| 1. |
- Bally, Marta, 1981, et al.
(författare)
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Interaction of Single Viruslike Particles with Vesicles Containing Glycosphingolipids
- 2011
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Ingår i: Physical Review Letters. - : American Physical Society. - 0031-9007 .- 1079-7114. ; 107:18
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Tidskriftsartikel (refereegranskat)abstract
- Glycosphingolipids are involved in the first steps of virus-cell interaction, where they mediate specific recognition of the host cell membrane. We have employed total-internal-reflection fluorescence microscopy to explore the interaction kinetics between individual unlabeled noroviruslike particles, which are attached to a glycosphingolipid-containing lipid bilayer, and fluorescent vesicles containing different types and concentrations of glycosphingolipids. Under association equilibrium, the vesicle-binding rate is found to be kinetically limited, yielding information on the corresponding activation energy. The dissociation kinetics are logarithmic over a wide range of time. The latter is explained by the vesicle-size-related distribution of the dissociation activation energy. The biological, pharmaceutical, and diagnostic relevance of the study is briefly discussed.
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| 2. |
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| 3. |
- Engel, Jörgen, 1942, et al.
(författare)
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Blockade of growth hormone secretagogue receptor 1A signaling by JMV 2959 attenuates the NMDAR antagonist, phencyclidine-induced impairments in prepulse inhibition
- 2015
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Ingår i: Psychopharmacology. - : Springer Science and Business Media LLC. - 0033-3158 .- 1432-2072. ; 232:23, s. 4285-4292
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Tidskriftsartikel (refereegranskat)abstract
- Schizophrenic-spectrum patients commonly display deficits in preattentive information processing as evidenced, for example, by disrupted prepulse inhibition (PPI), a measure of sensorimotor gating. Similar disruptions in PPI can be induced in rodents and primates by the psychotomimetic drug phencyclidine (PCP), a noncompetitive inhibitor of the NMDA receptor. Mounting evidence suggests that the hunger hormone ghrelin and its constitutively active receptor influences neuronal circuits involved in the regulation of mood and cognition. In the present series of experiments, we investigated the effects of ghrelin and the growth hormone secretagogue receptor (GHS-R1A) neutral antagonist, JMV 2959, on acoustic startle responses (ASR), PPI, and PCP-induced alterations in PPI. Intraperitoneal (i.p.) administration of ghrelin (0.033, 0.1, and 0.33 mg/kg) did not alter the ASR or PPI in rats. Conversely, i.p. injection of JMV 2959 (1, 3, and 6 mg/kg), dose dependently decreased the ASR and increased PPI. Pretreatment with JMV 2959 at a dose with no effect on ASR or PPI per se, completely blocked PCP-induced (2 mg/kg) deficits in PPI while pretreatment with the highest dose of ghrelin did not potentiate or alter PPI responses of a sub-threshold dose of PCP (0.75 mg/kg). These findings indicate that the GHS-R1A is involved in specific behavioral effects of PCP and may have relevance for patients with schizophrenia.
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| 4. |
- Engel, Jörgen, 1942, et al.
(författare)
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Neonatal herpes simplex virus type 1 brain infection affects the development of sensorimotor gating in rats.
- 2000
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Ingår i: Brain research. - 0006-8993. ; 863:1-2, s. 233-40
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Tidskriftsartikel (refereegranskat)abstract
- The effect of neonatal brain infection of herpes simplex virus type 1 (HSV-1) on the development of sensorimotor function in the rat was investigated using an acoustic startle paradigm. Intracerebral inoculation of HSV-1 at day 2 after birth, but not at day 4, caused a significant delay in the development of prepulse inhibition of acoustic startle. A decrease in prepulse inhibition was shown at 37, 46 and 58 days of age in these rats compared to control rats. No evidence was obtained for other behavioural dysfunctions such as differences in sensorimotor reactivity, sensorimotor response habituation, spontaneous locomotor activity, rearing activity or stereotyped behaviour. Prepulse inhibition of acoustic startle is an accepted model of sensorimotor gating in the CNS, a function which has been shown diminished in schizophrenic persons. The present results suggest that early viral infections during a neurone-susceptible period may contribute to the development of this deficit.
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| 5. |
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| 6. |
- 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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| 7. |
- 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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| 8. |
- Hård, Ernest, 1925, et al.
(författare)
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Behavioral reactivity in spontaneously hypertensive rats.
- 1985
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Ingår i: Physiology & behavior. - 0031-9384. ; 35:4, s. 487-92
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Tidskriftsartikel (refereegranskat)abstract
- Spontaneously hypertensive rats of the Okamoto strain (SHR) were compared with inbred normotensive rats of the Wistar-Kyoto strain (WKY) and with normally bred Wistar rats (NT) in tests on the audiogenic immobility reaction (freezing), open-field behavior in a dark and an enlightened arena respectively, auditory startle response and male sexual behavior. Compared to the WKYs the SHRs showed increased locomotion and rearing in the open-field situations, reduced startle response and shortened immobility reaction. The SHRs differed in the same way from the NT rats with the exception for motor activity in the dark arena, where no differences were observed. The WKY rats showed less motor activity than the NT animals. Both SH and WKY rats showed shorter latency time for ejaculation than the NT rats. The characteristics of the behavior patterns displayed by the SH rats were interpreted as indicating a reduced propensity for fear reactions in this strain of rats compared to the WKY and NT strains used in the present study.
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| 9. |
- Jerlhag, Elisabeth, 1978, et al.
(författare)
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Alpha-conotoxin MII-sensitive nicotinic acetylcholine receptors are involved in mediating the ghrelin-induced locomotor stimulation and dopamine overflow in nucleus accumbens.
- 2008
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Ingår i: European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. - : Elsevier BV. - 0924-977X. ; 18:7, s. 508-18
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Tidskriftsartikel (refereegranskat)abstract
- Previously, we have reported that the orexigenic peptide ghrelin activates the cholinergic-dopaminergic reward link, involving nicotinic acetylcholine receptors (nAChR). The alpha(3)-alpha(7) and beta(2)-beta(4) subunits of the nAChR can be combined into pentameric nAChRs, with different functional roles. The present experiments show that the locomotor stimulatory effects of ghrelin, either into laterodorsal tegmental area (LDTg) or ventral tegmental area (VTA), are mediated via ventral tegmental nAChR, but neither the alpha(4)beta(2) (using dihydro-beta-erythroidine) nor the alpha(7) (using methyllycaconitine) subtypes appears to be involved. On the other hand, the alpha(3)beta(2), beta(3) and/or alpha(6) (using alpha-conotoxin MII) subtypes in the VTA mediate the stimulatory and DA-enhancing effects of ghrelin, a pattern that ghrelin shares with ethanol (n=5-8). Radioligand-binding experiments shown that ghrelin does not interfere directly with nAChRs (n=26). We therefore suggest that the alpha(3)beta(2), beta(3) and/or alpha(6) subtypes might be pharmacological targets for treatment of addictive behaviours including compulsive overeating and alcoholism.
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| 10. |
- Jerlhag, Elisabeth, 1978, et al.
(författare)
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Ghrelin administration into tegmental areas stimulates locomotor activity and increases extracellular concentration of dopamine in the nucleus accumbens.
- 2007
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Ingår i: Addiction biology. - : Wiley. - 1355-6215 .- 1369-1600. ; 12:1, s. 6-16
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Tidskriftsartikel (refereegranskat)abstract
- Ghrelin stimulates appetite, increases food intake and causes adiposity by mechanisms that include direct actions on the brain. Previously, we showed that intracerebroventricular administration of ghrelin has stimulatory and dopamine-enhancing properties. These effects of ghrelin are mediated via central nicotine receptors, suggesting that ghrelin can activate the acetylcholine-dopamine reward link. This reward link consists of cholinergic input from the laterodorsal tegmental area (LDTg) to the mesolimbic dopamine system that originates in the ventral tegmental area (VTA) and projects to the nucleus accumbens. Given that growth hormone secretagogue receptors (GHSR-1A) are expressed in the VTA and LDTg, brain areas involved in reward, the present series of experiments were undertaken to examine the hypothesis that these regions may mediate the stimulatory and dopamine-enhancing effects of ghrelin, by means of locomotor activity and in vivo microdialysis in freely moving mice. We found that local administration of ghrelin into the VTA (1 microg in 1 microl) induced an increase in locomotor activity and in the extracellular concentration of accumbal dopamine. In addition, local administration of ghrelin into the LDTg (1 microg in 1 microl) caused a locomotor stimulation and an increase in the extracellular levels of accumbal dopamine. Taken together, this indicates that ghrelin might, via activation of GHSR-1A in the VTA and LDTg, stimulate the acetylcholine-dopamine reward link, implicating that ghrelin is a part of the neurochemical overlap between the reward systems and those that regulate energy balance.
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| 11. |
- Jerlhag, Elisabeth, 1978, et al.
(författare)
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Ghrelin stimulates locomotor activity and accumbal dopamine-overflow via central cholinergic systems in mice: implications for its involvement in brain reward.
- 2006
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Ingår i: Addiction biology. - : Wiley. - 1355-6215 .- 1369-1600. ; 11:1, s. 45-54
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Tidskriftsartikel (refereegranskat)abstract
- It is becoming increasingly apparent that there is a degree of neurochemical overlap between the reward systems and those regulating energy balance. We therefore investigated whether ghrelin, a stomach-derived and centrally derived orexigenic peptide, might act on the reward systems. Central ghrelin administration (1 microg/microL, to the third ventricle) induced an acute increase in locomotor activity as well as dopamine-overflow in the nucleus accumbens, suggesting that ghrelin can activate the mesoaccumbal dopamine system originating in the ventral tegmental area, a system associated with reward and motivated behaviour. The cholinergic afferents to the ventral tegmental area have been implicated in natural reward and in regulating mesoaccumbal dopamine neurons. The possibility that nicotinic receptors are involved in mediating the stimulatory and dopamine-enhancing effects of ghrelin is supported by the findings that peripheral injection of the unselective nicotinic antagonist mecamylamine (2.0 mg/kg) blocked these ghrelin-induced effects. Tentatively, ghrelin may, via activation of the acetylcholine-dopamine reward link, increase the incentive values of signals associated with motivated behaviours of importance for survival such as feeding behaviour. It will be important to discover whether this has therapeutic implications for compulsive addictive behaviours, such as eating behaviour disorders and drug dependence.
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| 12. |
- Jerlhag, Elisabeth, 1978, et al.
(författare)
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Role of the subunit composition of central nicotinic acetylcholine receptors for the stimulatory and dopamine-enhancing effects of ethanol.
- 2006
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Ingår i: Alcohol and Alcoholism. ; 41:5, s. 486-493
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: The stimulatory, rewarding, and dopamine (DA)-enhancing effects of ethanol may involve central nicotinic acetylcholine receptors (nAChR), especially those located in the ventral tegmental area (VTA). Identifying the subunit composition that mediates these effects of ethanol would increase the understanding of the neurochemical basis underlying the addictive properties of ethanol. In the present series of experiments, the role of the alpha(3)beta(2)(*) and/or beta(3)(*) and/or alpha(6)(*) subunits of the nAChR for the stimulatory and DA-enhancing effects of ethanol was investigated by using alpha-conotoxin MII (alphaCtxMII), selective to the alpha(3)beta(2)(*) and/or beta(3)(*) and/or the alpha(6)(*) subunits of the nAChR, and the alpha-conotoxin PIA-analogue (alphaCtxPIA-analogue), suggested to be selective to the alpha(6)(*) subunits. METHODS: alphaCtxMII and the alphaCtxPIA-analogue were synthesized using a modified literature procedure. The purity and identity of the peptides were confirmed with HPLC and FAB-MS analyses, respectively. Locomotor activity and in vivo microdialysis in freely moving mice were used. RESULTS: alphaCtxMII and the alphaCtxPIA-analogue were synthesized in good yields (>95%; >90%). In addition, we found that synthesized alphaCtxMII antagonized ethanol-induced locomotor stimulation, which confirms our previous results with the commercially available alphaCtxMII. Furthermore, the synthesized alphaCtxPIA-analogue, assumably also selective for alpha(6)(*) subunits of the nAChR, did neither antagonize the stimulatory nor the accumbal DA-enhancing effects of ethanol. CONCLUSION: These results indicate that alphaCtxMII- but not alphaCtxPIA-analogue-sensitive receptors, i.e. the alpha(3)beta(2)(*) and/or beta(3)(*) rather than the alpha(6)(*) subunits of the nAChR, appear to be of greater importance for these effects of ethanol and that these subunits could constitute neurochemical targets for developing new drugs for the treatment of alcohol dependence.
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| 13. |
- Johansson, C, et al.
(författare)
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Nitric oxide synthase inhibition blocks phencyclidine-induced behavioural effects on prepulse inhibition and locomotor activity in the rat.
- 1997
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Ingår i: Psychopharmacology. - 0033-3158. ; 131:2, s. 167-73
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Tidskriftsartikel (refereegranskat)abstract
- The ability of the nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), to block the behavioural effects of the potent psychotomimetic, phencyclidine, was tested in rats using two different behavioural models. L-NAME was found to block both phencyclidine-induced disruption of prepulse inhibition of acoustic startle and phencyclidine-induced stimulation of locomotor activity. A selective action of L-NAME on the effects of phencyclidine was indicated, since L-NAME did not alter the effects of amphetamine, another potent psychotomimetic, in these behavioural models. These observations suggest that a nitric oxide-dependent mechanism may be involved in the effects of phencyclidine in the central nervous system.
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| 14. |
- 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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| 15. |
- Klamer, Daniel, 1976, et al.
(författare)
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Antagonism of the nitric oxide synthase inhibitor, L-NAME, of the effects of phencyclidine on latent inhibition in taste aversion conditioning
- 2005
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Ingår i: Behav Brain Res. ; 161:1, s. 60-8
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Tidskriftsartikel (refereegranskat)abstract
- Latent inhibition (LI) is a behavioural procedure used to evaluate the potential propsychotic and antipsychotic properties of psychoactive drugs. In the present study, a conditioned taste aversion (CTA) procedure was used to investigate the effects of the nitric oxide (NO) synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), and the psychotomimetic drugs, phencyclidine (PCP) and d-amphetamine (d-AMP) on LI. PCP (2 mg/kg) and d-AMP (0.5 mg/kg) were both found to enhance LI in this procedure. The effect of d-AMP on LI was less pronounced and this drug also caused a weak disruption of taste aversion conditioning. Pretreatment with L-NAME (10 mg/kg) blocked the LI enhancing effect of PCP on LI but not that of d-AMP. L-NAME by itself caused an attenuation of LI. L-NAME has been shown to block also other behavioural and biochemical effects of PCP in previous studies and these results and the present findings suggest that at least some of the effects PCP are dependent on NO and possibly also that some NOS inhibitors may exert antipsychotic properties.
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| 16. |
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| 17. |
- Klamer, Daniel, 1976, et al.
(författare)
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Effects of phencyclidine on acoustic startle and prepulse inhibition in neuronal nitric oxide synthase deficient mice
- 2005
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Ingår i: Eur Neuropsychopharmacol. ; 15:5, s. 587-90
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Tidskriftsartikel (refereegranskat)abstract
- Prepulse inhibition of acoustic startle is a behavioural response, which is used to estimate sensorimotor gating deficits in schizophrenia. Recent studies show that several behavioural effects of the psychotomimetic drug, phencyclidine (PCP), in rodents are blocked by nitric oxide synthase (NOS) inhibitors suggesting that NO plays an important role in the pharmacological effects of PCP. The present study was conducted to examine the effects of PCP on prepulse inhibition in neuronal NOS (nNOS) deficient mice. PCP treatment caused a significant and dose-related increase in prepulse inhibition in nNOS-/- mice whereas prepulse inhibition was not significantly affected in +/+ and +/- mice. Basal prepulse inhibition level did not differ significantly between the groups. Furthermore, PCP caused a dose-related decrease in startle response reactivity in +/+ mice but did not significantly affect this measure in +/- and -/- mice. Basal startle response level did not differ between +/+ and +/- but was significantly lower in -/- mice. It is concluded that nNOS plays a role in the NO-sensitive effects of PCP.
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| 18. |
- Klamer, Daniel, 1976, et al.
(författare)
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Habituation of acoustic startle is disrupted by psychotomimetic drugs: differential dependence on dopaminergic and nitric oxide modulatory mechanisms
- 2004
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Ingår i: Psychopharmacology (Berl). ; 176:3-4, s. 440-50
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Tidskriftsartikel (refereegranskat)abstract
- RATIONALE: A deficit in attention and information processing has been considered a central feature in schizophrenia, which might lead to stimulus overload and cognitive fragmentation. It has been shown that patients with schizophrenia display a relative inability to gate incoming stimuli. Thus, patients repeatedly subjected to acoustic startle-eliciting stimuli habituate less to these stimuli than controls. Furthermore, schizophrenia-like symptoms can be induced by pharmacological manipulations in humans by psychotomimetic drugs, e.g. phencyclidine (PCP) and D-amphetamine (D-AMP). Recent studies show that the behavioural and biochemical effects of PCP in rodents are blocked by nitric oxide synthase (NOS) inhibitors, suggesting that NO plays an important role in at least the pharmacological effects of PCP. OBJECTIVES: The first aim of the present study was to investigate if PCP, MK-801 and D-AMP impair habituation of acoustic startle in mice. Secondly, we examine the effect of the NOS inhibitor, L-NAME, and the dopamine receptor antagonist, haloperidol, on drug-induced deficit in habituation. RESULTS: PCP (4 mg/kg), MK-801 (0.4 mg/kg) and D-AMP (5.0 mg/kg), impaired habituation of the acoustic startle response in mice. This effect was reversed by the NOS inhibitor, L-NAME. The typical antipsychotic, haloperidol, reversed the effects of PCP and D-AMP, but not that of MK-801. CONCLUSIONS: The finding that PCP, MK-801 and D-AMP impair habituation in mice is consistent with the idea that these treatments model certain filter deficits seen in schizophrenic patients. Furthermore, the present results suggest that NO is critically involved in these effects on habituation, whereas that of dopamine is less clear.
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| 19. |
- Klamer, Daniel, 1976, et al.
(författare)
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Phencyclidine-induced behaviour in mice prevented by methylene blue
- 2004
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Ingår i: Basic & Clinical Pharmacology & Toxicology. - 1742-7835. ; 94:2, s. 65-72
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Tidskriftsartikel (refereegranskat)abstract
- Schizophrenia is a major public health problem that affects approximately 1% of the population worldwide. Schizophrenia-like symptoms can be induced in humans by phencyclidine (PCP), a drug with marked psychotomimetic properties. Phencyclidine disrupts prepulse inhibition of acoustic startle in rodents, a measure which has also been shown to be disrupted in schizophrenic patients. This effect is blocked by nitric oxide synthase (NOS) inhibitors, suggesting that nitric oxide plays an important role in this effect of phencyclidine. Methylene blue, a guanylate cyclase and nitric oxide syntase inhibitor, has shown therapeutic value as an adjuvant to conventional antipsychotics in the therapy of schizophrenia. The aim of the present study was to investigate if phencyclidine-(4 mg/kg)induced disruption of prepulse inhibition could be affected by methylene blue (50 or 100 mg/kg) in mice. Furthermore, the effect of methylene blue (50 mg/kg) on phencyclidine-(4 mg/kg)induced hyperlocomotion was investigated. The present study shows that phencyclidine readily disrupts prepulse inhibition in mice without affecting pulse-alone trials. It was also found that methylene blue prevents the decrease in prepulse inhibition caused by phencyclidine in a dose-related manner. Furthermore, the increase in locomotor activity caused by phencyclidine was reduced by pretreatment with methylene blue. The results from the present study further support the suggestion that the nitric oxide synthase/guanylate cyclase pathway is involved in pharmacological and behavioural effects of phencyclidine. Since phencyclidine as well exerts psychotomimetic characteristics, agents that interfere with the nitric oxide synthase/guanylate cyclase pathway may be of therapeutic value also in the treatment of schizophrenia.
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| 20. |
- 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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| 21. |
- Klamer, Daniel, 1976, et al.
(författare)
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Selective interaction of nitric oxide synthase inhibition with phencyclidine: behavioural and NMDA receptor binding studies in the rat
- 2005
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Ingår i: Behav Brain Res. ; 159:1, s. 95-103
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Tidskriftsartikel (refereegranskat)abstract
- The psychotomimetic drugs, phencyclidine (PCP) and MK-801, are non-competitive antagonists of the N-methyl-d-aspartate (NMDA) receptor and used as pharmacological tools to mimic a possible NMDA receptor hypofunction in schizophrenia. These drugs were tested in two behavioural paradigms in the present study: prepulse inhibition (PPI) of acoustic startle and locomotor activity (LMA) in an open field. Recent studies show that several behavioural and biochemical effects of PCP are blocked by nitric oxide synthase (NOS) inhibition. Hence, it is likely that some effects of PCP are mediated via an increase in NO production, an assumption not in accordance with the NMDA receptor antagonistic effect of PCP. Experiments were conducted in rats to further elucidate the involvement of NO-dependent mechanisms in the effects of PCP and MK-801, and how these effects may involve the NMDA receptor. The NOS inhibitor N(G)-nitro-l-arginine methyl ester (L-NAME) (10 mg/kg) normalised the disruptive effect of PCP (2 mg/kg) on PPI and the stimulatory effect of PCP (4 mg/kg) on LMA. In contrast to these observations, the deficit in PPI induced by MK-801 (0.1 mg/kg) was not affected by L-NAME (10, 20 or 40 mg/kg). MK-801 (0.15 mg/kg)-induced hyperlocomotion was not affected by L-NAME (10 mg/kg), but attenuated by L-NAME (40 mg/kg). Furthermore, receptor binding studies aimed at investigating the influence of L-NAME on the binding of PCP to the MK-801-sensitive NMDA receptor binding site failed to show such an influence. These results suggest that the NO-sensitive effects of PCP are not sufficiently explained by its antagonistic effect at the NMDA receptor channel complex.
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| 22. |
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| 23. |
- Klamer, Daniel, 1976, et al.
(författare)
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The neuronal selective nitric oxide synthase inhibitor, Nomega-propyl-L-arginine, blocks the effects of phencyclidine on prepulse inhibition and locomotor activity in mice
- 2004
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Ingår i: Eur J Pharmacol. ; 503:1-3, s. 103-7
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Tidskriftsartikel (refereegranskat)abstract
- Phencyclidine has frequently been used to model schizophrenia in animals. In the present study, the ability of the neuronal selective nitric oxide synthase (NOS) inhibitor, Nomega-propyl-L-arginine, to block the behavioural effects of phencyclidine in mice was investigated. N(omega)-propyl-L-arginine (20 mg/kg) was found to block both phencyclidine (4 mg/kg)-induced disruption of prepulse inhibition and phencyclidine-induced stimulation of locomotor activity in the mice tested. It is concluded that the NOS-sensitive behavioural effects of phencyclidine in rodents is dependent on neuronal NOS and that NO may play a role in the psychotomimetic effects of phencyclidine.
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| 24. |
- Larsson, Anna, 1973, et al.
(författare)
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Is an alpha-conotoxin MII-sensitive mechanism involved in the neurochemical, stimulatory, and rewarding effects of ethanol?
- 2004
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Ingår i: Alcohol. ; 34:2-3, s. 239-250
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Tidskriftsartikel (refereegranskat)abstract
- Ethanol and nicotine are the most commonly abused drugs among human beings, and a large body of evidence, from both epidemiologic and preclinical studies, indicates that there is a positive correlation between intake of both drugs. Findings of studies from our research group have demonstrated that nicotinic acetylcholine receptors, especially those located in the ventral tegmental area, are important for the stimulatory, rewarding, and dopamine-enhancing effects of ethanol. Furthermore, results of recent work indicate that the alpha4beta2* and the alpha7* receptor subunits of the nicotinic acetylcholine receptors do not seem to be involved in the neurochemical and behavioral effects of ethanol in rodents. The aim of the current study was to investigate further the role of different nicotinic acetylcholine receptor subunits in the stimulatory, dopamine-enhancing, and rewarding effects of ethanol in rodents by using the peptide alpha-conotoxin MII (5 nmol; an antagonist of the alpha3beta2*, beta3*, and alpha6* subunits of the nicotinic acetylcholine receptor) administered locally into the ventral tegmental area. A significant reduction of ethanol-induced accumbal dopamine overflow, measured by means of in vivo microdialysis, and of locomotor stimulation was observed in mice. Furthermore, alpha-conotoxin MII was demonstrated to reduce voluntary ethanol intake significantly in both rats and mice. These results indicate that alpha-conotoxin MU-sensitive receptors may be important in mediating the stimulatory, dopamine-enhancing, and rewarding effects of ethanol, and that alpha-conotoxin MII-sensitive receptors may constitute targets for development of new adjuvant for treatment of ethanol dependence.
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| 25. |
- Larsson, Anna, 1973, et al.
(författare)
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Role of different nicotinic acetylcholine receptors in mediating behavioral and neurochemical effects of ethanol in mice.
- 2002
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Ingår i: Alcohol. ; 28:3, s. 157-167
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Tidskriftsartikel (refereegranskat)abstract
- Ethanol and nicotine are the most abused drugs, and it is well known that co-abuse of ethanol and nicotine is frequent in human beings. We have previously obtained results indicating that the ethanol-induced stimulation of both the mesolimbic dopamine system and locomotor activity may involve activation of central nicotinic acetylcholine receptors (nAChRs), especially those located in the ventral tegmental area. Different subpopulations of nAChRs have been identified, and, in the present series of experiments, we have studied the effects of various nAChR antagonists on the stimulation of dopamine overflow in the nucleus accumbens and on locomotor activity induced by ethanol in male mice. Ethanol (2.0 g/kg, i.p.) enhanced dopamine overflow in the nucleus accumbens by approximately 40%, measured by means of in vivo microdialysis in awake, freely moving mice. Mecamylamine (negative allosteric modulator of nAChR; 2.0 mg/kg, i.p.) blocked the ethanol-induced stimulation of both locomotor activity and accumbal dopamine overflow. Methyllycaconitine citrate (alpha(7) antagonist; 2.0 mg/kg, i.p.) and dihydro-beta-erythroidine (competitive and selective alpha(4)beta(2) antagonist; 0.5 mg/kg, s.c.), in doses that had no marked effects per se, did not significantly reduce the behavioral and neurochemical stimulation caused by ethanol. The present results support the suggestion that the stimulatory effects of ethanol on locomotor activity and dopamine release do not involve the alpha(4)beta(2) or alpha(7) subunit compositions of the nAChR and that the effects of mecamylamine are mediated through a site not directly associated with the alpha(4)beta(2) or alpha(7) nAChR subunits.
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| 26. |
- Larsson, Anna, 1973, et al.
(författare)
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Voluntary ethanol intake increases extracellular acetylcholine levels in the ventral tegmental area in the rat.
- 2005
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Ingår i: Alcohol and Alcoholism. - : Oxford University Press (OUP). - 0735-0414 .- 1464-3502. ; 40:5, s. 349-358
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Concurrent use of ethanol and nicotine (tobacco) is often seen in human beings. In previous animal experiments, we have demonstrated that nicotinic acetylcholine receptors, especially alpha-conotoxin MII and mecamylamine sensitive receptors located in the ventral tegmental area may be involved in the stimulatory, dopamine enhancing, and rewarding effects of ethanol in rodents. Ethanol may exert these effects via direct interaction with nicotinic acetylcholine receptors and/or indirectly via enhancement of extracellular acetylcholine levels in the ventral tegmental area. The present experiments investigated a possible indirect effect of ethanol in stimulating the mesoaccumbal dopamine system. METHODS: Neurochemical effects of voluntary ethanol intake on extracellular ventral tegmental acetylcholine and accumbal dopamine levels were measured by means of in vivo microdialysis with a two-probe approach in freely moving rats. RESULTS: Obtained data indicate that voluntary ethanol intake ( approximately 0.7 g/kg/h) leads to an increase of extracellular acetylcholine levels in the ventral tegmental area, and an almost time-locked increase of dopamine levels in the nucleus accumbens. A positive correlation between the ventral tegmental acetylcholine levels and ethanol intake as well as preference was also observed. CONCLUSION: The present results suggest that voluntary ethanol intake enhances extracellular ventral tegmental acetylcholine that may interact with nicotinic acetylcholine receptors, possibly alpha-conotoxin MII sensitive receptors, localized in the ventral tegmental area that subsequently may stimulate dopamine overflow in the nucleus accumbens.
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| 27. |
- Nilsson, Ingrid, 1952-
(författare)
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Grundskollärares tankar om kompetensutveckling
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The development in society and school activities that have taken place during the past twenty years, form the background to the problem in this thesis. Liberal democratisation in the society as a whole (Gutmann, 1990, 1995) and the global explosion of knowledge (Hargreaves, 1999; Pittman, 2000) have made it necessary for teachers continuously to develop new knowledge.The over all aim of the thesis concerned the development of knowledge of variations in teachers’ thoughts about teachers’ competence development through an empirical investigation. One specific aim concerned the development of knowledge of variation in teachers’ thoughts about relevant content of competence development. The second specific aim concerned the development of knowledge about variations in teachers’ thoughts about teachers’ possibilities of relevant use of competence development in the school activity. An analysis, inspired by the method Contextual analysis (Svensson, 1976) was used as the methodological starting-point and the theory of knowledge (Natanson,1970; Schutz, 1966, 1932/1997; Schutz & Luckmann, 1973, 1983/1989) as a theoretical framework. The analysis resulted in a hierarchical system of four categories of description, with similar types of structures as described by Biggs and Collis (1982). The first category of description is called Development of integrated general teacher competence, subject knowledge and competences in teaching the subject as a base for better development of the activity in school. This category of description is also the most complex. The second category of description is called Development of general teacher competence, subject knowledge and competences in teaching the subject as a base for better cooperation with colleagues. The third category of description is called Better subject knowledge and competences in teaching the subject as a base for better design of pupils learning situations. The fourth category of description is called Better knowledge of school subjects as a base for development of teachers own school teaching.In the most complex category of description teachers saw an integrated development of general teacher competence, subject knowledge and competences in teaching the subject as a base for better development of the activity in school. In the other three categories of description the teachers did not integrate all the mentioned competences. They explicated a competence development relevant to a more narrow activity in school. Further, the results point to relations between the teachers’ thoughts about interpretational relevant content and about area of application, regarding development of competence. The relations involve that if a teacher is making complex statements about the interpretational relevant content, the teacher also is making complex statements about the area of application. The results could be of importance to principals and teachers which ought to develop competence of how to make relevant knowledge of politics of education relevant for all teachers in the activity, both as individuals and as a professional collective. At last, the results are indicating that Schutz’ system of personal relevance of knowledge (Schutz, 1966), in addition, seems to be a system equivalent to the personal relevance system of competence development, according to the teachers’ thoughts of competence development. However, the teachers’ thoughts of competence development do not indicate a shared professional ground of teachers’ knowledge.
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| 28. |
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| 29. |
- Pålsson, Erik, 1975, et al.
(författare)
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Increased cortical nitric oxide release after phencyclidine administration.
- 2009
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Ingår i: Synapse (New York, N.Y.). - : Wiley. - 1098-2396 .- 0887-4476. ; 63:12, s. 1083-1088
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Tidskriftsartikel (refereegranskat)abstract
- Phencyclidine exerts psychotomimetic effects in humans and is used as a pharmacological animal model for schizophrenia. We, and others, have demonstrated that phencyclidine induces cognitive deficits in rats that are associated with schizophrenia. These cognitive deficits can be normalized by inhibition of nitric oxide synthase. The development of selective microelectrochemical nitric oxide sensors may provide direct evidence for the involvement of nitric oxide in these effects. The aim of the present study was to use LIVE (long term in vivo electrochemistry) to investigate the effect of phencyclidine, alone or in combination with the nitric oxide synthase inhibitor L-NAME, on nitric oxide levels in the medial prefrontal cortex of freely moving rats. Phencyclidine (2 mg kg(-1)) produced an increase in cortical nitric oxide levels and this increase was ameliorated by L-NAME (10 mg kg(-1)). Tentatively, the results from the present study provide a biochemical rationale for the involvement of nitric oxide in the phencyclidine model of schizophrenia. Synapse 63:1083-1088, 2009. (c) 2009 Wiley-Liss, Inc.
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| 30. |
- Pålsson, Erik, 1975, et al.
(författare)
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The amino acid L-lysine blocks the disruptive effect of phencyclidine on prepulse inhibition in mice.
- 2007
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Ingår i: Psychopharmacology. - : Springer Science and Business Media LLC. - 0033-3158 .- 1432-2072. ; 192:1, s. 9-15
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Tidskriftsartikel (refereegranskat)abstract
- RATIONALE: The cognitive and attentional deficits observed in schizophrenic patients are now considered central to the pathophysiology of the disorder. These deficits include an inability to filter sensory input as measured by, e.g., prepulse inhibition (PPI) reflex. Administration of phencyclidine (PCP), a drug that can induce a schizophrenia-like psychosis in humans, disrupts PPI in experimental animals. In rodents, this PCP-induced deficit can be blocked by pretreatment with nitric oxide (NO) synthase inhibitors. This suggests that some of the behavioral effects of PCP are mediated via NO. The substrate for in vivo NO production is L-arginine, and active transport of L-arginine via the cationic amino acid transporter may serve as a regulatory mechanism in NO production. OBJECTIVES: The aim of the present study was to study the effects of L-arginine transport inhibition, using acute and repeated L-lysine treatment, on PCP-induced disruption of PPI in mice. RESULTS: Subchronic, and to some extent acute, pretreatment with L-lysine blocked a PCP-induced deficit in PPI without affecting basal PPI. CONCLUSIONS: L-lysine has been shown to block L-arginine transport in vitro, most likely via a competitive blockade and down regulation of cationic amino acid transporters. However, the importance of L-arginine transport as a regulatory mechanism in NO production in vivo is still not clear. The present results lend further support to the notion that some of the effects of PCP in the central nervous system are mediated via NO and that L-arginine transport may play a role in the regulation of NO production in the brain.
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| 31. |
- Pålsson, Erik, 1975, et al.
(författare)
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The effects of phencyclidine on latent inhibition in taste aversion conditioning: differential effects of preexposure and conditioning
- 2005
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Ingår i: Behav Brain Res. ; 157:1, s. 139-46
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Tidskriftsartikel (refereegranskat)abstract
- Latent inhibition (LI) is a behavioural procedure in which preexposure to a stimulus not followed by reinforcement retards subsequent conditioning to this stimulus when it is paired with reinforcement. Changes in LI thus reflect greater or lesser retardation of learning which essentially implies a potentiation or an attenuation of the LI effect. LI has proved sensitive to psychotomimetic and antipsychotic treatment, which has encouraged its use to model learning and attention deficits in schizophrenia. In the present study, experiments were conducted to evaluate the effects of the psychotomimetic drug, phencyclidine (PCP, 2 mg/kg), and compare it with D-amphetamine (D-AMP, 0.33 and 1 mg/kg), on LI using a conditioned taste aversion procedure. PCP was found to potentiate LI when administered acutely prior to the conditioning trails, while no such effect was observed when administered prior to the preexposure trials. D-AMP, on the other hand, disrupted LI possibly due to a failure to induce a persistent taste aversion conditioning.
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| 32. |
- Wallén-Mackenzie, Åsa, et al.
(författare)
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Restricted cortical and amygdaloid removal of vesicular glutamate transporter 2 in preadolescent mice impacts dopaminergic activity and neuronal circuitry of higher brain function.
- 2009
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Ingår i: The Journal of neuroscience : the official journal of the Society for Neuroscience. - 1529-2401 .- 0270-6474. ; 29:7, s. 2238-51
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Tidskriftsartikel (refereegranskat)abstract
- A major challenge in neuroscience is to resolve the connection between gene functionality, neuronal circuits, and behavior. Most, if not all, neuronal circuits of the adult brain contain a glutamatergic component, the nature of which has been difficult to assess because of the vast cellular abundance of glutamate. In this study, we wanted to determine the role of a restricted subpopulation of glutamatergic neurons within the forebrain, the Vglut2-expressing neurons, in neuronal circuitry of higher brain function. Vglut2 expression was selectively deleted in the cortex, hippocampus, and amygdala of preadolescent mice, which resulted in increased locomotor activity, altered social dominance and risk assessment, decreased sensorimotor gating, and impaired long-term spatial memory. Presynaptic VGLUT2-positive terminals were lost in the cortex, striatum, nucleus accumbens, and hippocampus, and a downstream effect on dopamine binding site availability in the striatum was evident. A connection between the induced late-onset, chronic reduction of glutamatergic neurotransmission and dopamine signaling within the circuitry was further substantiated by a partial attenuation of the deficits in sensorimotor gating by the dopamine-stabilizing antipsychotic drug aripiprazole and an increased sensitivity to amphetamine. Somewhat surprisingly, given the restricted expression of Vglut2 in regions responsible for higher brain function, our analyses show that VGLUT2-mediated neurotransmission is required for certain aspects of cognitive, emotional, and social behavior. The present study provides support for the existence of a neurocircuitry that connects changes in VGLUT2-mediated neurotransmission to alterations in the dopaminergic system with schizophrenia-like behavioral deficits as a major outcome.
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| 33. |
- Wass, Caroline, 1976, et al.
(författare)
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Effects of phencyclidine on spatial learning and memory: nitric oxide-dependent mechanisms
- 2006
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Ingår i: Behav Brain Res. ; 171:1, s. 147-53
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Tidskriftsartikel (refereegranskat)abstract
- Cognitive deficits of schizophrenia constitute a disabling part of the disease predicting treatment success as well as functional outcome. Phencyclidine (PCP), a non-competitive NMDA receptor antagonist was used to model schizophrenic cognitive dysfunctions of learning and memory using the Morris water maze paradigm for reference memory. In experiment 1 male Sprauge-Dawley rats were acutely administered PCP (0.5, 1.0 and 2.0 mg/kg s.c.) before the first swim session on each of the four acquisition days. Probe test for reference memory was performed 2 days after the last acquisition day; the first probe without drug treatment to assess reference memory and a second probe with prior drug treatment to control for state dependency effects of PCP. In experiment 2 the effects of pre-treatment (10 min before PCP) with the nitric oxide synthase inhibitor, L-NAME (10 mg/kg s.c.), on the PCP (2 mg/kg)-induced spatial memory deficit was evaluated in the Morris water maze paradigm for reference memory. The results showed that PCP in a dose of 2 mg/kg disrupts spatial learning as estimated by prolonged search time to find platform during acquisition as well as the reference memory test as measured by less time spent in target quadrant during probe trial. No state dependency effects of PCP were found. Pre-treatment with L-NAME completely reversed the PCP-induced disruption of acquisition learning. The reference memory disruption was, however, not completely restored as measured by probe trial.
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| 34. |
- Wass, Caroline, et al.
(författare)
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L-lysine as adjunctive treatment in patients with schizophrenia: a single-blinded, randomized, cross-over pilot study.
- 2011
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Ingår i: BMC medicine. - : Springer Science and Business Media LLC. - 1741-7015. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: BACKGROUND: Accumulating evidence suggests that the brain's nitric oxide (NO) signalling system may be involved in the pathophysiology of schizophrenia and could thus constitute a novel treatment target. The study was designed to investigate the benefit of L-lysine, an amino acid that interferes with NO production, as an add-on treatment for schizophrenia. METHODS: L-lysine, 6 g/day, was administered to ten patients with schizophrenia as an adjunctive to their conventional antipsychotic medication. The study was designed as a single-blinded, cross-over study where patients were randomly assigned to initial treatment with either L-lysine or placebo and screened at baseline, after four weeks when treatment was crossed over, and after eight weeks. RESULTS: L-lysine treatment caused a significant increase in blood concentration of L-lysine and was tolerated well. A significant decrease in positive symptom severity, measured by the Positive And Negative Syndrome Scale (PANSS), was detected. A certain decrease in score was also observed during placebo treatment and the effects on PANSS could not unequivocally be assigned to the L-lysine treatment. Furthermore, performance on the Wisconsin Card Sorting Test was significantly improved compared to baseline, an effect probably biased by training. Subjective reports from three of the patients indicated decreased symptom severity and enhanced cognitive functioning. CONCLUSIONS: Four-week L-lysine treatment, 6 g/day, caused a significant increase in blood concentration of L-lysine that was well tolerated. Patients showed a significant decrease in positive symptoms as assessed by PANSS in addition to self-reported symptom improvement by three patients. The NO-signalling pathway is an interesting, potentially new treatment target for schizophrenia, however the effects of L-lysine need further evaluation to decide its' potentially beneficial effects on symptom severity in schizophrenia. Trial registration: NCT00996242.
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| 35. |
- Wass, Caroline, 1976, et al.
(författare)
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Nitric oxide synthase inhibition attenuates phencyclidine-induced disruption of cognitive flexibility.
- 2008
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Ingår i: Pharmacology, biochemistry, and behavior. - : Elsevier BV. - 0091-3057. ; 89:3, s. 352-9
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Tidskriftsartikel (refereegranskat)abstract
- Schizophrenia encompasses, amongst other symptoms, a heavy load of cognitive dysfunctionality. Using the psychotomimetic agent, phencyclidine (PCP), we have previously found that PCP-induced disruptions of cognitive function in translational rodent models of schizophrenia are dependent on nitric oxide (NO) production. In the present study, male Sprague-Dawley rats were subjected to a Morris water maze task designed to assess cognitive flexibility (i.e. the ability to cope with an increasingly demanding cognitive task) by means of a "constant reversal learning paradigm". Experiments were conducted to evaluate the effects of the NO synthase inhibitor, L-NAME (10 mg/kg), on PCP-induced (2 mg/kg) impairments. Control animals significantly improved their learning over the first 3 consecutive days, whereas PCP-treated animals failed to show any significant learning. Pretreatment with L-NAME normalized the PCP-induced disruption of learning to control levels. These findings suggest that PCP-induced disruptions of cognitive flexibility (i.e. ability to modify behaviour according to an increasingly demanding cognitive task) are dependent upon NO production. These observations, together with accumulated clinical findings, suggest that the NO system is a potential treatment target for cognitive dysfunctions in schizophrenia.
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| 36. |
- Wass, Caroline, 1976, et al.
(författare)
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Phencyclidine affects memory in a nitric oxide-dependent manner: working and reference memory
- 2006
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Ingår i: Behav Brain Res. ; 174:1, s. 49-55
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Tidskriftsartikel (refereegranskat)abstract
- Phencyclidine (PCP), a non-competitive NMDA receptor antagonist, was used to model schizophrenia-like cognitive dysfunctions of learning and memory in rats using the Morris water maze model for spatial memory. A protocol introduced by Baldi and co-workers was used to distinguish working memory from reference memory. Male Sprague-Dawley rats were administered PCP (2.0 mg/kg) before the first swimming trial on each of five spatial memory acquisition days, either alone or after pre-treatment with the nitric oxide synthase inhibitor, L-NAME (10 mg/kg). Probe tests for memory were conducted before and after each acquisition session. The results showed that PCP disrupted the acquisition of both working and reference memory. Pre-treatment with L-NAME reversed both these effects of PCP. L-NAME treatment by itself did not significantly alter either acquisition or retention of spatial memory.
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| 37. |
- Zhang, Jianhua, 1961, et al.
(författare)
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Involvement of the medial geniculate body in prepulse inhibition of acoustic startle.
- 1999
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Ingår i: Psychopharmacology. - 0033-3158. ; 141:2, s. 189-96
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Tidskriftsartikel (refereegranskat)abstract
- Prepulse inhibition of acoustic startle is the normal reduction in startle response to an intense auditory stimulus when this stimulus is immediately preceded by a weaker prestimulus. Previous studies have shown that several neuroanatomical structures and pathways in the brain are involved in the modulation of prepulse inhibition. In the present study, the functional importance of the medial geniculate body (MG) in the modulation of prepulse inhibition was investigated. To this end, in vivo brain microdialysis probes were used to infuse drugs locally into the MG of awake, freely moving rats simultaneously with startle response and prepulse inhibition measurements in the same animals. Intrageniculate infusion of the sodium channel blocker, tetrodotoxin, significantly reduced prepulse inhibition without affecting baseline startle amplitude. A similar effect was obtained after intrageniculate infusion of the GABA(B) receptor agonist, baclofen. In addition, intrageniculate infusion of muscimol, an agonist at the GABA(A) receptor complex, reduced prepulse inhibition, although this effect was obtained at a higher concentration of the drug compared to that of baclofen. These studies suggest that the MG is involved in the modulation of prepulse inhibition and that auditory signals relayed via the MG may be subjected to inhibitory control at this level, involving GABA neurotransmission.
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| 38. |
- Zhang, Jianhua, 1961, et al.
(författare)
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Repeated administration of amphetamine induces sensitisation to its disruptive effect on prepulse inhibition in the rat.
- 1998
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Ingår i: Psychopharmacology. - 0033-3158. ; 135:4, s. 401-6
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Tidskriftsartikel (refereegranskat)abstract
- Male Sprague-Dawley rats were repeatedly treated with amphetamine (AMP, 1 mg/kg, SC) at 3- day intervals for 15 days and tested for prepulse inhibition of acoustic startle after each treatment. This treatment regimen induced sensitisation in the animals as evidenced by a progressive increase in the disruptive effect of AMP on prepulse inhibition. Persistent changes in brain function was indicated, since an increase in disruptive effect was observed in sensitised animals also after a 22-day-long drug- and test-free period. The development of sensitisation was blocked by pretreatment with haloperidol (HPD, 0.1 mg/kg, SC), which suggests that sensitisation to the disruptive effect of AMP was dependent on dopamine (DA) D2 receptor activation. Furthermore, the development of sensitisation was blocked by adrenalectomy, which suggests that sensitisation was dependent also on circulating adrenal hormones. Increased DA-ergic activity has been implicated in the pathophysiology of schizophrenia and AMP-induced sensitisation to the neuronal functions that modulate prepulse inhibition may be an experimental model to investigate this hypothesis.
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