Counteractive effects of antenatal glucocorticoid treatment on D1 receptor modulation of spatial working memory

RATIONALE: Antenatal exposure to the glucocorticoid dexamethasone dramatically increases the number of mesencephalic dopaminergic neurons in rat offspring. However, the consequences of this expansion in midbrain dopamine (DA) neurons for behavioural processes in adulthood are poorly understood, including working memory that depends on DA transmission in the prefrontal cortex (PFC). OBJECTIVES: We therefore investigated the influence of antenatal glucocorticoid treatment (AGT) on the modulation of spatial working memory by a D1 receptor agonist and on D1 receptor binding and DA content in the PFC and striatum. METHODS: Pregnant rats received AGT on gestational days 16-19 by adding dexamethasone to their drinking water. Male offspring reared to adulthood were trained on a delayed alternation spatial working memory task and administered the partial D1 agonist SKF38393 (0.3-3 mg/kg) by systemic injection. In separate groups of control and AGT animals, D1 receptor binding and DA content were measured post-mortem in the PFC and striatum. RESULTS: SKF38393 impaired spatial working memory performance in control rats but had no effect in AGT rats. D1 binding was significantly reduced in the anterior cingulate cortex, prelimbic cortex, dorsal striatum and ventral pallidum of AGT rats compared with control animals. However, AGT had no significant effect on brain monoamine levels. CONCLUSIONS: These findings demonstrate that D1 receptors in corticostriatal circuitry down-regulate in response to AGT. This compensatory effect in D1 receptors may result from increased DA-ergic tone in AGT rats and underlie the resilience of these animals to the disruptive effects of D1 receptor activation on spatial working memory

Spatial discrimination deficits by excitotoxic lesions in the MORRIS WATER ESCAPE TASK

The effects of the cholinesterase inhibitors (ChEI) metrifonate and donepezil were assessed on spatial performance of rats with bilateral lesions of the entorhinal cortex (EC), which is thought to model early changes in the brains of patients suffering from Alzheimer's disease. In the present study, we found that spatial discrimination deficits in rats, induced by bilateral ibotenic acid (IBO) lesions of the EC region can partially be antagonised by treatment with the cholinesterase inhibitors metrifonate (30 mg kg-1) and donepezil (0.3 and 3 mg kg-1). Performance was improved in the spatial discrimination task compared with that of the EC-lesioned control group. It is concluded that the rat with bilateral EC lesions is a suitable deficit model for the assessment of effects of putative Alzheimer therapeutic

Effects of acute and repeated administration of a cholinesterase inhibitor on timing behaviour

It has been hypothesised that a leftward shift in the response distribution obtained in the peak interval (PI) procedure is a characteristic of cognitive enhancement in which mental processes are speeded. Metrifonate, a cholinesterase inhibitor with reported cognitive enhancing properties in many animal models of learning and memory, was tested in the PI procedure. Acute administration of 3 and 60 mg/kg but not 1 and 30 mg/kg in fully trained rats shifted the response distribution to the right, whereas subchronic administration of 10, 30 or 50 mg/kg during task acquisition had no effect on timing behaviour. On the basis of the present data, it can be concluded that the effects of a cognition enhancer in the PI procedure cannot be predicted from the scalar expectancy theory (SET). Furthermore, SET does not appear to be an appropriate tool for analysing the acquisition of timing behaviour. (C) 2003 Elsevier B.V/ECNP. All rights reserved