Neuropharmacology
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Controlled Clinical Trial
Enhancing a declarative memory in humans: the effect of clonazepam on reconsolidation.
A consolidated memory recalled by a specific reminder can become unstable (labile) and susceptible to facilitation or impairment for a discrete period of time. This labilization phase is followed by a process of stabilization called reconsolidation. The phenomenon has been shown in diverse types of memory, and different pharmacological agents have been used to disclose its presence. ⋯ We discuss the GABAergic role in reconsolidation, which shows a collateral effect on other memories when the treatment is aimed at treating anxiety disorders. Further studies might elucidate the role of GABA in the reconsolidation process associated with dissimilar scenarios. This article is part of a Special Issue entitled 'Cognitive Enhancers'.
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Comparative Study
Matching biochemical and functional efficacies confirm ZIP as a potent competitive inhibitor of PKMζ in neurons.
PKMζ is an autonomously active, atypical protein kinase C (aPKC) isoform that is both necessary and sufficient for maintaining long-term potentiation (LTP) and long-term memory. The myristoylated ζ-pseudosubstrate peptide, ZIP, potently inhibits PKMζ biochemically in vitro, within cultured cells, and within neurons in hippocampal slices, and reverses LTP maintenance and erases long-term memory storage. A recent study (Wu-Zhang et al., 2012), however, suggested ZIP was not effective on a PKMζ fusion protein overexpressed in cultured cells. ⋯ However, here we show that staurosporine does not affect PDK1 phosphorylation of the endogenous PKMζ in hippocampal slices. Thus, the biochemical in vitro effects of PKMζ inhibitors correspond with their intracellular effects, and ZIP and chelerythrine, together with scrambled ZIP and staurosporine as controls, are effective tools to examine the function of PKMζ in neurons. This article is part of a Special Issue entitled 'Cognitive Enhancers'.
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Beneficial effects of caffeine on memory processes have been observed in animal models relevant to neurodegenerative diseases and aging, although the underlying mechanisms remain unknown. Because brain-derived neurotrophic factor (BDNF) is associated with memory formation and BDNF's actions are modulated by adenosine receptors, the molecular targets for the psychostimulant actions of caffeine, we here compare the effects of chronic caffeine (1 mg/mL drinking solution for 30 days) on short- and long term memory and on levels of hippocampal proBDNF, mature BDNF, TrkB and CREB in young (3 month old) and middle-aged (12 month old) rats. ⋯ These data provide new evidence in favor of the hypothesis that modifications in BDNF and related proteins in the hippocampus contribute to the pro-cognitive effects of caffeine on age-associated losses in memory encoding. This article is part of a Special Issue entitled 'Cognitive Enhancers'.
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GABA-A receptor positive allosteric modulators (PAMs) mediate robust analgesia in animal models of pathological pain, in part via enhancing injury-induced loss of GABA-A-α2 and -α3 receptor function within the spinal cord. As yet, a lack of clinically suitable tool compounds has prevented this concept being tested in humans. Prior to assessing the efficacy of GABA-A receptor PAMs in a human volunteer pain model we have compared compounds capable of variously modulating GABA-A receptor function in comparable rat models of capsaicin-induced acute nocifensive flinching behaviour and secondary mechanical hypersensitivity. ⋯ This was surprising as both NS11394 and TPA023 robustly attenuated late phase (6-30 min post-injection) capsaicin-induced flinching, a pain-like behaviour that is putatively driven by peripheral and central sensitizing mechanisms. Diazepam also attenuated capsaicin-induced nocifensive behaviours, albeit at doses previously shown to impair locomotor function. Our data indicate that GABA-A receptor PAMs with optimal selectivity and efficacy profiles reduce centrally-mediated mechanical hypersensitivity in capsaicin-injected rats, an observation that we expect can translate directly to human volunteer studies.
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GABA(B) receptor antagonists have been shown to have antidepressant-like properties in animal models and thus, could represent a novel approach for the treatment of depression. The neurobiological mechanisms underlying these effects are currently unknown. Adult hippocampal neurogenesis (the birth of new neurons) is thought to play a role in antidepressant drug action. ⋯ This topographical segregation concurs with the hypothesis that the ventral hippocampus is primarily involved in the regulation of stress and emotionality. Taken together, our data suggest that increased hippocampal cell proliferation is a plausible mechanism for the antidepressant-like effects of GABA(B) receptor antagonists following chronic but not acute treatments. Moreover, altered behavioural effects in the FST does not correlate with changes in neurogenesis.