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| 2. |
- Fejgin, Kim, 1978, et al.
(författare)
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Nitric oxide signaling in the medial prefrontal cortex is involved in the biochemical and behavioral effects of phencyclidine.
- 2008
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Ingår i: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. - : Springer Science and Business Media LLC. - 0893-133X. ; 33:8, s. 1874-83
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Tidskriftsartikel (refereegranskat)abstract
- The prefrontal cortex (PFC) is believed to play an important role in the cognitive impairments observed in schizophrenia and has also been shown to be involved in the modulation of prepulse inhibition (PPI), a measure of preattentive information processing that is impaired in schizophrenic individuals. Phencyclidine (PCP), a noncompetitive inhibitor of the NMDA receptor, exerts psychotomimetic effects in humans, disrupts PPI, and causes hypofrontality in rodents and monkeys. We have previously demonstrated that interfering with the production of nitric oxide (NO) can prevent a wide range of PCP-induced behavioral deficits, including PPI disruption. In the present study, the role of NO signaling for the behavioral and biochemical effects of PCP was further investigated. Dialysate from the medial PFC of mice receiving systemic treatment with PCP and/or the NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME, 40 mg/kg), was analyzed for cGMP content. Furthermore, a specific inhibitor of NO-sensitive soluble guanylyl cyclase (sGC), 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ, 0.01-1 mM), was administered into the medial PFC of mice in combination with systemic injections of PCP, followed by PPI and locomotor activity testing. PCP (5 mg/kg) caused an increase in prefrontal cGMP that could be attenuated by pretreatment with the NO synthase inhibitor, L-NAME. Moreover, bilateral microinjection of the sGC inhibitor, ODQ, into the medial PFC of mice attenuated the disruption of PPI, but not the hyperlocomotion, caused by PCP. The present study shows that NO/sGC/cGMP signaling pathway in the medial PFC is involved in specific behavioral effects of PCP that may have relevance for the disabling cognitive dysfunction found in patients with schizophrenia.
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| 3. |
- Fejgin, Kim, 1978, et al.
(författare)
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Prefrontal GABA(B) Receptor Activation Attenuates Phencyclidine-Induced Impairments of Prepulse Inhibition: Involvement of Nitric Oxide.
- 2009
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Ingår i: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. - : Springer Science and Business Media LLC. ; 34:7, s. 1673-84
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Tidskriftsartikel (refereegranskat)abstract
- Recent theories propose that both GABA and glutamate signaling are compromised in patients with schizophrenia. These deficits can be observed in several brain regions including the prefrontal cortex (PFC), an area extensively linked to the cognitive dysfunction in this disease and notably affected by NMDA receptor antagonists such as phencyclidine (PCP). We have previously demonstrated that inhibition of the nitric oxide (NO) pathways in the brain, particularly in the PFC, prevents a wide range of PCP-induced behavioral deficits including disruption of prepulse inhibition (PPI). This study investigated the role of GABA(B) receptor signaling and NO in the effects of PCP on PPI. Mice received systemic or prefrontal injections of the GABA(B) receptor agonist baclofen (2.5-5 mg/kg and 1 mM) before PCP treatment (5 mg/kg) and were thereafter tested for PPI. GABA/NO interactions were studied by combining baclofen and the NO synthase inhibitor L-NAME (20 mg/kg) in subthreshold doses. The role of GABA(B) receptors for NO production in vivo was assessed using NO-sensors implanted into the rat PFC. PCP-induced PPI deficits were attenuated in an additive manner by systemic baclofen treatment, whereas prefrontal microinjections of baclofen completely blocked the effects of PCP, without affecting PPI per se. The combination of baclofen and L-NAME was more effective in preventing the effects of PCP than any compound by itself. Additionally, baclofen decreased NO release in the PFC in a dose-related manner. This study proposes a role for GABA(B) receptor signaling in the effects of PCP, with altered NO levels as a downstream consequence. Thus, prefrontal NO signaling mirrors an altered level of cortical inhibition that may be of importance for information processing deficits in schizophrenia.Neuropsychopharmacology (2009) 34, 1673-1684; doi:10.1038/npp.2008.225; published online 14 January 2009.
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| 4. |
- Fejgin, Kim, 1978, et al.
(författare)
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The atypical antipsychotic, aripiprazole, blocks phencyclidine-induced disruption of prepulse inhibition in mice.
- 2007
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Ingår i: Psychopharmacology. - : Springer Science and Business Media LLC. - 0033-3158 .- 1432-2072. ; 191:2, s. 377-85
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Tidskriftsartikel (refereegranskat)abstract
- RATIONALE: The psychotomimetic drug, phencyclidine, induces schizophrenia-like behavioural changes in both humans and animals. Phencyclidine-induced disruption of sensory motor gating mechanisms, as assessed by prepulse inhibition of the acoustic startle, is widely used in research animals as a screening model for antipsychotic properties in general and may predict effects on negative and cognitive deficits in particular. Dopamine (DA) stabilizers comprise a new generation of antipsychotics characterized by a partial DA receptor agonist or antagonist action and have been suggested to have a more favourable clinical profile. OBJECTIVE: The aim of the present study was to investigate the ability of first, second and third generation antipsychotics to interfere with the disruptive effect of phencyclidine on prepulse inhibition in mice. RESULTS: Aripiprazole blocked the phencyclidine-induced disruption of prepulse inhibition. The atypical antipsychotic clozapine was less effective, whereas olanzapine, and the typical antipsychotic haloperidol, failed to alter the effects of phencyclidine on prepulse inhibition. CONCLUSIONS: The somewhat superior efficacy of clozapine compared to haloperidol may be explained by its lower affinity and faster dissociation rate for DA D2 receptors possibly combined with an interaction with other receptor systems. Aripiprazole was found to be more effective than clozapine or olanzapine, which may be explained by a partial agonist activity of aripiprazole at DA D2 receptors. In conclusion, the present findings suggest that partial DA agonism leading to DA stabilizing properties may have favourable effects on sensorimotor gating and thus tentatively on cognitive dysfunctions in schizophrenia.
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| 5. |
- Fejgin, Kim, 1978
(författare)
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The prefrontal cortex and information processing : nitric oxide signaling studied in an animal model of schizophrenia
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The prefrontal cortex has been extensively linked to several cognitive domains that are severely compromised in schizophrenia. It has therefore become a key region for studies on the disabling cognitive dysfunction commonly observed in patients with schizophrenia. The absence of effective treatment options for cognitive deficits makes the identification of novel drug targets urgent, and this search is largely dependent on validated animal models. Administration of the NMDA receptor antagonist phencyclidine (PCP) has proven effective in mimicking several features of schizophrenia, including disrupted information processing and aberrant prefrontal cortex function. Previous studies show that a range of cognition-related behavioral deficits induced by PCP in experimental animals, including impaired pre-attentive information processing as measured by prepulse inhibition (PPI), can be blocked by inhibiting the production of nitric oxide (NO). The aim of the present thesis was to study the role of prefrontal NO signaling in the effects of PCP on information processing. Measurements of NO and its main effector, cGMP, were performed using in vivo voltammetry and microdialysis. This was combined with PPI and locomotor activity studies following pharmacological modulation of NO and GABA signaling. Systemic administration of PCP to mice disrupted PPI, which was blocked in a dose-dependent manner by inhibiting substrate availability for NO synthase using L-lysine, and by microinjections of an inhibitor of cGMP synthesis into the mouse medial prefrontal cortex. Furthermore, PCP caused an increase in prefrontal cGMP levels that was blocked by the NO synthase inhibitor, L-NAME. Similarly, prefrontal NO release, as measured by a novel microelectrochemical sensor, was increased by PCP, and this increase was blocked by pretreatment with L-NAME in the rat. Finally, systemic pretreatment with a combination of sub-threshold doses of the GABAB agonist baclofen and L-NAME, increased PPI per se, and prevented the effects of PCP on PPI. On a regional level, prefrontal microinjections with baclofen fully blocked the effects of PCP on PPI in mice, and NO levels in the rat prefrontal cortex were decreased following systemic baclofen administration. In conclusion, the present thesis presents biochemical and behavioral support for the involvement of a prefrontal NO/cGMP signaling pathway in the effects of PCP. Furthermore, this mechanism may partly be explained by a decrease in inhibitory power of GABAergic interneurons, followed by increased NO signaling in the prefrontal cortex. Thus, studies of GABA/NO interactions in the prefrontal cortex may prove valuable when searching for novel treatment targets for cognitive dysfunction in schizophrenia.
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| 6. |
- Klamer, Daniel, 1976, et al.
(författare)
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Activation of a nitric-oxide-sensitive cAMP pathway with phencyclidine: elevated hippocampal cAMP levels are temporally associated with deficits in prepulse inhibition
- 2005
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Ingår i: Psychopharmacology (Berl). ; 179:2, s. 479-88
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Tidskriftsartikel (refereegranskat)abstract
- RATIONALE: Schizophrenic patients show deficits in pre-attentive information processing as evidenced, for example, by disrupted prepulse inhibition, a measure of sensorimotor gating. A similar disruption can be observed in animals treated with the psychotomimetic agent, phencyclidine (PCP). However, the mechanism by which PCP alters brain function has not been fully elucidated. Recent studies have demonstrated that certain behavioural and neurochemical effects of PCP in rats and mice are blocked by nitric oxide (NO) synthase inhibition, suggesting an important role for NO in the effects of PCP. OBJECTIVE: The aim of the present study was to investigate the effects of PCP on cAMP production in the ventral hippocampus and the role of NO in these effects using in vivo microdialysis in rats. Furthermore, the effects of PCP on acoustic startle reactivity and prepulse inhibition of acoustic startle were compared with changes in cAMP levels in the ventral hippocampus. RESULTS: Significant increases in cAMP levels were observed in the ventral hippocampus following both local infusion (10(-4) mol/l and 10(-3) mol/l) and systemic administration (2 mg/kg) of PCP. The PCP-induced changes in prepulse inhibition and startle reactivity were associated in magnitude and duration with the increase in cAMP levels in the hippocampus. Furthermore, systemic administration of the NO synthase inhibitor, L: -NAME (10 mg/kg), blocked both the changes in cAMP levels and the behavioural responses induced by PCP. CONCLUSIONS: These findings indicate that the effects of PCP on prepulse inhibition and startle reactivity are associated with an increase in cAMP levels in the ventral hippocampus, and that this change in cAMP response may be linked to the production of NO.
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| 8. |
- Klamer, Daniel, 1976, et al.
(författare)
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Prefrontal NMDA receptor antagonism reduces impairments in pre-attentive information processing.
- 2011
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Ingår i: European Neuropsychopharmacology. - 0924-977X. ; 21:3, s. 248-253
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Tidskriftsartikel (refereegranskat)abstract
- A well established theory proposes that glutamate signalling via the NMDA receptor is compromised in patients with schizophrenia. Deficits related to NMDA receptor signalling can be observed in several brain regions including the prefrontal cortex (PFC), an area extensively linked to the cognitive dysfunction in this disease and notably affected by NMDA receptor antagonists such as phencyclidine (PCP). In addition, a number of studies suggest that normalizing of PFC function could constitute a treatment rationale for schizophrenia. To further study the role of PFC function we investigated the effect of local PFC NMDA receptor blockade on impaired prepulse inhibition (PPI) induced by systemic administration of PCP. Mice received prefrontal injections of PCP (0.01, 0.1 or 1 mM) before PCP treatment (5 mg/kg) and were thereafter tested for PPI. PCP induced deficits in PPI were ameliorated by prefrontal PCP (0.1 mM) treatment whereas PPI was not affected by prefrontal cortex PCP administration per se at any of the doses tested. Taken together, inhibition of NMDA receptors in the PFC does not seem to be enough to impair PPI per se but NMDA receptor mediated signalling in the PFC may be a key factor for the PPI-disruptive effects of global NMDA receptor inhibition. This indicates that targeting PFC NMDA receptor signalling may have potential as a treatment target for schizophrenia although further studies are needed to understand pharmacology and pathophysiological role of PFC NMDA receptors.
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