| 1. |
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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. |
- 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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| 6. |
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| 7. |
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| 8. |
- Olsson, Yasmin, et al.
(författare)
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Free-access intravenous alcohol self-administration in social drinkers and individuals with alcohol use disorder: Evaluation of relationships with phosphatidylethanol and self-reported alcohol consumption
- 2023
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Ingår i: Alcoholism: Clinical and Experimental Research. - 0145-6008. ; 47:8, s. 1453-1466
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Tidskriftsartikel (refereegranskat)abstract
- Background: The free-access (FA) intravenous alcohol self-administration (IV-ASA) paradigm is an experimental approach that can identify modulators of alcohol consumption in humans. Moreover, the outcome measures of IV-ASA paradigms are associated with self-reported alcohol intake using the timeline follow-back method (TLFB). To evaluate how FA IV-ASA reflects drinking in real life, we examined the relationship between an objective marker of recent alcohol intake, phosphatidylethanol in blood (B-PEth), and TLFB and measures obtained during IV-ASA in individuals with alcohol use disorder (AUD) and social drinkers (SD). We also explored the associations between these measures and gut-brain peptides involved in AUD pathophysiology.Methods: Thirty-eight participants completed a laboratory session in which they self-administered alcohol intravenously. The safety limit was 200 mg%, and main outcomes were mean and peak breath alcohol concentrations (BrAC). Blood samples were drawn prior to IV-ASA and subjective alcohol effects were rated during the experiment.Results: The study sample comprised 24 SD and 14 participants with DSM-5 mild AUD. Although BrACs were not associated with B-PEth or TLFB in the full sample or AUD subgroup, there was an association with TLFB in SD. In both subgroups, BrACs were associated with alcohol craving but with differential timing. Total ghrelin levels were higher in AUD participants than in SD.Conclusions: No associations between B-PEth levels and achieved BrACs were observed in the mild AUD group, the SD group, or the full sample. The ability for FA IV-ASA to reflect recent drinking was confirmed only for TLFB in SD, whereas there were no associations within the smaller subsample of participants with mild AUD or in the full sample. Further studies that include a larger AUD sample are warranted. The association of BrACs with craving for alcohol suggests that the IV-ASA method may be useful for assessing interventions that target craving. This could be explored by using the FA IV-ASA model to evaluate the effects on craving of approved pharmacotherapies for AUD.
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| 9. |
- Pålsson, Erik, 1975, et al.
(författare)
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Agmatine attenuates the disruptive effects of phencyclidine on prepulse inhibition.
- 2008
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Ingår i: European journal of pharmacology. - : Elsevier BV. - 0014-2999. ; 590:1-3, s. 212-6
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Tidskriftsartikel (refereegranskat)abstract
- Agmatine, a decarboxylation product of arginine, is thought to be an important neuromodulator in the mammalian brain. It is proposed to exert neuroprotective, anxiolytic and antidepressant effects. The receptor-binding profile of agmatine is complex and includes interaction with alpha(2)-adrenergic and imidazoline I(1) receptors. Furthermore, agmatine is an NMDA-receptor antagonist and inhibits nitric oxide synthase. Prepulse inhibition (PPI) of the acoustic startle response is used as a measure of the pre-attentive information processing. PPI is lowered in schizophrenia and this impairment can be mimicked in experimental animals using the psychotomimetic drug phencyclidine (PCP). The aim of the present study was to investigate the effects of agmatine per se on the PPI response and the effects of agmatine pre-treatment on a PCP-induced disruption of PPI. Agmatine administration (10, 20 and 40 mg/kg) did not change the PPI response or the acoustic startle response. However, pre-treatment with agmatine 20 mg/kg, but not agmatine 40 mg/kg, significantly attenuated a PCP (5 mg/kg)-induced disruption of the PPI response. These results emphasize the potential role of agmatine as a neuromodulator and potential target for novel treatments for brain disorders.
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| 10. |
- 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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| 11. |
- 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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| 12. |
- 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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| 13. |
- 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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| 14. |
- 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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| 15. |
- 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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| 16. |
- Wass, Caroline, 1976, et al.
(författare)
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The importance of nitric oxide in social dysfunction.
- 2009
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Ingår i: Behavioural brain research. - : Elsevier BV. - 1872-7549 .- 0166-4328. ; 200:1, s. 113-6
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Tidskriftsartikel (refereegranskat)abstract
- Schizophrenia is a chronic disorder generally considered to encompass positive symptoms, negative symptoms and cognitive deficits. Increasing attention has been paid to the social cognitive deficits of the disorder as these dysfunctions are particularly handicapping, predictive of functional outcome and show poor treatment response. Phencyclidine (PCP) is a psychotomimetic drug used to model the different aspects of schizophrenia in experimental animal models. PCP-induced cognitive deficits and hyperlocomotion may be blocked by pretreatment with nitric oxide (NO) synthase inhibitors in rodents. The present study was carried out to evaluate the acute effects of PCP and NO synthase inhibition on social interaction in male Sprague-Dawley rats. The NO synthase inhibitor, L-NAME (10mg/kg) and PCP (2mg/kg) was injected subcutaneously to rats, which were then tested in pairs for social interactive behaviour. Twenty-four hours after the initial test a drug-free social interaction test was carried out to assess the rats' memory of the previous social interaction. The results showed that PCP reduced the time of social interaction on Day 1 compared to controls, and that pretreatment with the NO synthase inhibitor, L-NAME, attenuated this reduction towards control levels. Neither locomotor activity, nor frequency of social interactions were affected by the PCP treatment, suggesting that the PCP-induced effects observed were not due to drug-induced stereotypies. In combination with increasing clinical evidence for the involvement of NO in the pathophysiology of schizophrenia, the present results indicate that NO synthase inhibition may be a potentially new treatment strategy for alleviating social dysfunction in schizophrenia.
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| 17. |
- Anckarsäter, Rolf, 1956, et al.
(författare)
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Non-neurological surgery and cerebrospinal fluid biomarkers for neuronal and astroglial integrity.
- 2014
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Ingår i: Journal of neural transmission (Vienna, Austria : 1996). - : Springer Science and Business Media LLC. - 1435-1463 .- 0300-9564. ; 121:6, s. 649-653
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Tidskriftsartikel (refereegranskat)abstract
- Non-neurological surgery has both acute and long-term effects on the brain. Markers for Alzheimer pathology may be used to study surgically induced neurological changes relevant for postoperative confusion, asthenia or cognitive decline. Inflammatory biomarkers, total tau (T-tau) and phosphorylated tau (P-tau) were recently shown to increase progressively in the cerebrospinal fluid (CSF) during surgery for nasal CSF leak, suggesting a neuroinflammatory response with signs of neuronal damage. We used a study group of 35 patients, undergoing knee arthroplasty with a spinal blockade and propofol sedation, to replicate this finding. Five CSF biomarkers were analyzed before, 3h after and on the morning after the interventions: T-tau and P-tau for cortical axonal integrity and tangle pathology, respectively, the 42 amino acids form of amyloid β (Aβ42) for plaque formation, neurofilament light (NFL) for the integrity of large-caliber myelinated axons and glial fibrillary acidic protein (GFAp) for astroglial cell integrity. CSF T-tau concentrations increased significantly during and after surgery (p=0.028) and were significantly correlated with the administered doses of bupivacaine. P-tau, Aβ42 and NFL remained unchanged, while the mean GFAp concentration increased with a large standard deviation. CSF T-tau and P-tau correlated significantly with the CSF/serum albumin ratios as an indicator of blood-brain barrier permeability. Findings from earlier studies showing a significant increase in biomarkers for Alzheimer's pathology during surgery were partly replicated, as neurochemical signs of impaired cortical axonal integrity during non-neurological surgery were detected. Bupivacaine may be involved in these reactions.
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| 18. |
- Bromander, Sara, et al.
(författare)
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Cerebrospinal fluid insulin during non-neurological surgery.
- 2010
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Ingår i: J Neural Transm (Vienna, Austria:1996). - : Springer Science and Business Media LLC. - 1435-1463 .- 0300-9564. ; 20, s. 328-329
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Tidskriftsartikel (refereegranskat)abstract
- Insulin plays an important metabolic and transmitter role in the central nervous system, but few studies have investigated the relationship between central and peripheral insulin concentrations. 35 patients undergoing knee surgery had cerebrospinal fluid (CSF) samples drawn before, 3 h after, and in the morning following surgery. Serum insulin concentrations increased after surgery and CSF insulin concentrations changed in the same direction with far smaller amplitude. These results indicate that the blood-brain barrier protects the brain from stress-induced peripheral hormonal fluctuations.
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| 19. |
- Bromander, Sara, et al.
(författare)
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Changes in serum and cerebrospinal fluid cytokines in response to non-neurological surgery: an observational study.
- 2012
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Ingår i: Journal of neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: Background: Surgery launches an inflammatory reaction in the body, as seen through increased peripheral levels of cytokines and cortisol. However, less is known about perioperative inflammatory changes in the central nervous system (CNS). Our aim was to compare inflammatory markers in serum and cerebrospinal fluid (CSF) before and after surgery and evaluate their association with measures of blood–brain barrier (BBB) integrity. Methods: Thirty-five patients undergoing knee arthroplastic surgery with spinal anesthesia had CSF and serum samples drawn before, after and on the morning following surgery. Cytokines and albumin in serum and CSF and cortisol in CSF were assessed at all three points. Results: Cytokines and cortisol were significantly increased in serum and CSF after surgery (Ps <0.01) and CSF increases were greater than in serum. Ten individuals had an increased cytokine response and significantly higher CSF/serum albumin ratios (Ps <0.01), five of whom had albumin ratios in the pathological range (>11.8). Serum and CSF levels of cytokines were unrelated, but there were strong correlations between CSF IL-2, IL-10 and IL-13, and albumin ratios (Ps <0.05) following surgery. Conclusion: Cytokine increases in the CNS were substantially greater than in serum, indicating that the CNS inflammatory system is activated during peripheral surgery and may be regulated separately from that in the peripheral body. CSF cytokine increase may indicate sensitivity to trauma and is linked to BBB macromolecular permeability.
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| 20. |
- Gustavson, Christina, et al.
(författare)
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Platelet Monoamine Oxidase B Activity Did Not Predict Destructive Personality Traits or Violent Recidivism: A Prospective Study in Male Forensic Psychiatric Examinees.
- 2010
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Ingår i: Neuropsychobiology. - : S. Karger AG. - 1423-0224 .- 0302-282X. ; 61:2, s. 87-96
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Tidskriftsartikel (refereegranskat)abstract
- Aims: This prospective study was designed to replicate previous findings of an association between the platelet monoamine oxidase B (MAO-B) activity and factors of relevance for criminal behaviour in a well-documented clinical study population. Methods: Subjects (n = 77, aged 17-76 years, median 30 years) were recruited among consecutive perpetrators of severe interpersonal violent and/or sexual crimes referred to forensic psychiatric investigation. Participants were extensively investigated by structured psychiatric, psychological and social workups, including state-of-the-art rating instruments and official records, and with laboratory tests including venous blood sampling for determination of MAO-B activity. A subset of 36 individuals had lumbar punctures to measure cerebrospinal fluid concentrations of monoamine neurotransmitter metabolites. Results: Platelet MAO-B activity did not show any significant correlation with assessments of childhood behavioural disorders, substance abuse, or psychosocial adversity, nor with any crime-related factors, such as scores on the Life History of Aggression Scale, the Psychopathy Checklist or recidivistic violent crime. No significant correlation was found between MAO-B and any of the monoamine metabolites. Analyses in subgroups of smokers/non-smokers did not change this overall result. Conclusions: The findings of the present study did not support the use of MAO-B as a biological marker for aggression-related personality traits or as a predictor for violent recidivism among violent offenders.
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| 21. |
- Nilsson, Thomas, 1954, et al.
(författare)
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Neurochemical measures co-vary with personality traits: Forensic psychiatric findings replicated in a general population sample
- 2010
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Ingår i: Psychiatry Research. - : Elsevier BV. - 1872-7123 .- 0165-1781. ; 178:3, s. 525-530
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Tidskriftsartikel (refereegranskat)abstract
- Neurobiological markers in cerebrospinal fluid (CSF) and in serum, previously found to co-vary with destructive personality traits in violent offenders, were explored in a general population sample of 21 patients undergoing knee surgery. Results on the Karolinska Scales of Personality (KSP) and the Temperament and Character Inventory (TCI) were compared with CSF/serum albumin ratios and serum concentrations of beta-trace protein (beta TP) (as markers for blood-brain barrier (BBB) permeability), to CSF/serum albumin ratios between the dopamine and serotonin metabolites homovanillic acid (HVA)/5-hydroxyindoleacetic acid (HIM) and to CSF and serum ratios between activated thyroid hormone (T3) and its precursor T4. Serum beta TP concentrations correlated with CSF/serum albumin ratios (P=0.018), but not with preoperative serum creatinine concentrations. Serum beta TP correlated significantly with Monotony Avoidance and Impulsiveness: CSF HVA/5-HIAA ratios with Irritability and low Cooperativeness. The beta TP is a potential serum marker for the integrity of the BBB that does not necessitate lumbar puncture. Thyroid hormones did not correlate with personality traits. As reported in forensic psychiatric patients, aggressive, unempathic personality traits were thus associated with increased dopaminergic activity in relation to the serotonergic activity and impulsivity to increased BBB permeability also in a general population group. (C) 2010 Elsevier Ireland Ltd. All rights reserved.
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| 22. |
- Struckmann, Wiebke, et al.
(författare)
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Unchanged cognitive performance and concurrent prefrontal blood oxygenation after accelerated intermittent theta-burst stimulation in depression : a sham-controlled study
- 2021
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Ingår i: Frontiers in Psychiatry. - : Frontiers Media S.A.. - 1664-0640. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Intermittent theta-burst stimulation (iTBS) delivered over the dorsomedial prefrontal cortex (DMPFC) has shown promise as a treatment for anhedonia and amotivation in patients with depression. Here, we investigated whether this protocol modulates cognitive performance and concurrent prefrontal blood oxygenation. We also examined whether depressed patients exhibit cognitive dysfunction and prefrontal hypoactivity at baseline compared to healthy controls.Methods: This sham-controlled study comprises 52 patients randomized to either active or sham accelerated iTBS over the DMPFC (applied twice daily) for 10 consecutive treatment days, and 55 healthy controls. Cognitive performance was assessed at baseline and once again 4 weeks later using a cognitive test battery targeting attention, inhibitory control, and numerical, verbal, and visual working memory. Concurrent prefrontal oxygenated hemoglobin (oxy-Hb) was captured with functional near-infrared spectroscopy.Results: Active iTBS over DMPFC did not affect cognitive performance or concurrent oxy-Hb change compared to sham iTBS in patients with depression. Compared to controls, patients at baseline showed impaired performance in the Trail Making Test,the Rey Auditory Verbal Learning Test, the Animal Naming Test, and the Digit Symbol Substitution Test, however no difference in prefrontal oxy-Hb was observed.Conclusion: Patients with treatment-resistant depression displayed cognitive deficits, however without prefrontal hypoactivity, compared to healthy controls at baseline. iTBS treatment did not alter cognitive performance, nor concurrent prefrontal blood oxygenation, in patients. Taken together, iTBS can likely be considered a cognitively safe treatment option in this sample of patients.
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| 23. |
- Svensson, Johan, 1964, et al.
(författare)
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Endocrine, liver-derived IGF-I is of importance for spatial learning and memory in old mice.
- 2006
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Ingår i: The Journal of endocrinology. - : Bioscientifica. - 0022-0795 .- 1479-6805. ; 189:3, s. 617-27
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Tidskriftsartikel (refereegranskat)abstract
- IGF-I is a neuroprotective hormone, and neurodegenerative disorders, including Alzheimer's disease, have been associated with decreased serum IGF-I concentration. In this study, IGF-I production was inactivated in the liver of adult mice (LI-IGF-I(-/-)), resulting in an approximately 80-85% reduction of circulating IGF-I concentrations. In young (6-month-old) mice there was no difference between the LI-IGF-I(-/-) and the control mice in spatial learning and memory as measured using the Morris water maze test. In old (aged 15 and 18 months) LI-IGF-I(-/-) mice, however, the acquisition of the spatial task was slower than in the controls. Furthermore, impaired spatial working as well as reference memory was observed in the old LI-IGF(-/-) mice. Histochemical analyses revealed an increase in dynorphin and enkephalin immunoreactivities but decreased mRNA levels in the hippocampus of old LI-IGF-I(-/-) mice. These mice also displayed astrocytosis and increased metabotropic glutamate receptor 7a-immunoreactivity. These neurochemical disturbances suggest synaptic dysfunction and early neurodegeneration in old LI-IGF-I(-/-) mice. The decline in serum IGF-I with increasing age may therefore be important for the age-related decline in memory function.
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| 24. |
- 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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| 25. |
- Wass, Caroline, 1976
(författare)
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Cognition and social behaviour in schizophrenia: An animal model investigating the potential role of nitric oxide
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cognitive deficits are the single strongest predictor of functional outcome in patients with schizophrenia. Furthermore, these deficits are not satisfactorily alleviated by available antipsychotic treatment. Functional outcome is also dependent upon social functioning and patients with schizophrenia display social dysfunctions including specific impairment in social cognition. Thus, cognitive deficits and social dysfunctions make up core symptoms of schizophrenia that needs to be further investigated in order to find novel treatment targets. Phencyclidine (PCP) is a psychotomimetic compound that produces symptoms in humans that closely resemble schizophrenia. Consequently, the PCP-model is consistently used for studying schizophrenia in experimental animals. Previous studies from our lab demonstrate that PCP-induced deficits in several translational animal models of schizophrenia can be blocked by inhibition of nitric oxide (NO) production. Such PCP-induced deficits range from impairment in pre-cognitive (pre-attentive) sensory information processing and habituation of acoustic startle to selective attention. In addition, several clinical studies indicate that the NO-signalling pathway may be involved in the pathophysiology of schizophrenia. The overall aim of this thesis was to investigate the effects of PCP and NO synthase (NOS) inhibition on higher order cognitive functions, i.e. memory, and social interaction. Therefore, we investigated the effects of PCP and the NOS-inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) on; (1) spatial learning, working memory, long-term memory, and cognitive flexibility using different versions of the Morris water maze, and (2) social function and memory using a social interaction paradigm. The results demonstrate that acute PCP-treatment impaired spatial learning, working memory, long-term memory, and cognitive flexibility in rats. These PCP-induce deficits were normalized by pretreatment with the NOS-inhibitor, L-NAME. Furthermore, PCP-treatment decreased time spent in social interaction, a deficit that was independent of motor activity and frequency of interactions. This social interaction deficit was blocked by NOS-inhibition. Taken together these results suggest that the effects of PCP, on cognitive functioning and social interaction, depend on the NO-signalling system. In addition, several studies from our research group show that systemic PCP-treatment in fact seems to increase NO production in the rodent brain. Based on these findings, in addition to the results from this thesis, we propose a ?NO-dysregulation hypothesis for schizophrenia?. Moreover, this hypothesis suggests that the NO-signalling pathway may be a potential new treatment target for schizophrenia.
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| 26. |
- 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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| 27. |
- Wintzell, Lisa, 1992, et al.
(författare)
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Upregulation of the Endogenous Peptide Antisecretory Factor Enhances Hippocampal Long-term Potentiation and Promotes Learning in Wistar Rats.
- 2022
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Ingår i: Neuroscience. - : Elsevier BV. - 0306-4522. ; 490, s. 120-130
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Tidskriftsartikel (refereegranskat)abstract
- Antisecretory Factor (AF) is an endogenous peptide known for its powerful antisecretory and anti-inflammatory properties. We have previously shown that AF also acts as a neuromodulator of GABAergic synaptic transmission in rat hippocampus in a way that results in disinhibition of CA1 pyramidal neurons. Disinhibition is expected to facilitate the induction of long-term potentiation (LTP), and LTP is known to play a crucial role in learning and memory acquisition. In the present study we investigated the effect of AF on LTP in CA3-CA1 synapses in rat hippocampus. In addition, endogenous AF plasma activity was upregulated by feeding the rats with specially processed cereals (SPC) and spatial learning and memory was studied in the Morris Water Maze (MWM). We found that LTP was significantly enhanced in the presence of AF, both when added exogenously in vitro as well as when upregulated endogenously by SPC-feeding. In the presence of the GABAA-receptor antagonist picrotoxin (PTX) there was however no significant enhancement of LTP. Moreover, rats fed with SPC demonstrated enhanced spatial learning and short-term memory, compared with control animals. These results show that the disinhibition of GABAergic transmission in the hippocampus by the endogenous peptide AF enhances LTP as well as spatial learning and memory.
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