The international journal of neuropsychopharmacology
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Int. J. Neuropsychopharmacol. · Nov 2009
Comparative StudyDizocilpine (MK-801) induces distinct changes of N-methyl-D-aspartic acid receptor subunits in parvalbumin-containing interneurons in young adult rat prefrontal cortex.
N-methyl-D-aspartic acid receptor (NMDAR) hypofunction has long been implicated in schizophrenia and NMDARs on gamma-aminobutyric acid (GABA)ergic interneurons are proposed to play an essential role in the pathogenesis. However, controversial results have been reported regarding the regulation of NMDAR expression, and direct evidence of how NMDAR antagonists act on specific subpopulations of prefrontal interneurons is missing. We investigated the effects of the NMDAR antagonist dizocilpine (MK-801) on the expression of NMDAR subtypes in the identified interneurons in young adult rat prefrontal cortex (PFC) by using laser microdissection and real-time polymerase chain reaction, combined with Western blotting and immunofluorescent staining. ⋯ In contrast, subunit mRNAs of NMDARs in PV-ir interneurons were significantly down-regulated at low doses, unaltered at medium doses, and significantly decreased again at high doses, suggesting a biphasic dose response to MK-801. The differential effects of MK-801 in mRNA expression of NMDAR subunits were consistent with the protein expression of NR2A and NR2B subunits revealed with Western blotting and double immunofluorescent staining. These results suggest that PV-containing interneurons in the PFC exhibit a distinct responsiveness to NMDAR antagonism and that NMDA antagonist can differentially and dose-dependently regulate the functions of pyramidal neurons and GABAergic interneurons in the prefrontal cortical circuitry.
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Int. J. Neuropsychopharmacol. · Oct 2009
Prefrontal cortical D1 dopamine receptors modulate subcortical D2 dopamine receptor-mediated stress responsiveness.
Increased responsiveness to stress plays an important role in the manifestation of schizophrenia symptoms. Evidence indicates that the prefrontal cortex (PFC), and dopamine neurotransmission in the PFC in particular, is involved in the modulation of stress responsiveness. Decreased dopaminergic activity and loss of dopamine fibres have been reported in PFC in schizophrenia patients. ⋯ This effect was significantly ameliorated by infusions of a D1 dopamine receptor agonist directly into the mPFC in a dose-dependent manner but not by infusion of a D2 dopamine receptor agonist. In addition, stress-induced behavioural changes in prefrontal cortical dopamine-depleted rats were significantly reduced following selective discrete infusions of a D2 dopamine receptor antagonist into the NAc shell. The results suggest that dopaminergic transmission via D1 receptors in the mPFC modulates D2 dopamine receptor-mediated stress responsiveness in the NAc, a feature that may be disrupted in schizophrenia patients.
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Int. J. Neuropsychopharmacol. · Sep 2009
Tramadol and another atypical opioid meperidine have exaggerated serotonin syndrome behavioural effects, but decreased analgesic effects, in genetically deficient serotonin transporter (SERT) mice.
The serotonin syndrome is a potential side-effect of serotonin-enhancing drugs, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs). We recently reported a genetic mouse model for the serotonin syndrome, as serotonin transporter (SERT)-deficient mice have exaggerated serotonin syndrome behavioural responses to the MAOI tranylcypromine and the serotonin precursor 5-hydroxy-l-tryptophan (5-HTP). As numerous case reports implicate the atypical opioids tramadol and meperidine in the development of the human serotonin syndrome, we examined tramadol and meperidine as possible causative drugs in the rodent model of the serotonin syndrome in SERT wild-type (+/+), heterozygous (+/-) and knockout (-/-) mice. ⋯ Further, we show that morphine-, meperidine- and tramadol-induced analgesia is markedly decreased in SERT-/- mice. These studies suggest that caution seems warranted in prescribing or not warning patients receiving SSRIs or MAOIs that dangerous side-effects may occur during concurrent use of tramadol and similar agents. These findings suggest that it is conceivable that there might be increased vulnerability in individuals with SERT polymorphisms that may reduce SERT by more than 50%, the level in SERT+/- mice.
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Int. J. Neuropsychopharmacol. · Jul 2009
Randomized Controlled TrialHaloperidol counteracts the ketamine-induced disruption of processing negativity, but not that of the P300 amplitude.
Antagonists of the N-methyl-D-aspartate (NMDA) receptors such as ketamine, induce abnormalities in healthy subjects similar to those found in schizophrenia. However, recent evidence, suggests that most of the currently known NMDA antagonists have a broader receptor profile than originally thought. Besides exerting an antagonistic effect on NMDA receptors, they have agonistic effects on dopamine D2 receptors. ⋯ In addition, ketamine reduced both P300 amplitude and processing negativity. In contrast to the P300 amplitude, the disruptive effects of ketamine on processing negativity could be prevented by pretreatment with haloperidol. The current results suggest that ketamine reduced P300 amplitude by its antagonistic effect on glutamatergic activity, while it reduced processing negativity by its agonistic effect on dopaminergic D2 activity.
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Int. J. Neuropsychopharmacol. · May 2009
Role of different monoamine receptors controlling MK-801-induced release of serotonin and glutamate in the medial prefrontal cortex: relevance for antipsychotic action.
Several studies have demonstrated that systemically administered N-methyl-d-aspartate (NMDA) receptor antagonists increase serotonin (5-HT) and glutamate release in the medial prefrontal cortex (mPFC). Previously we showed that the perfusion of clozapine in the mPFC prevented the MK-801-induced increase in extracellular glutamate and 5-HT whereas haloperidol blocked only the effect of MK-801 on glutamate. To study the contribution of different monoaminergic receptors (for which clozapine and haloperidol exhibit distinct affinities) to these effects, here we used in-vivo microdialysis to examine the role of local blockade of dopamine D2, 5-HT2A and alpha1-adrenergic receptors as well as agonism at dopamine D1 and 5-HT1A receptors in the mPFC on the increased efflux of glutamate and 5-HT elicited by MK-801. ⋯ However, raclopride, eticlopride (dopamine D2 antagonists) and SKF-38393 (dopamine D1 agonist) were able to prevent the increased efflux of glutamate (but not that of 5-HT) elicited by MK-801. We propose that D2 receptor antagonists and D1 agonists would act predominantly on a subpopulation of GABAergic interneurons of the mPFC, thus leading to an enhanced cortical inhibition that would prevent an excessive glutamatergic transmission. On the other hand, atypical antipsychotic drugs might further act upon 5-HT2A, 5-HT1A and alpha1-adrenoceptors present in pyramidal cells (including those projecting to the dorsal raphe nucleus), which would directly inhibit an excessive excitability of these cells.