ABSTRACT
Tryptophan depletion techniques are effective in reducing central serotonergic function and have been used to investigate its role in mood and cognition. In the present study a tryptophan-free diet was fed to Lister-hooded male rats chronically for 21 days to investigate the effect of lowering central serotonin concentration on cognition using the novel object-recognition paradigm. Chronically tryptophan-depleted rats had impaired object-recognition memory; this was accompanied by a reduction in central serotonin of 40-50% in the hippocampus, frontal cortex and striatum. In a subsequent experiment, the atypical antipsychotic, risperidone (0.2 mg/kg), but not the typical antipsychotic, haloperidol (0.1 mg/kg), administered i.p. 30 min prior to the retention test, significantly attenuated the chronic tryptophan depletion impairment. These data show that chronic lowering of central serotonin is associated with impaired cognitive performance, and that this can be reversed by the atypical antipsychotic, risperidone.
Subject(s)
Memory Disorders/metabolism , Recognition, Psychology/drug effects , Risperidone/pharmacology , Serotonin Antagonists/pharmacology , Tryptophan/deficiency , Animals , Brain/metabolism , Brain/pathology , Chromatography/methods , Diet , Disease Models, Animal , Hydroxyindoleacetic Acid/metabolism , Male , Memory Disorders/etiology , Memory Disorders/pathology , Motor Activity/drug effects , Rats , Serotonin/metabolism , Tryptophan/bloodABSTRACT
Residues 61-95 of the non-amyloid component (NAC(61-95)) domain of alpha-synuclein are responsible for the aggregation and neurotoxicity of this protein. This study evaluated the effect of N((omega))-nitro-l-arginine methyl ester (l-NAME), a nitric oxide synthase inhibitor, on the behavior of rats bilaterally injected into the CA3 area of the dorsal hippocampus with aggregated NAC(61-95). Twenty-four male Sprague-Dawley rats were trained to respond under an alternating-lever cyclic-ratio (ALCR) operant schedule. When responding was stable, 12 rats were injected bilaterally into the CA3 area of the hippocampus with aggregated NAC(61-95) (5muicro per side; concentration 10(-4)M), the remaining 12 rats were similarly injected with sterile water (SW), six of the NAC(61-95) injected rats and six of the SW injected rats were treated for 90 days post-injections with 0.05mg/ml l-NAME in drinking water available ad libitum. Treatment with l-NAME alleviated NAC(61-95)-induced behavioral deficits, indicated through the measurement of lever switching errors and incorrect lever perseverations under the ALCR schedule, and reduced the number of activated astrocytes proximal to the injection sites.
Subject(s)
CA3 Region, Hippocampal/drug effects , Conditioning, Operant/drug effects , NG-Nitroarginine Methyl Ester/pharmacology , Peptide Fragments/pharmacology , alpha-Synuclein/pharmacology , Analysis of Variance , Animals , Astrocytes/drug effects , Enzyme Inhibitors/pharmacology , Immunohistochemistry , Male , Rats , Rats, Sprague-DawleyABSTRACT
Pre-aggregated non-amyloid component of alpha-synuclein, NAC(61-95), was injected bilaterally into the CA3 area of rat hippocampus and behaviour was assessed using an alternating-lever cyclic-ratio (ALCR) schedule of operant responding. Four groups of rats were used (n=6 per group), subgroups were treated orally with either ibuprofen (40mg/kg) or vehicle (10% sucrose) twice daily. Intrahippocampal injection of NAC(61-95) increased lever switching errors and numbers of activated astrocytes, and ibuprofen treatment alleviated these effects.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , CA3 Region, Hippocampal/drug effects , Ibuprofen/therapeutic use , Mental Disorders/chemically induced , Mental Disorders/drug therapy , Peptide Fragments , alpha-Synuclein , Animals , Behavior, Animal/drug effects , CA3 Region, Hippocampal/pathology , Conditioning, Operant/drug effects , Ibuprofen/pharmacology , Male , Rats , Rats, Sprague-Dawley , Reinforcement ScheduleABSTRACT
A sub-chronic administration of phencyclidine to the rat brings about enduring pathophysiological and cognitive changes that resemble some features of schizophrenia. The present study aimed to determine whether the behavioural consequence of this phencyclidine regime extends to a long-term disruption of social interaction that might provide a parallel with some negative symptoms of the disease. Rats were treated with phencyclidine (2mg/kg bi-daily for 1 week) or vehicle followed by a drug-free period. Social interaction was assessed 24h, 1 week, 3 weeks and 6 weeks post-treatment. A long-lasting disturbance of social behaviour was observed in the phencyclidine group, namely more contact and non-contact interaction with an unfamiliar target rat at all time points. Six weeks post-phencyclidine, analysis of brains showed a reduction in expression of parvalbumin immunoreactive neurons in the hippocampus with significant reductions localised to the CA1 and dentate gyrus regions. These results show that sub-chronic phencyclidine produces long-lasting disruptions in social interaction that, however, do not model the social withdrawal seen in patients with schizophrenia. These disturbances of social behaviour may be associated with concurrent pathophysiological brain changes.
Subject(s)
Behavior, Animal/drug effects , Hallucinogens/administration & dosage , Interpersonal Relations , Phencyclidine/administration & dosage , Schizophrenia/physiopathology , Analysis of Variance , Animals , Disease Models, Animal , Hippocampus/metabolism , Male , Motor Activity/drug effects , Parvalbumins/metabolism , Rats , Schizophrenia/chemically induced , Schizophrenia/pathology , Time FactorsABSTRACT
Dietary induced acute tryptophan depletion (ATD) is used to reduce central serotonergic function and to investigate the role of serotonin (5-HT) in psychiatric illness. In healthy volunteers ATD produces working memory deficits and decreases mood in some studies. Brain-derived neurotrophic factor (BDNF) plays a role in both cognition and in the regulation of mood; however, the possible contribution of central BDNF changes to the effects of ATD has not been examined. Therefore, using a rat model we have examined the effect of amino acid mixture-induced ATD on plasma and central BDNF protein levels. ATD significantly reduced free-plasma TRP by 79% and central hippocampal 5-HT by 35% when compared to controls. However, plasma or central BDNF protein levels in the hippocampus and midbrain were not significantly altered by ATD. These results suggest that changes in central BDNF do not contribute to the cognitive or mood effects of ATD.