The international journal of neuropsychopharmacology
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Int. J. Neuropsychopharmacol. · Oct 2011
The M₁/M₄ preferring agonist xanomeline reverses amphetamine-, MK801- and scopolamine-induced abnormalities of latent inhibition: putative efficacy against positive, negative and cognitive symptoms in schizophrenia.
A major challenge in developing schizophrenia pharmacotherapy is treating the different symptoms of this disorder, typically divided into positive, negative and cognitive symptoms. M₁/M₄ muscarinic acetylcholine receptor (mAChR) agonists have emerged as a promising therapeutic target, particularly for positive and cognitive symptoms. Here, we examined the activity of the M₁/M₄ mAChR-preferring agonist xanomeline in four pharmacological latent inhibition (LI) models. ⋯ Activity of xanomeline on NMDA antagonist-induced behaviour was demonstrated here for the first time and suggests that the drug is effective against negative/cognitive symptoms. Finally, xanomeline alleviated abnormally persistent LI induced by scopolamine, which was suggested to model antipsychotic drug-resistant cognitive impairments, providing further evidence for the cognition-enhancing capacity of xanomeline. Although the use of xanomeline in schizophrenia was discontinued due to cholinergic-related side-effects, our findings suggest that M₁/M₄ mAChR agonism should be an important target in drug development in schizophrenia, potentially beneficial for treatment of positive, negative and cognitive symptoms.
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Int. J. Neuropsychopharmacol. · Sep 2011
ReviewA systematic review on reporting and assessment of adverse effects associated with transcranial direct current stimulation.
Transcranial direct current stimulation (tDCS) is a non-invasive method of brain stimulation that has been intensively investigated in clinical and cognitive neuroscience. Although the general impression is that tDCS is a safe technique with mild and transient adverse effects (AEs), human data on safety and tolerability are largely provided from single-session studies in healthy volunteers. In addition the frequency of AEs and its relationship with clinical variables is unknown. ⋯ Our results suggested that some AEs such as itching and tingling were more frequent in the tDCS active group, although this was not statistically significant. Although results suggest that tDCS is associated with mild AEs only, we identified a selective reporting bias for reporting, assessing and publishing AEs of tDCS that hinders further conclusions. Based on our findings, we propose a revised adverse effects questionnaire to be applied in tDCS studies in order to improve systematic reporting of tDCS-related AEs.
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Int. J. Neuropsychopharmacol. · Jun 2011
The effect of electrode placement and pulsewidth on asystole and bradycardia during the electroconvulsive therapy stimulus.
Electroconvulsive therapy (ECT) is the most effective treatment for severe depression, and different forms are increasingly used in clinical practice. This study investigated the acute cardiac effects of different forms of ECT: bitemporal and bifrontal (1.5 times seizure threshold), and right unilateral (RUL) (five times seizure threshold). For RUL ECT, the effect of stimulus pulsewidth (1.0 or 0.3 ms) was also examined. ⋯ Modelling showed, for a mean pre-ECT heart rate of 86 bpm, expected heart rates were 43 bpm (ultrabrief RUL) and 26 bpm (RUL). Bradycardia and asystole were relatively common side-effects during the ECT stimulus. Bifrontal ECT was associated with the lowest risk of bradycardia and asystole during ECT and should be considered for patients at risk of arrhythmias and prolonged asystole during ECT.
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Int. J. Neuropsychopharmacol. · Jun 2011
The schizophrenia susceptibility gene neuregulin 1 modulates tolerance to the effects of cannabinoids.
Cannabis increases the risk of schizophrenia in genetically vulnerable individuals. In this study we aim to show that the schizophrenia susceptibility gene neuregulin 1 (Nrg1) modulates the development of tolerance to cannabinoids in mice. Nrg1 heterozygous (HET) and wild-type (WT) mice were treated daily for 15 d with the synthetic analogue of Δ9-tetrahydrocannabinol, CP55,940 (0.4 mg/kg). ⋯ These effects of CP55,940 on PPI were not maintained as both genotypes became tolerant to cannabinoid action with repeated exposure. Our results highlight that Nrg1 modulates the development of cannabinoid tolerance dependent on the parameter being measured. Furthermore, these data reinforce the notion that the VLS is an important brain region involved in Nrg1-cannabinoid interactions.
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Int. J. Neuropsychopharmacol. · Apr 2011
Cocaine sensitization models an anhedonia-like condition in rats.
Anhedonia is a core symptom of depression that also characterizes substance abuse-related mood disorders, in particular those secondary to stimulant abuse. This study investigated the long-lasting condition of cocaine sensitization as an inducing condition for anhedonia in rats. Cortical-mesolimbic dopamine plays a central role in assessing the incentive value of a stimulus and an increased dopamine output in these areas after a novel palatable meal seems to correlate with the ability to acquire an instrumental behaviour aimed at earning it again. ⋯ Indeed, non-food-deprived cocaine-sensitized rats showed no interest in palatable food, no dopaminergic response after a palatable meal in terms of increased dopamine output and DARPP-32 phosphorylation changes, and no ability to acquire a palatable food-sustained instrumental behaviour. Repeated administration of an established antidepressant compound, imipramine, corrected these deficits and reinstated the dopaminergic response in the cortico-mesolimbic areas to control values. Thus, the behavioural modifications observed in cocaine-sensitized rats satisfy some requirements for an experimental model of anhedonia since they are induced by repeated cocaine administration (aetiological validity), they mimic an anhedonia-like symptom (construct validity), and are reversed by the administration of imipramine (predictive validity).