dose of muscimol (0.05 μg/mouse) impaired memory consolidation. Furthermore, post-training intra-CA1 microinjection of cannabinoid CB2 receptor agonist, GP1a (100 μg/mouse) impaired memory consolidation. Interestingly, post-training intra-CA1 co-injection of different doses of GP1a (1, 10 and 100 μg/mouse) along with an effect dose of muscimol (0.05 μg/mouse) significantly intensified impairment of memory consolidation induced by GP1a (10 μg/mouse). Moreover, all above doses of drugs did not significantly change locomotor activity. These findings suggest possible interaction between the CA1 cannabinoid CB2 and GABAA mechanisms on modulation of memory consolidation in mice.

Very low doses of muscimol and baclofen ameliorate cognitive deficits and regulate protein expression in the brain of a rat model of streptozocin-induced Alzheimer's disease

Recent studies devoted to neuroprotection have focused on the role of the gamma-aminobutyric acid (GABA) system in regulating neuroinflammatory processes which play a key role in the neurodegenerative processes observed in Alzheimer's disease (AD) by inducing glial cell overactivation and impairing neurotransmission.Data on the efficacy of classical GABA-A and GABA-B receptor agonists (muscimol and baclofen, respectively) in animal models of AD are not available. Moreover, no published studies have examined the ability of optimal doses of these compounds to prevent neuroinflammation, the alterations in neurotransmission and cognitive deficits. In the present study, we used a non-transgenic rat model of AD obtained by intracerebroventricular streptozocin (STZ) injection and assessed the effects of muscimol and baclofen at very low doses (0.01–0.05mg/kg) on spatial memory and the expression of cortical and hippocampal proteins related to neuroinflammation, namely proteins involved in astroglial functions (glial fibrillary acidic protein, GFAP), GABA synthesis (GABA synthesizing enzyme, glutamic acid decarboxylase 67, GAD67) and acetylcholine degradation (acetylcholine esterase).The presented study demonstrated that in a rat model of STZ-induced AD both muscimol and baclofen at the tested doses exerted memory-enhancing and anti-inflammatory effects, as well as normalization of acetylcholine esterase and GABA expression. We suggested that the function of very low doses of GABA receptor agonists differs from typical GABA-related inhibition and may be mediated by the allosteric sites of GABA receptors or other non-specific cell regulatory pathways.

Cross state-dependency of learning between arachidonylcyclopropylamide (ACPA) and muscimol in the mouse dorsal hippocampus

The aim of the present study was to examine cross state-dependent learning between ACPA (a selective cannabinoid CB1 receptor agonist) and muscimol (a selective GABAA receptor agonist) in the step-down inhibitory avoidance learning task. The dorsal hippocampal CA1 regions of adult male NMRI mice were bilaterally cannulated, and all drugs were microinjected into the intended sites of injection.Post-training and/or pre-test administration of ACPA (1 and 2ng/mouse) dose-dependently induced amnesia. Pre-test microinjection of the same doses of ACPA reversed the post-training ACPA-induced amnesia. This event has been named ACPA state-dependent learning (SDL).Post-training and/or pre-test microinjection of muscimol (0.05 and 0.1μg/mouse) dose-dependently induced amnesia. Pre-test administration of the same doses of muscimol reversed the post-training muscimol-induced amnesia, suggesting muscimol SDL.The amnesia induced by post-training administration of ACPA was reversed by pre-test administration of muscimol (0.05 and 0.1μg/mouse). Furthermore, the pre-test microinjection of muscimol (0.025 and 0.05μg/mouse) with an ineffective dose of ACPA (0.5ng/mouse) significantly restored memory retrieval and induced ACPA SDL.In another series of experiments, the amnesia induced by post-training administration of muscimol was reversed by pre-test administration of ACPA (1 and 2ng/mouse). Moreover, pre-test microinjection of ACPA (0.5 and 1ng/mouse) with an ineffective dose of muscimol (0.025μg/mouse) significantly restored memory retrieval and induced muscimol SDL.It is important to note that pre-test intra-CA1 injection of a selective GABAA receptor antagonist, bicuculline (0.125 and 0.25μg/mouse), 5min before the administration of muscimol (0.1μg/mouse) or ACPA (2ng/mouse) dose-dependently inhibited muscimol- and ACPA-induced SDL, respectively. Pre-test intra-CA1 administration of bicuculline (0.0625, 0.125 and 0.25μg/mouse) by itself did not affect memory retention.In conclusion, the data strongly revealed a cross SDL among ACPA and muscimol in the dorsal hippocampal CA1 regions.

Role of CA1 GABAA and GABAB receptors on learning deficit induced by D-AP5 in passive avoidance step-through task

To investigate the interaction between hippocampal γ-aminobutyric acid GABAA receptor (GABAAR) or GABAB receptor (GABABR) and N-methyl-D-aspartate receptor (NMDAR) in the acquisition of passive avoidance memory in rats, we used GABAA or GABAB agents, D-AP5 (as a NMDAR antagonist), and a combination of the mentioned drugs in a step-through task. All agents were microinjected into the intra-CA1 regions at a volume of 1 µl/rat, prior to training. GABAAR agonist muscimol (0.2 µg/rat), selective GABABR agonist baclofen (0.5 µg/rat) or NMDAR antagonist D-AP5 (0.25 µg/rat) decreased step-through latency, indicating a memory retention impairment. Neither GABAAR antagonist bicuculline (0.0625–0.25 µg/rat) nor GABABR antagonist phaclofen (0.1–0.5 µg/rat) altered memory retrieval by itself. Moreover, the lower dose of muscimol (0.05 µg/rat) decreased D-AP5 (0.125 µg/rat) response on memory acquisition, but bicuculline did not alter the D-AP5 response. Furthermore, baclofen and phaclofen at the dose of 0.1 µg/rat potentiated D-AP5 response at the doses of 0.0625 and 0.125 µg/rat, but abolished memory impairment induced by D-AP5 at the higher dose (0.25 µg/rat). The results suggest that the microinjection of GABAA and GABAB agents into the CA1 region differently affects memory acquisition deficit induced by D-AP5. The activation of GABAARs increased the impairment effect of D-AP5 on passive avoidance memory, but their blockade did not have an effect. Also, the activation or blockade of GABABRs induced a similar and dual effect.