Doses Of Muscimol Research Articles

The memory-impairing effects of septal GABA receptor activation involve GABAergic septo-hippocampal projection neurons

Septal infusions of the gamma-aminobutyric acid (GABA)(A) agonist muscimol impair memory, and the effect likely involves the hippocampus. GABA(A) receptors are present on the perikarya of cholinergic and GABAergic septo-hippocampal (SH) projections. The current experiments determined whether GABAergic SH projections are involved in the memory-impairing effects of septal GABA(A) receptor activation. Experiment 1 tested whether combining septal co-infusions of subeffective doses of muscimol with scopolamine, a drug that selectively influences GABA SH projections, would produce memory deficits. Experiment 2 tested whether hippocampal infusions of a GABA(A) receptor antagonist would block the effects of septal muscimol infusions. Fifteen minutes prior to assessing spontaneous alternation (SA) or training in a multiple trial inhibitory avoidance (CMIA) task, male Sprague-Dawley rats were given septal infusions of vehicle, muscimol, scopolamine, or co-infusions of muscimol with scopolamine, or septal infusions of vehicle or muscimol combined with hippocampal infusions of vehicle or bicuculline. Septal co-infusions of muscimol with scopolamine significantly impaired SA and CMIA. Hippocampal bicuculline infusions blocked deficits produced by septal muscimol infusions in SA and attenuated deficits produced in CMIA. Combined, these findings suggest that GABAergic SH projections are involved in the memory-impairing effects of septal GABA receptor activation.

Alteration of behavior in mice by muscimol is associated with regional electroencephalogram synchronization

We tested the hypothesis that the effects of GABAergic agonists on behavior and the electroencephalogram (EEG) result from an increased regional synchronization in cortical circuits. The relationship between regional EEG topography, EEG synchronization and alteration of behavior was investigated by administering male C57BL/6 mice ( n=7) a high, 3 mg/kg i.p. dose of muscimol, a selective GABA A agonist. Parietal and frontal cortical EEG, electromyogram, infrared and running wheel activity were recorded for 3 h before and 9 h after injection. Muscimol consistently elicited biphasic behavioral changes. Initially, it induced a catalepsy-like state lasting 96.0±12.4 min. This state was followed by a hyperactivity period of 49.7±5.4 min, during which the mice engaged in vigorous wheel running. During catalepsy, the EEG exhibited high amplitude waves which showed a consistent phase relationship between the frontal and parietal derivation. Moreover, the typical regional differences between the EEG spectra of the two derivations were abolished, and a redistribution of EEG power toward lower frequencies (<3 Hz) occurred in both derivations. In contrast, during hyperactivity the parietal EEG was dominated by theta-activity (7–9 Hz), which is typical for running behavior, while high amplitude slow waves, resembling the normal non–rapid eye movement sleep EEG pattern, predominated in the frontal EEG. The data indicate that the GABAergic system is involved in the regulation of cortical synchronization of neuronal activity and suggest a link between regional EEG synchronization and behavioral states.

Reversible inactivation of the entorhinal cortex disrupts the establishment and expression of latent inhibition of cued fear conditioning in C57BL/6 mice

For latent inhibition, preexposure to a conditioned stimulus (CS) prior to training with an unconditioned stimulus (US) results in decreased conditioned responses (CRs) to the CS at the time of testing. The mechanism by which decreased CRs occurs, however, is unknown; CS preexposure may interfere with subsequent conditioning, or modulate the expression of CRs. Previous research has suggested that the entorhinal cortex (EC) is necessary for latent inhibition of a variety of tasks. However, no studies have specifically compared the role of the EC in acquisition vs. expression of latent inhibition. The present study used reversible inactivation of the EC to address this issue. The GABA agonist muscimol (0.5 microg/side) was directly infused into the EC of mice prior to CS preexposure, training, or testing. Our results indicate that muscimol inactivation of the EC before CS preexposure disrupts latent inhibition of cued fear conditioning. Importantly, this same dose of muscimol did not disrupt cued fear conditioning, nor did it affect latent inhibition when infused into the subiculum. Furthermore, inactivation of the EC at testing disrupted the expression of latent inhibition of cued fear conditioning; that is, CS preexposed mice that received entorhinal cortical muscimol infusion at testing showed CRs compared to saline-infused CS preexposed mice. These findings suggest that repeated preexposure to the CS during latent inhibition may alter entorhinal cortical activity thereby allowing the EC to exert inhibitory control over the expression of CRs during testing of CS preexposed mice.

Muscimol inactivation of the septo-preoptic complex affects medial forebrain bundle self-stimulation only when directed at the complex's ventrolateral components

Elements of the septo-preoptic basal forebrain complex, particularly the lateral and medial septum, the diagonal band of Broca, and the magnocellular preoptic area, have been linked to medial forebrain bundle (MFB) self-stimulation. This study examines the roles of these areas in MFB self-stimulation by temporarily inactivating them with 25 and 50 ng doses of the GABA A receptor agonist muscimol. Changes in performance capacity and stimulation reward effectiveness were evaluated with the rate–frequency curve shift paradigm. When infused into the lateral and medial septum and the vertical limb of the diagonal band of Broca, both doses of muscimol were as ineffective as saline in altering either the rats’ maximum rate of response for stimulation or the frequency required to maintain half-maximal response rate (required frequency). However, when infused into the horizontal limb of the diagonal band of Broca or the magnocellular preoptic area, muscimol substantially decreased maximal response rate and modestly increased required frequency. Changes in maximum rate were dose-dependent, but changes in required frequency were not. Muscimol infusions contralateral to the stimulated hemisphere were as effective as ipsilateral infusions; bilateral infusions tended to so suppress responding that resulting rate–frequency curves were often invalid. These results suggest a role in MFB self-stimulation for only the ventrolateral components of the septo-preoptic complex, and support past observations of considerable bilaterality in the neural systems that support self-stimulation.

GABA A but not GABA B receptors in the rostral anterior cingulate cortex selectively modulate pain-induced escape/avoidance behavior

The rostral anterior cingulate cortex (rACC) is involved in supraspinal nociceptive processing. ACC lesions relieve persistent pain, but do not affect the patient's ability to localize a noxious stimulus. Since the rACC has a high density of GABA receptors, it is possible that pain processing is influenced by these receptors in the rACC. The present experiments examined the involvement of rat rACC GABA A and GABA B receptors in regard to sensitivity to mechanical stimulation and escape/avoidance behavior in response to a noxious stimulus following L5 spinal nerve ligation. Rats were or were not afflicted with a neuropathic pain condition by an L5 spinal nerve ligation. rACC microinjection of 10 μg/μl GABA, a GABA A agonist (0.001 μg/μl, 0.1 μg/μl, or 0.5 μg/μl muscimol), a GABA B agonist (0.1 μg/μl, 1 μg/μl, or 5 μg/μl baclofen), or saline, did not alter mechanical withdrawal thresholds. Importantly, following 10 μg/μl GABA, 0.1 μg/μl, or 0.5 μg/μl muscimol microinjected into the rACC, place escape/avoidance behavior to a noxious mechanical stimulus was attenuated in injured animals. The attenuation was specific to the rACC and was blocked by a preadministered microinjection of the appropriate antagonist(s) into the rACC. In conclusion, microinjection of GABA and higher doses of muscimol did not decrease mechanical hyperalgesia but did attenuate place escape/avoidance behavior that is associated with mechanical stimulation of the ligated paw. These results provide additional support for the role of the rACC in higher order supraspinal processing of noxious events and suggest that rACC GABA A receptors significantly contribute to this processing.

Co-modulation of acute ethanol-induced motor impairment by mouse cerebellar adenosinergic A 1 and GABA A receptor systems

We have previously demonstrated that cerebellar adenosine modulates ethanol ataxia. Using Rotorod method, we investigated the role of cerebellar GABA A receptors in the adenosinergic modulation of ethanol ataxia in mice. Direct cerebellar microinfusion of GABA A agonist, muscimol (2.5, 5 and 10 ng) and antagonist, bicuculline (50, 100 and 200 ng), via permanently implanted guide cannulas, produced a marked and dose-dependent accentuation and attenuation, respectively, of ethanol (2 g/kg; IP) ataxia. The accentuation of ethanol ataxia by intracerebellar muscimol was through GABA A receptor because intracerebellar pretreatment with bicuculline virtually abolished muscimol effect. Intracerebellar microinfusion of adenosine A 1 agonist, N 6-cyclohexyladenosine (CHA: 4 ng), and antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX: 100 ng) markedly accentuated and attenuated, respectively, ethanol ataxia consistent with our previously published data. Intracerebellar microinfusion of CHA (4 ng) or DPCPX (100 ng) markedly enhanced and reduced, respectively, muscimol (10 ng)-induced accentuation of ethanol ataxia suggesting co-modulation of ethanol ataxia by cerebellar adenosinergic A 1 and GABA A receptors. Similarly, intracerebellar bicuculline (200 ng) pretreatment not only prevented CHA-induced accentuation of ethanol ataxia, but caused further decrease in ethanol ataxia. No change in the normal coordination was observed when microinfusion of the highest dose of muscimol, bicuculline, DPCPX or CHA alone or in combination was followed by saline injection instead of ethanol. The results of the present study suggest a functional similarity between GABA A and adenosine A 1 receptors even though both receptor types are known to couple to different signaling system and their location is on the opposite ends of the cerebellar granule cells, axons and axonal terminals (i.e., GABA A at the granule cells and adenosine A 1 on axons and axonal terminals of the granule cells) and act as co-modulators of ethanol ataxia.

Microinjection of muscimol into caudal periaqueductal gray lowers body temperature and attenuates increases in temperature and activity evoked from the dorsomedial hypothalamus

Microinjection of the neuronal inhibitor muscimol into the midbrain lateral/dorsolateral periaqueductal gray (l/dlPAG) suppresses increases in heart rate (HR) and mean arterial pressure (MAP) evoked by microinjection of the GABA A receptor antagonist bicuculline methiodide (BMI) into the dorsomedial hypothalamus (DMH) in rats. Injection of BMI into the DMH also increases body temperature (Tco) and motor activity. Here, our goal was to extend previous findings by examining the effect of microinjection of muscimol into the PAG on these thermogenic and behavioral responses in conscious freely moving rats. Microinjection of muscimol (300 pmol and 1 nmol) alone into the l/dlPAG reduced baseline Tco without affecting activity, HR, or MAP. Similar injection of a dose that failed to alter baseline Tco (100 pmol) suppressed the increases in Tco evoked from the DMH and significantly attenuated DMH-induced increases in locomotor activity. Whereas microinjection of 1 nmol muscimol into the ldlPAG abolished the increases in Tco evoked from the DMH and in fact lowered body temperature to a degree similar to that seen after this dose of muscimol alone, 1 nmol muscimol at adjacent sites outside the targeted region of the PAG had no significant effect on DMH-induced increases in Tco or any other parameter. These results indicate a role for neuronal activity in the l/dlPAG in (1) the temperature and behavioral responses to disinhibition of neurons in the DMH, and (2) the maintenance of basal body temperature in conscious freely moving rats.

GABAA receptors of hippocampal CA1 regions are involved in the acquisition and expression of morphine-induced place preference

In the present study, the effects of bilateral intra-hippocampal CA1 (intra-CA1) injections of GABAA receptor agonist and/or antagonist on the acquisition and expression of morphine-induced place preference in male Wistar rats have been investigated. The conditioning treatments with subcutaneous (s.c.) injections of different doses of morphine (0.5–7.5 mg/kg) induced a conditioned place preference (CPP) for the drug-associated place in a dose-dependent manner. Intra-CA1 administration of the GABAA receptor agonist, muscimol (0.25, 0.5 and 1 μg/rat) significantly inhibited the morphine (5 mg/kg, s.c.)-induced CPP. Intra-CA1 injections of different doses of the GABAA receptor antagonist, bicuculline (0.25, 0.5 and 1 μg/rat), in combination with an ineffective dose of morphine (0.5 mg/kg, s.c.) elicited a significant CPP. However, muscimol or bicuculline by themselves did not elicit any effect on place conditioning. Furthermore, the muscimol-induced inhibition of morphine response was reversed by bicuculline (1 μg/rat, intra-CA1) administration. On the other hand, the bilateral intra-CA1 injections of muscimol (0.25, 0.5 and 1 μg/rat) or bicuculline (0.5, 1 and 2 μg/rat) significantly decreased the expression of morphine-induced CPP. Intra-CA1 administration of different doses of muscimol or bicuculline had no effect on locomotor activity in the testing phase. Our data indicated that the GABAA receptors of the hippocampal CA1 regions may play an important role in the acquisition and expression of morphine-induced place preference.

P.1.c.009 Ethanol state-dependent learning: involvement of dopamine D2 receptors of dorsal hippocampus

In the present study, the effects of bilateral intra-hippocampal CA1 (intra-CA1) injections of GABAA receptor agonist and/or antagonist on the acquisition and expression of morphine-induced place preference in male Wistar rats have been investigated. The conditioning treatments with subcutaneous (s.c.) injections of different doses of morphine (0.5–7.5 mg/kg) induced a conditioned place preference (CPP) for the drug-associated place in a dose-dependent manner. Intra-CA1 administration of the GABAA receptor agonist, muscimol (0.25, 0.5 and 1 μg/rat) significantly inhibited the morphine (5 mg/kg, s.c.)-induced CPP. Intra-CA1 injections of different doses of the GABAA receptor antagonist, bicuculline (0.25, 0.5 and 1 μg/rat), in combination with an ineffective dose of morphine (0.5 mg/kg, s.c.) elicited a significant CPP. However, muscimol or bicuculline by themselves did not elicit any effect on place conditioning. Furthermore, the muscimol-induced inhibition of morphine response was reversed by bicuculline (1 μg/rat, intra-CA1) administration. On the other hand, the bilateral intra-CA1 injections of muscimol (0.25, 0.5 and 1 μg/rat) or bicuculline (0.5, 1 and 2 μg/rat) significantly decreased the expression of morphine-induced CPP. Intra-CA1 administration of different doses of muscimol or bicuculline had no effect on locomotor activity in the testing phase. Our data indicated that the GABAA receptors of the hippocampal CA1 regions may play an important role in the acquisition and expression of morphine-induced place preference.

EFFECT OF GABA RECEPTOR AGONISTS OR ANTAGONISTS ON MORPHINE-INDUCED STRAUB TAIL IN MICE

The effects of GABA receptor agents on Straub tail induced by morphine were investigated in mice. Subcutaneous injection of different doses of morphine (10–60 mg/kg) induced a dose-dependent Straub tail in mice. Maximum response was obtained with 40 mg/kg of the drug, 30 min after the drug administration. The morphine response was decreased by subcutaneous injection of naloxone (0.5–2 mg/kg). Intraperitoneal administration of different doses of baclofen (2–8 mg/kg) reduced Straub tail induced by morphine (40 mg/kg). The response of baclofen was decreased by Intraperitoneal injection of CGP35348 (150 mg/kg). CGP35348 by itself did not elicit any response. Different Intraperitoneally doses of muscimol (1–4 mg/kg) bicuculline (1–3 mg/kg), or picrotoxin (1–3 mg/kg) also reduced morphine effect. The effect of muscimol was not altered by bicuculline pretreatment. It is concluded that both GABAA and GABAB receptor activation reduced Straub tail induced by morphine.

Amygdaloid GABA, not glutamate neurotransmission or mRNA transcription controls footshock-associated fear arousal in the acoustic startle paradigm

In Pavlovian conditioning the fear-evoking properties of the aversive unconditioned stimulus are represented by the conditioned stimulus. A major challenge for theories of classical fear conditioning has been to understand how associations are formed between a conditioned stimulus and unconditioned stimulus. Although the cellular mechanisms in the amygdala that underlie fear learning have received considerable attention relatively little is known about the neural substrates underlying unconditioned stimulus-associated fear. In the present study we examined the role of GABA A, N-methyl- d-aspartic acid and non- N-methyl- d-aspartic acid receptors, and protein synthesis inhibition on the immediate fear arousal produced by footshock as measured by the shock sensitization of acoustic startle. Laboratory rats showed shock-enhanced startle after infusion into the basolateral amygdala of the N-methyl- d-aspartic acid receptor antagonist d(−)-2-amino-5-phosphonopentanoic acid (5.0μg), the non- N-methyl- d-aspartic acid receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione disodium (5.0μg) and the protein synthesis inhibitor anisomycin (80.0μg). We concluded that fear arousal provoked by footshock is not mediated by glutamate neurotransmission in the amygdala and does not involve de novo protein synthesis. Bilateral infusion into the basolateral amygdala of the GABA A receptor agonist muscimol in doses ranging from 0.001–0.5μg reliably blocked the shock sensitization of acoustic startle responding. None of the muscimol doses altered shock reactivity amplitudes indicating the normal perception of footshock. The muscimol results were interpreted to suggest that decreased GABA neurotransmission in the amygdala may be essential for the neural causation of fear that is acquired and expressed by conditioned stimuli.

Anxiolytic-like actions of the hexane extract from leaves of Annona cherimolia in two anxiety paradigms: Possible involvement of the GABA/benzodiazepine receptor complex

A hexane extract of leaves of Annona cherimolia produced anxiolytic-like actions when administered to mice and tested in two animal models of anxiety: the mouse avoidance exploratory behavior and the burying behavior tests. In order to discard unspecific drug-actions on general activity, all treatments studied in the anxiety paradigms were also analyzed in the open field test. Results showed that A. cherimolia induced anxiolytic-like actions at the doses of 6.25, 12.5, 25.0 and 50.0 mg/kg. Picrotoxin (0.25 mg/kg), a GABA-gated chloride ion channel blocker, antagonized the anxiolytic-like actions of A. cherimolia, while a sub-effective dose of muscimol (0.5 mg/kg), a selective GABA A receptor agonist, facilitated the effects of a sub-optimal dose of A. cherimolia (3.12 mg/kg). Thus, the involvement of the GABA A receptor complex in the anxiolytic-like actions of A. cherimolia hexane extract is suggested. In addition the extract was also able to enhance the duration of sodium pentobarbital induced sleeping time. Taken together, results indicate that the hexane extract of A. cherimolia has depressant activity on the Central Nervous System and could interact with the GABA A receptor complex. On the other hand, the chromatographic separation of this extract led to the isolation of palmitone, and β-sitosterol as major constituents. In addition a GC-MS study of some fractions revealed the presence of several compounds such β-cariophyllene, β-selinene, α-cubebene, and linalool that have been reported to show effects on behavior that could explain some of the extract effects.

Centrally-mediated antinociceptive actions of GABA A receptor agonists in the rat spared nerve injury model of neuropathic pain

Gamma aminobutyric acid (GABA) plays a major role in the central hyperexcitabilty associated with nerve damage. The precise antinociceptive actions mediated by GABA A receptor agonists remain unclear as previous studies have shown mixed results in neuropathic pain models. Thus, various drugs which modulate GABA A receptor function were tested in the rat spared nerve injury (SNI) model of neuropathic pain. The selective GABA A receptor agonist gaboxadol dose-dependently (6 and 15 mg/kg, s.c.) reversed hindpaw mechanical allodynia and hyperalgesia for at least 150 min after administration. The GABA A receptor agonist muscimol (0.02–2 mg/kg, s.c.) also dose-dependently reversed mechanical allodynia, although the maximal effect achieved was less than that observed for gaboxadol. Mechanical hyperalgesia was attenuated only by the highest dose of muscimol. In contrast, the selective GABA A receptor agonist isoguvacine (20 mg/kg, s.c.) which has poor central nervous system penetration, and the benzodiazepine-site ligand zolpidem (20 mg/kg, s.c.) were ineffective against either nociceptive behaviour. In the rotarod test, both gaboxadol (15 mg/kg) and zolpidem impaired motor function for at least 60 min after injection; muscimol (2 mg/kg) and gaboxadol (6 mg/kg) were ineffective. Importantly, the ataxic effects induced by gaboxadol resolved 1–2 h after administration, a time point where clear antiallodynic and antihyperalgesic actions still occurred. Thus, systemic administration of blood–brain penetratable selective GABA A receptor agonists attenuate nociceptive behaviours in the SNI rat model of neuropathic pain that can be considered to occur independently of other effects on motor function.

Differential neuroprotective effects for three GABA-potentiating compounds in a model of hypoxia–ischemia

Clomethiazole (CMZ) is a GABA A-potentiating compound; however, it is unclear whether this mode of action is responsible for its neuroprotective effects in animal models of ischemia. This study compared the neuroprotective efficacies of muscimol and midazolam, two potent GABA A-potentiating compounds, to that of CMZ in a model of hypoxia–ischemia (H–I). To establish a neuroprotective profile for CMZ, CMZ (60, 95, or 125 mg kg −1, i.p.) was administered to post-natal day 25 male rats at numerous post-hypoxic time points and the rats were sacrificed 1 or 4 weeks later. Varying degrees of histological protection were evident when CMZ was administered 1, 2, or 3 h post-hypoxia with the 125 mg kg −1 dose producing complete histological protection if administered 3 h post-hypoxia. To determine whether midazolam or muscimol could match the protection provided by CMZ administered 3 h post-hypoxia, H–I rats received varying doses of these compounds 3 h post-hypoxia and were sacrificed 1 week later. Under identical conditions, no dose of muscimol or midazolam provided equivalent neuroprotection to that provided by CMZ. In fact, muscimol showed no neuroprotective ability whatsoever. Thus, CMZ, administered as late as 3 h post-hypoxia, was able to completely prevent H–I-induced cell death while a full dose range of other GABA-potentiating agents did not. Such direct comparison of these compounds in this model suggests the mechanism underlying the protective effects of CMZ may not rely solely on GABA A-potentiating properties. Elucidation of a novel mechanism of action for CMZ may expose new therapeutic targets in stroke treatment.

Inactivation of the medial prefrontal cortex with the GABA A receptor agonist muscimol increases open-arm activity in the elevated plus-maze and attenuates shock-probe burying in rats

This study examined the effects of infusions of a direct GABA A receptor agonist, muscimol, into the medial prefrontal cortex (MPFC), on fear behavior measured in the elevated plus-maze and shock-probe burying tests. Bilateral infusions of either a 0.175 or 4 nmol/0.5 μl dose of muscimol increased the percentage of entries and time spent in the open arms, and attenuated shock-probe burying. These findings indicate that intra-MPFC infusions of muscimol induce anxiolysis, and suggest that the direct stimulation of MPFC GABA A receptors attenuates fear-related behavior.

GABA A receptors in the basolateral amygdala are involved in mediating morphine reward

In the present study, the effects of intra-basolateral amygdala (BLA) injection of GABA A receptor agonist and antagonist on morphine-induced conditioned place preference (CPP) in male Wistar rats have been investigated. Subcutaneous (s.c.) administration of different doses of morphine sulfate (1–9 mg/kg) produced a dose-dependent CPP. Using a 3-day schedule of conditioning, it was found that the GABA A receptor agonist, muscimol (0.125, 0.25 and 0.5 μg/rat) or the GABA A receptor antagonist, bicuculline (0.125, 0.25 and 0.5 μg/rat), did not produce a significant place preference or place aversion. Intra-BLA administration of muscimol (0.25 and 0.5 μg/rat) decreased the acquisition of CPP induced by morphine (6 mg/kg). On the other hand, intra-BLA injection of bicuculline (0.25 and 0.5 μg/rat) in combination with an ineffective dose of morphine (1 mg/kg) elicited a significant CPP. The response of different doses of muscimol was attenuated by bicuculline (0.125 and 0.25 μg/rat). Furthermore, intra-BLA administration of bicuculline but not muscimol before testing significantly decreased the expression of morphine (6 mg/kg)-induced place preference. The administration of the higher doses of bicuculline (0.25 and 0.5 μg/rat) during acquisition and the higher dose of muscimol (2 μg/rat) on the test day decreased the locomotor activity of the animals on the testing phase. It can be concluded that GABA A receptors in the amygdala are involved in morphine reward.

Altered GABAergic neurotransmission in mice lacking dopamine D2 receptors

The levels of glutamic acid decarboxylase (GAD) were strongly increased in the cortex and the striatum in dopamine D2 receptors null (D2R−/−) mice, which show a significant locomotor impairment. In this study, the effects of different GABAergic drugs on locomotor activity were analyzed in D2R−/− mice. After administering muscimol (1 mg/kg), a GABA A receptor agonist, the D2R−/− mice showed increased locomotor activity up to 200%. When the muscimol dose was increased (4–6 mg/kg), the D2R−/− mice exhibited seizure-like behavior, and the electroencephalographic (EEG) recordings during these behaviors showed a high amplitude rhythmic epileptiform activity in these mice. In situ hybridization showed that after injecting muscimol in the D2R−/− mice, the expression of enkephalin and immediate early gene, NGFI-A, was closely regulated with the locomotor activity regulated by GABAergic stimulation. These results suggest that the absence of D2R alters the GABAergic neurotransmission, specifically on GABA A-receptor mediated signaling, and stimulating the GABA A receptor can reverse the dysfunction of GABAergic inhibition in the motor circuits in the basal ganglia.

Spatial Learning Deficits Induced by Muscimol and CL218,872: Lack of Effect of Prenatal Malnutrition

The sensitivity of prenatal protein malnourished rats to the amnestic properties of the direct GABA<PRE>A</PRE> receptor agonist muscimol and the selective benzodiazepine (BZ) receptor agonist, CL218,872, was studied in the male offspring of rats provided with a protein deficient diet (6% casein) for 5 weeks prior to mating and throughout pregnancy. At postnatal day 90, rats were tested during acquisition of the submerged platform version of the Morris water maze task using four systemic doses of muscimol (0.1, 0.3, 1.0 and 1.8 mg/kg i.p.) or three systemic doses of CL218,872 (1.0, 3.2, and 5.6 mg/kg i.p.). In a dose dependent manner both drugs impaired acquisition of the task and impaired accuracy of the search pattern on the probe trial (platform removed). However, neither drug dissociated the performance of the two nutritional groups. These data are important in light of previous findings of differential behavioral effects of the non-specific BZ agonist, chlordiazepoxide (CDP), on spatial learning and on drug discrimination in prenatally malnourished rats and in the context of previous findings of reduced sensitivity to the anxiolytic effects of non-specific BZ receptor agonists across a wide variety of models of malnutrition. The present findings also support the concept that prenatal malnutrition does not affect the global functioning of the GABA<PRE>A</PRE> receptor, but fundamentally alters the way in which a subset of GABA<PRE>A</PRE> receptors (i.e. those containing the 2, 3 and/or the 5 but not the 1 subunit) is modulated by BZs.

GABAergic system and imipramine-induced impairment of memory retention in rats

In this study, the influence of GABAergic agents, imipramine and their interactions on memory retention have been investigated. Intracerebroventricular (i.c.v.; 1–6 μg/rat) or intraperitoneal (i.p.; 5–40 mg/kg) injection of imipramine decreased memory retention. i.c.v. administration of GABA receptor agonists baclofen and muscimol also reduced memory retention. The combination of i.p. or i.c.v. injection of imipramine with a low dose of muscimol (1 μg/rat, i.c.v.) induced a higher decrease in memory retention. The higher dose of GABA B receptor antagonist CGP35348 [ p-(3-aminopropyl)- p-diethoxymethyl-phosphinic acid] (10 μg/rat) increased memory retention by itself, and decreased the response induced by baclofen or imipramine. Bicuculline (1, 2 and 4 μg/rat, i.c.v.) tends to increase memory retention by itself. Furthermore, bicuculline in same doses reduced the response induced by muscimol or imipramine, but it did not show interaction with the latter drugs. It is concluded that the GABA B receptor mechanism is involved in memory impairment induced by imipramine.

Switching to cue-directed behavior: specific for ventral striatal dopamine but not ventral pallidum/substantia innominata gaba as revealed by a swimming-test procedure in rats

In this study it was investigated whether ventral striatal dopamine-induced changes in switching to cue-directed behavioral patterns were funnelled via the rostral areas of the ventral pallidum/substantia innominata (VP/SI) complex and, if so, whether changes in switching to cue-directed behavioral patterns could be elicited in the VP/SI complex by manipulating GABAergic activity. To this end rats were bilaterally equipped with cannulae directed at the ventral striatum and/or rostral VP/SI complex and subjected to a swimming-test procedure for 6 min. Injections of the dopamine-releasing agent d-amphetamine (10 μg/0.5 μl per side) enhanced the number of different cue-directed behavioral patterns while they had no effect upon the number of different non-cue-directed behavioral patterns in line with previous studies (Life Sci - 1989 1697). This increase was attenuated by a low dose of the GABAa agonist muscimol (1 ng/0.5 μl) into the rostral VP/SI complex. This dose of muscimol when injected alone into the rostral VP/SI complex had no effect upon the number of different cue-directed behavioral patterns. Only the lowest dose of the GABAa antagonist bicuculline (10–25 ng/0.5 μl per side) into the rostral VP/SI complex slightly, and in a non- d-amphetamine-like manner, increased the number of different cue-directed behavioral patterns while none of the doses had an effect on the number of different non-cue-directed behavioral patterns. Both injections of d-amphetamine into the ventral striatum and injections of bicuculline into the rostral VP/SI complex strongly increased motor activity in the 10-min period preceding the swimming test. We conclude from the data that switching to cue-directed behavioral patterns is sensitive to manipulations with the dopaminergic activity in the ventral striatum but not with the GABAergic activity in the VP/SI complex although the VP/SI transmits it to other brain structures. In contrast motor activity is sensitive to manipulations with both ventral striatal dopamine and rostral VP/SI complex GABA.