Neuropharmacology
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Cholinergic fibers from the brainstem and basal forebrain innervate the medial prefrontal cortex (mPFC) modulating neuronal activity and synaptic plasticity responses to hippocampal inputs. Here, we investigated the muscarinic and glutamatergic modulation of long-term depression (LTD) in the intact projections from CA1 to mPFC in vivo. Cortical-evoked responses were recorded in urethane-anesthetized rats for 30 min during baseline and 4 h following LTD. ⋯ Our data also indicate that NMDA receptor pre-activation is essential to the muscarinic enhancement of mPFC synaptic depression, since AP7 microinjection into the mPFC blocked the conversion of transient depression into long-lasting LTD produced by PILO. In addition, AP7 effectively blocked the long-lasting LTD induced by LFS900. Therefore, our findings suggest that the glutamatergic co-activation of prefrontal neurons is important for the effects of PILO on mPFC synaptic depression, which could play an important role in the control of executive and emotional functions.
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Diabetes causes mitochondrial dysfunction in sensory neurons that may contribute to peripheral neuropathy. Ciliary neurotrophic factor (CNTF) promotes sensory neuron survival and axon regeneration and prevents axonal dwindling, nerve conduction deficits and thermal hypoalgesia in diabetic rats. In this study, we tested the hypothesis that CNTF protects sensory neuron function during diabetes through normalization of impaired mitochondrial bioenergetics. ⋯ Studies in mice with STZ-induced diabetes demonstrated that systemic therapy with CNTF prevented functional indices of peripheral neuropathy along with deficiencies in dorsal root ganglion (DRG) NF-κB p50 expression and DNA binding activity. DRG neurons derived from STZ-diabetic mice also exhibited deficiencies in maximal oxygen consumption rate and associated spare respiratory capacity that were corrected by exposure to CNTF for 24 h in an NF-κB-dependent manner. We propose that the ability of CNTF to enhance axon regeneration and protect peripheral nerve from structural and functional indices of diabetic peripheral neuropathy is associated with targeting of mitochondrial function, in part via NF-κB activation, and improvement of cellular bioenergetics.
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The endocannabinoid system (ECS) may either enhance or inhibit responses to aversive stimuli, possibly caused by its modulatory activity on diverse neurotransmitters. The aim of this work was to investigate the involvement of serotonin (5-HT) and catecholamines, as well as the role of glutamatergic and GABAergic cannabinoid type 1 (CB(1)) receptor, in responses to the antidepressant-like doses of the CB(1) receptor agonist Δ(9)-tetrahydrocannabinol (THC) and the antagonist rimonabant in the forced swim test (FST). Mice received acute injections of low doses of THC (0.1 or 0.5 mg/kg) or high dose of rimonabant (3 or 10 mg/kg) after treatment with the 5-HT synthesis inhibitor pCPA (100 mg/kg, 4 days), the 5-HT(1A) receptor antagonist WAY100635 (1 mg/kg, acute) or the non-selective blocker of catecholamine synthesis, AMPT (20 mg/kg, acute). ⋯ The effect of THC persisted in mutant mice with CB(1) receptor inactivation in GABAergic neurons, whereas rimonabant effects were alleviated in these mutants. Thus, employing both pharmacological and genetic tools, we could show that the ECS regulates stress responses by influencing GABAergic, glutamatergic and monoaminergic transmission. The antidepressant-like action of THC depends on serotonergic neurotransmission, whereas rimonabant effects are mediated by CB(1) receptor on GABAergic neurons and by catecholamine signaling.
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Randomized Controlled Trial
Effects of modafinil on non-verbal cognition, task enjoyment and creative thinking in healthy volunteers.
Modafinil, a putative cognitive enhancing drug, has previously been shown to improve performance of healthy volunteers as well as patients with attention deficit disorder and schizophrenia, mainly in tests of executive functions. The aim of this study was to investigate the effects of modafinil on non-verbal cognitive functions in healthy volunteers, with a particular focus on variations of cognitive load, measures of motivational factors and the effects on creative problem-solving. ⋯ Modafinil reliably enhanced task enjoyment and performance on several cognitive tests of planning and working memory, but did not improve paired associates learning. The findings confirm that modafinil can enhance aspects of highly demanding cognitive performance in non-sleep deprived individuals. 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'.