Effects of intrahippocampal injection of GABAergic drugs on memory retention of passive avoidance learning in rats

Zarrindast, Mohammad‐Reza; Bakhsha, A.; Rostami, Parastoo; Shafaghi, Bijan

doi:10.1177/026988110201600405

Cited by 93 publications

(55 citation statements)

References 50 publications

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“…2). Overall, these data are consistent with previous reports demonstrating cognitive impairing effects of both baclofen and chlordiazepoxide on passive avoidance behavior (Swartzwelder et al, 1987;Castellano et al, 1989;Zarrindast et al, 2002). Furthermore, they exemplify the better side effect profile of GABA B receptor-positive modulators over that of full agonists and benzodiazepine anxiolytics.…”

Section: Discussionsupporting

confidence: 91%

Behavioral Characterization of the Novel GABA_B Receptor-Positive Modulator GS39783 (N,N′-Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine): Anxiolytic-Like Activity without Side Effects Associated with Baclofen or Benzodiazepines

Cryan

Kelly²,

Chaperon³

et al. 2004

J Pharmacol Exp Ther

196

134

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The role of GABA B receptors in various behavioral processes has been largely defined using the prototypical GABA B receptor agonist baclofen. However, baclofen induces sedation, hypothermia and muscle relaxation, which may interfere with its use in behavioral paradigms. Although there is much evidence for a role of the inhibitory neurotransmitter GABA in the pathophysiology of anxiety, the role of GABA B receptors in these disorders is largely unclear. We recently identified GS39783 (N,NЈ-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine) as a selective allosteric positive modulator at GABA B receptors. The aim of the present study was to broadly characterize the effects of GS39783 in well-validated rodent models for motor activity, cognition, and anxiety. The following tests were included: locomotor activity in rats and mice, rotarod and traction tests (including determinations of core temperature) in mice, passive avoidance in mice and rats, elevated plus maze in rats, elevated zero maze in mice and rats, stress-induced hyperthermia in mice, and pentobarbital-and ethanol-induced sleep in mice. Unlike baclofen and/or the benzodiazepine chlordiazepoxide, GS39783 had no effect in any of the tests for locomotion, cognition, temperature, or narcosis. Most interestingly, GS39783 had anxiolytic-like effects in all the tests used. Overall, the data obtained here suggest that positive modulation of GABA B receptors may serve as a novel therapeutic strategy for the development of anxiolytics, with a superior side effect profile to both baclofen and benzodiazepines.

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Section: Discussionsupporting

confidence: 91%

Behavioral Characterization of the Novel GABA_B Receptor-Positive Modulator GS39783 (N,N′-Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine): Anxiolytic-Like Activity without Side Effects Associated with Baclofen or Benzodiazepines

Cryan

Kelly²,

Chaperon³

et al. 2004

J Pharmacol Exp Ther

196

134

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“…Furthermore, infusion of bicuculline, a GABA A antagonist, decreased the memory-impairing effect of muscimol alone. This supports the conclusion that memory-impairing effects of muscimol occur through GABA A receptors (Zarrindast et al 2002). Other work demonstrates that intrahippocampal infusion of muscimol impaired one trial inhibitory avoidance when infused immediately but not more than 30 min after training (Rossato et al 2004).…”

supporting

confidence: 79%

“…For example, Zarrindast et al (2002) found that muscimol, a GABA A agonist, infused into the hippocampus after training in a passive avoidance task dose dependently decreased memory retention. Furthermore, infusion of bicuculline, a GABA A antagonist, decreased the memory-impairing effect of muscimol alone.…”

mentioning

confidence: 99%

Effects of post-training hippocampal injections of midazolam on fear conditioning

Gafford¹,

Parsons²,

Helmstetter³

2005

Learn. Mem.

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Benzodiazepines have been useful tools for investigating mechanisms underlying learning and memory. The present set of experiments investigates the role of hippocampal GABA A /benzodiazepine receptors in memory consolidation using Pavlovian fear conditioning. Rats were prepared with cannulae aimed at the dorsal hippocampus and trained with a series of white noise-shock pairings. In the first experiment, animals received intrahippocampal infusion of midazolam or vehicle immediately or 3 h after training. Then, 24 h later, freezing to the training context and the white noise were measured independently. Results show infusion of midazolam immediately, but not 3 h, after training selectively attenuates contextual fear conditioning. In the second experiment, animals received intrahippocampal infusions of an antisense oligodeoxynucleotide (ODN) targeting the ␣5 subunit of the GABA A receptor or a missense control for several days prior to training and testing. Immediately after training, animals received an infusion of either midazolam or vehicle. Western blots conducted after testing showed a significant decrease in ␣5-containing GABA A receptor protein. This reduction did not alter the effectiveness of midazolam immediately after training at impairing context fear memory. Therefore, ␣5-containing GABA A receptors may not contribute to the effects of midazolam on context fear conditioning when given immediately post-training.Pavlovian fear conditioning produces fear through learning that an aversive event is predicted by some neutral stimulus (for review, see LeDoux 2000;Maren 2001;Schafe et al. 2001). Rats quickly learn to associate a conditional stimulus (CS) with a noxious unconditional stimulus (US) and produce conditional responses (CRs) that can be reliably measured. In particular, freezing is a CR defined as the absence of all body movement except that related to respiration (Blanchard and Blanchard 1969;Fanselow 1980). Fear conditioning creates a long-lasting memory of the contextual and discrete cues present at the time of training.Post-training manipulations of the hippocampus have been shown to impair contextual fear conditioning (Kim and Fanselow 1992;Maren et al. 1997;Frankland et al. 1998;Anagnostaras et al. 1999;Barrientos et al. 2002;Dash et al. 2002;Wallenstein et al. 2002;Ji et al. 2003). One current area of research regarding the hippocampus is the analysis of the time course of mechanisms that underlie consolidation. Consolidation refers to the period after acquisition when a new memory transforms from an easily disrupted short-term state to a stable long-term memory (McGaugh 2000). Recent research using inhibitors of protein synthesis and gene expression suggests that memory for inhibitory avoidance has two phases of consolidation, one that occurs around the time of training and another occurring 3 to 6 h after training (Quevedo et al. 1999;Igaz et al. 2002). Similarly, the consolidation of contextual fear memory is also time dependent and may have multiple periods of susceptibility to protein sy...

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“…Indiscriminant reduction in GABA A R-mediated inhibition by nonselective antagonists facilitates synaptic plasticity (Wigström and Gustafsson, 1983), increases vigilance (Ferraro et al, 1999), and improves memory performance (Zarrindast et al, 2002); however, these nonselective drugs have no therapeutic utility because of their proconvulsant and anxiogenic properties (Ben-Ari et al, 2007). Inverse agonists selective for ␣5GABA A Rs facilitate some forms of learning and enhance synaptic potentiation without a proconvulsant effect (Atack et al, 2006a).…”

Section: Discussionmentioning

confidence: 99%

α5GABA_AReceptor Activity Sets the Threshold for Long-Term Potentiation and Constrains Hippocampus-Dependent Memory

Martin¹,

Zurek²,

MacDonald³

et al. 2010

J. Neurosci.

168

138

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Synaptic plasticity, which is the neuronal substrate for many forms of hippocampus-dependent learning, is attenuated by GABA type A receptor (GABA A R)-mediated inhibition. The prevailing notion is that a synaptic or phasic form of GABAergic inhibition regulates synaptic plasticity; however, little is known about the role of GABA A R subtypes that generate a tonic or persistent inhibitory conductance. We studied the regulation of synaptic plasticity by ␣5 subunit-containing GABA A Rs (␣5GABA A Rs), which generate a tonic inhibitory conductance in CA1 pyramidal neurons using electrophysiological recordings of field and whole-cell potentials in hippocampal slices from both wild-type and null mutant mice for the ␣5 subunit of the GABA A R (Gabra5 ؊/؊ mice). In addition, the strength of fearassociated memory was studied. The results showed that ␣5GABA A R activity raises the threshold for induction of long-term potentiation in a highly specific band of stimulation frequencies (10 -20 Hz) through mechanisms that are predominantly independent of inhibitory synaptic transmission. The deletion or pharmacological inhibition of ␣5GABA A Rs caused no change in baseline membrane potential or input resistance but increased depolarization during 10 Hz stimulation. The encoding of hippocampus-dependent memory was regulated by ␣5GABA A Rs but only under specific conditions that generate moderate but not robust forms of fear-associated learning. Thus, under specific conditions, ␣5GABA A R activity predominates over synaptic inhibition in modifying the strength of both synaptic plasticity in vitro and certain forms of memory in vivo.

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Effects of intrahippocampal injection of GABAergic drugs on memory retention of passive avoidance learning in rats

Cited by 93 publications

References 50 publications

Behavioral Characterization of the Novel GABA_B Receptor-Positive Modulator GS39783 (N,N′-Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine): Anxiolytic-Like Activity without Side Effects Associated with Baclofen or Benzodiazepines

Behavioral Characterization of the Novel GABA_B Receptor-Positive Modulator GS39783 (N,N′-Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine): Anxiolytic-Like Activity without Side Effects Associated with Baclofen or Benzodiazepines

Effects of post-training hippocampal injections of midazolam on fear conditioning

α5GABA_AReceptor Activity Sets the Threshold for Long-Term Potentiation and Constrains Hippocampus-Dependent Memory

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Effects of intrahippocampal injection of GABAergic drugs on memory retention of passive avoidance learning in rats

Cited by 93 publications

References 50 publications

Behavioral Characterization of the Novel GABAB Receptor-Positive Modulator GS39783 (N,N′-Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine): Anxiolytic-Like Activity without Side Effects Associated with Baclofen or Benzodiazepines

Behavioral Characterization of the Novel GABAB Receptor-Positive Modulator GS39783 (N,N′-Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine): Anxiolytic-Like Activity without Side Effects Associated with Baclofen or Benzodiazepines

Effects of post-training hippocampal injections of midazolam on fear conditioning

α5GABAAReceptor Activity Sets the Threshold for Long-Term Potentiation and Constrains Hippocampus-Dependent Memory

Contact Info

Product

Resources

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Behavioral Characterization of the Novel GABA_B Receptor-Positive Modulator GS39783 (N,N′-Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine): Anxiolytic-Like Activity without Side Effects Associated with Baclofen or Benzodiazepines

Behavioral Characterization of the Novel GABA_B Receptor-Positive Modulator GS39783 (N,N′-Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine): Anxiolytic-Like Activity without Side Effects Associated with Baclofen or Benzodiazepines

α5GABA_AReceptor Activity Sets the Threshold for Long-Term Potentiation and Constrains Hippocampus-Dependent Memory