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 D 1 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 D 1 agonist SKF38393 (0.3–3 mg/kg) by systemic injection. In separate groups of control and AGT animals, D 1 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. D 1 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 D 1 receptors in corticostriatal circuitry down-regulate in response to AGT. This compensatory effect in D 1 receptors may result from increased DA-ergic tone in AGT rats and underlie the resilience of these animals to the disruptive effects of D 1 receptor activation on spatial working memory.