Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
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Neuropsychopharmacology · Nov 2010
Late prenatal immune activation in mice leads to behavioral and neurochemical abnormalities relevant to the negative symptoms of schizophrenia.
Based on the human epidemiological association between prenatal infection and higher risk of schizophrenia, a number of animal models have been established to explore the long-term brain and behavioral consequences of prenatal immune challenge. Accumulating evidence suggests that the vulnerability to specific forms of schizophrenia-related abnormalities is critically influenced by the precise timing of the prenatal immunological insult. In the present study, we tested the hypothesis whether late prenatal immune challenge in mice may induce long-term behavioral and neurochemical dysfunctions primarily associated with the negative symptoms of schizophrenia. ⋯ In addition, male but not female offspring born to immune challenged mothers displayed behavioral/cognitive inflexibility as indexed by the presence of an abnormally enhanced latent inhibition (LI) effect. Prenatal immune activation in late gestation also led to numerous, partly sex-specific changes in basal neurotransmitter levels, including reduced dopamine (DA) and glutamate contents in the prefrontal cortex and hippocampus, as well as reduced γ-aminobutyric acid (GABA) and glycine contents in the hippocampus and prefrontal cortex, respectively. The constellation of behavioral and neurochemical abnormalities emerging after late prenatal Poly-I:C exposure in mice leads us to conclude that this immune-based experimental model provides a powerful neurodevelopmental animal model especially for (but not limited to) the negative symptoms of schizophrenia.
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Neuropsychopharmacology · Nov 2010
Effects of the nitric oxide synthase inhibitor L-NAME on recognition and spatial memory deficits produced by different NMDA receptor antagonists in the rat.
There is consistent experimental evidence that noncompetitive antagonists of the N-methyl-D-aspartate (NMDA) receptor, such as ketamine, MK-801, and phencyclidine (PCP), impair cognition and produce psychotomimetic effects in rodents. Nitric oxide (NO) is considered as an intracellular messenger in the brain. The implication of NO in learning and memory is well documented. ⋯ L-NAME (10 mg/kg) attenuated ketamine (15 mg/kg)-induced spatial working memory and retention deficits in the radial water maze paradigm. L-NAME, applied at 3 mg/kg, however, disrupted rodents' performance in this spatial memory task. The present findings indicate (1) that L-NAME is sensitive to glutamate hypofunction produced by other than PCP NMDA antagonists such as MK-801 and ketamine and (2) that L-NAME alone differentially affects rodents' spatial memory.
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Neuropsychopharmacology · Sep 2010
Randomized Controlled Trial Multicenter StudyA controlled, evidence-based trial of paliperidone palmitate, a long-acting injectable antipsychotic, in schizophrenia.
Paliperidone palmitate is a long-acting injectable antipsychotic agent. This 13-week, multicenter, randomized (1 : 1 : 1 : 1), double-blind, parallel-group study evaluated the efficacy, safety, and tolerability of fixed 25, 50, and 100 milligram equivalent (mg equiv.) doses of paliperidone palmitate vs placebo administered as gluteal injections on days 1 and 8, then every 4 weeks (days 36 and 64) in 518 adult patients with schizophrenia. The intent-to-treat analysis set (N=514) was 67% men and 67% White, with a mean age of 41 years. ⋯ Investigator-evaluated injection-site pain, swelling, redness, and induration were similar across treatment groups; scores for patient-evaluated injection-site pain (visual analog scale) were similar across groups and diminished with time. All doses of once-monthly paliperidone palmitate were efficacious and generally tolerated, both locally and systemically. Paliperidone palmitate offers the potential to improve outcomes in adults with symptomatic schizophrenia.
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Neuropsychopharmacology · Aug 2010
Clinical TrialCannabidiol attenuates the appetitive effects of Delta 9-tetrahydrocannabinol in humans smoking their chosen cannabis.
Worldwide cannabis dependence is increasing, as is the concentration of Delta(9)-tetrahydrocannabinol (THC) in street cannabis. At the same time, the concentration of the second most abundant cannabinoid in street cannabis, cannabidiol (CBD), is decreasing. These two cannabinoids have opposing effects both pharmacologically and behaviorally when administered in the laboratory. ⋯ Those smoking higher CBD : THC strains also showed lower self-rated liking of cannabis stimuli on both test days. Our findings suggest that CBD has potential as a treatment for cannabis dependence. The acute modulation of the incentive salience of drug cues by CBD may possibly generalize to a treatment for other addictive disorders.
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Neuropsychopharmacology · Aug 2010
Calcium/calmodulin-dependent protein kinase II mediates hippocampal glutamatergic plasticity during benzodiazepine withdrawal.
Benzodiazepine withdrawal anxiety is associated with potentiation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor (AMPAR) currents in hippocampal CA1 pyramidal neurons attributable to increased synaptic incorporation of GluA1-containing AMPARs. The contribution of calcium/calmodulin-dependent protein kinase II (CaMKII) to enhanced glutamatergic synaptic strength during withdrawal from 1-week oral flurazepam (FZP) administration was further examined in hippocampal slices. As earlier reported, AMPAR-mediated miniature excitatory postsynaptic current (mEPSC) amplitude increased in CA1 neurons from 1- and 2-day FZP-withdrawn rats, along with increased single-channel conductance in neurons from 2-day rats, estimated by non-stationary noise analysis. ⋯ Both GluA1 expression levels and CaMKII alpha-mediated GluA1 Ser(831) phosphorylation were increased in PSD-subfractions from 2-day FZP-withdrawn rats. As phospho-Thr(286)CaMKII alpha was unchanged, CaMKII alpha may be activated through an alternative signaling pathway. Synaptic insertion and subsequent CaMKII alpha-mediated Ser(831) phosphorylation of GluA1 homomers contribute to benzodiazepine withdrawal-induced AMPAR potentiation and may represent an important hippocampal pathway mediating both drug-induced and activity-dependent plasticity.