Rationale Glucocorticoid hormones facilitate sensitization to repeated administration of psychostimulants, an effect that is mediated by glucocorticoid receptors (GRs). It is still unclear, however... Show moreRationale Glucocorticoid hormones facilitate sensitization to repeated administration of psychostimulants, an effect that is mediated by glucocorticoid receptors (GRs). It is still unclear, however, at which stage of psychomotor sensitization are stress and GR-mediated effects involved.Objectives In the present study, we have tested the hypothesis that GR-mediated effects during the phase of repeated amphetamine injections play a crucial role in the long-term expression of sensitization. For this purpose, we used DBA/2 mice, an inbred strain commonly used for the study of stress effects on psychostimulant sensitization.Methods Animals were treated with the GR antagonist mifepristone (200 mg/kg) at 2.5 h before each daily injection of amphetamine (2.5 mg/kg) or saline in a 5-day protocol. The amphetamine or saline injections were given in the home or a novel context. This was followed by a 2.5-week withdrawal period, without any drug delivery. Following the withdrawal period, two low-dose amphetamine challenges (1.25 mg/kg) were given subsequently, without additional mifepristone.Results The animals receiving amphetamine in the novel context showed a higher expression of sensitization at challenge as compared to those in the home condition. Mifepristone treatment influenced locomotor response to repeated amphetamine injections, but this effect during the initial phase did not affect the expression of sensitization after a withdrawal period.Conclusion Our results indicate that GR-related processes during the initial phase of sensitization are involved in, but not crucial for, the development of long-term sensitization. Show less
Schizophrenia is heritable, but even in monozygotic twins differences in susceptibly exists. What is causing this difference in genetically identical individuals? The objective of this thesis was... Show moreSchizophrenia is heritable, but even in monozygotic twins differences in susceptibly exists. What is causing this difference in genetically identical individuals? The objective of this thesis was to identify novel susceptibility genes and pathways for psychosis in a psychostimulant mouse model which is considered a model for psychosis. Genome-wide analysis of transcripts in the hippocampal CA1, driving mesocortical dopaminergic activity, which has a prominent role in schizophrenia, revealed differential expression of target genes of Myocyte Enhancer Factor 2 (MEF2) and Glucocorticoid Receptor (GR). This suggest that this gene network is involved in sensitivity to amphetamine. In primary hippocampal neurons, knockdown of MEF2 reduced the expression of c-Jun and abolished its regulation by GR. Moreover, activation of MEF2 by neuronal depolarization was attenuated by glucocorticoids, suggesting a mutual feedback regulation of these transcription factors. Finally, in vivo MEF2 and GR appeared to be active in the induction phase of amphetamine sensitization. Overall, the findings suggest that in the hippocampus activation of GR can modulate the role of MEF2 target genes in induction of behavioral sensitization. This finding points to the hippocampus as an exciting target for further studies on the role of MEF2 and GR in the precipitation of psychosis susceptibility. Show less
