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

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Virdee, Kanwar 
Kentrop, Jiska 
Jupp, Bianca 
Venus, Bethany 
Hensman, Daniel 

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.

Dopamine, Dopamine receptors, Memory, Prefrontal cortex, Schizophrenia, 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine, Animals, Basal Forebrain, Behavior, Animal, Biogenic Monoamines, Brain, Corpus Striatum, Dexamethasone, Dopamine, Dopamine Agonists, Dopaminergic Neurons, Female, Glucocorticoids, Gyrus Cinguli, Locomotion, Male, Maze Learning, Memory, Short-Term, Neostriatum, Patch-Clamp Techniques, Prefrontal Cortex, Pregnancy, Prenatal Exposure Delayed Effects, Rats, Receptors, Dopamine D1, Spatial Memory, Synaptic Transmission
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Psychopharmacology (Berl)
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Springer Science and Business Media LLC
Medical Research Council (MR/J012084/1)
Medical Research Council (G1000183)
Wellcome Trust (093875/Z/10/Z)
Medical Research Council (G0701500)
Medical Research Council (G0001354)
The authors’ research is funded by the Wellcome Trust (grant number 086871/Z/08/Z), the MRC (G0701500), a joint award from the MRC (G1000183) and Wellcome Trust (093875/Z/10/ Z) in support of the Behavioral and Clinical Neuroscience Institute at Cambridge University, and an MRC strategic award to the Imperial College-Cambridge University-Manchester University (ICCAM) addiction cluster (G1000018).