ABSTRACT
There is growing evidence implicating dysfunctional glutamatergic neurotransmission and abnormal interactions between the glutamate and dopamine (DA) systems in the pathophysiology of various neuropsychiatric disorders including schizophrenia. The present study evaluated knockout (KO) mice lacking the L-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) GluR1 receptor subunit for a range of behaviors considered relevant to certain symptoms of schizophrenia. KO showed locomotor hyperactivity during exposure to open field and in response to a novel object, but normal activity in a familiar home cage. Open field locomotor hyperactivity in KO was effectively normalized to WT levels by treatment with the DA antagonist and neuroleptic haloperidol, while locomotor stimulant effects of the NMDA receptor antagonist MK-801 were absent in KO. Social behaviors during a dyadic conspecific encounter were disorganized in KO. KO showed deficits in prepulse inhibition of the acoustic startle response. In vivo chronoamperometric measurement of extracellular DA clearance in striatum demonstrated retarded clearance in KO. These data demonstrate behavioral abnormalities potentially pertinent to schizophrenia in GluR1 KO, together with evidence of dysregulated DA function. Present findings provide novel insight into the potential role of GluR1, AMPA receptors and glutamate x DA interactions in the pathophysiology of schizophrenia and other neuropsychiatric conditions.
Subject(s)
Corpus Striatum/metabolism , Dopamine/metabolism , Receptors, AMPA/deficiency , Schizophrenia/genetics , Acclimatization , Animals , Crosses, Genetic , Disease Models, Animal , Female , Glutamic Acid/metabolism , Hyperkinesis/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Motor Activity/genetics , Receptors, AMPA/genetics , Social BehaviorABSTRACT
BACKGROUND: Perinatal hypoxia alters the concentration of many neurochemicals in the brain, including adenosine, and promotes central nervous system (CNS) disorders in human infants such as periventricular leukomalacia or encephalopathy. OBJECTIVE: Using the postnatal rat as a model of perinatal human development, we examined the effects of sustained increases in brain adenosine on CNS regions thought to be involved with both planning and execution of motor activity. METHODS: To simulate hypoxia-induced changes in adenosine, Sprague-Dawley rats were injected twice daily from postnatal day (P) 3 to P14, with the adenosine uptake inhibitor dipyridamole (DIP) or the A(1) adenosine receptor agonist N(6)-cyclopentyladenosine (CPA). Vehicle-injected animals served as controls. Immunohistochemical and morphological analyses were then performed to examine the expression of calbindin D-28k (CB) and the thickness of the external granule cell layer (eGL) in the cerebellum. Additionally tyrosine hydroxylase (TH) expression in the caudate putamen and ventricular size were also examined. RESULTS: In the cerebellum, both DIP and CPA reduced the number of CB-positive Purkinje cells as well as decreased the thickness of the eGL compared to vehicle. In the caudate putamen we found that DIP but not CPA decreased TH expression when compared to vehicle. Neither agent significantly altered ventricular size when compared to vehicle. CONCLUSIONS: These observations suggest that elevations in brain adenosine, which can occur following hypoxia, leads to both neurochemical and cellular changes in regions of the brain which control the planning and execution of motor activity. Thus, therapeutic strategies that target brain regions most sensitive to adenosine may prevent or control at least some of the CNS damage observed following perinatal hypoxia.
Subject(s)
Dipyridamole/pharmacology , Gene Expression Regulation/drug effects , S100 Calcium Binding Protein G/genetics , Tyrosine 3-Monooxygenase/genetics , Adenosine/analogs & derivatives , Adenosine/pharmacology , Animals , Animals, Newborn , Calbindin 1 , Calbindins , Female , Gene Expression Regulation, Enzymologic/drug effects , Pregnancy , Rats , Rats, Sprague-DawleyABSTRACT
BACKGROUND: Neuropathic pain is associated with significant co-morbidity, including anxiety and depression, which impact considerably on the overall patient experience. However, pain co-morbidity symptoms are rarely assessed in animal models of neuropathic pain. To improve the clinical validity of a widely used rodent model of traumatic peripheral neuropathy, we have investigated fear-avoidance- and depression-related behaviours in nerve-injured and sham-operated mice over a 4 week period. METHODS: Male C57BL/6J mice were subjected to partial sciatic nerve ligation (PSNL) or sham surgery and were assessed on days 7, 14, and 28 after operation. Withdrawal thresholds to punctate mechanical and cooling stimuli were measured. Mice were tested on the novel open-field and elevated plus-maze tests for fear-avoidance behaviour, and on the tail suspension test for depression-related behaviour. RESULTS: Hypersensitivity to punctate mechanical and cool stimuli was evident up to day 28 after PSNL. However, there was no change in fear-avoidance- or depression-related behaviours regardless of interval after-surgery. CONCLUSION: These data demonstrate that pain behaviour in nerve-injured C57BL/6J mice was not associated with alterations in emotion-related behaviours.
