Antipsychotic drugs regulate gene transcription in striatal neurons by blocking dopamine D 2 -like receptors. Little is known about the underlying changes in chromatin structure, including covalent modifications at histone N-terminal tails that are epigenetic regulators of gene expression. We show that treatment with D 2 -like antagonists rapidly induces the phosphorylation of histone H3 at serine 10 and the acetylation of H3-lysine 14 in bulk chromatin from striatum and in nuclei of striatal neurons. We find that, in vivo, D 2 -like antagonistinduced H3 phospho-acetylation is inhibited by the NMDA receptor antagonist MK-801 and by the protein kinase A (PKA) inhibitor Rp-adenosine 3c¢,5c¢-cyclic monophosphorothioate triethylammonium salt but increased by the PKA activator Sp-adenosine 3c¢,5c¢-cyclic monophosphorothioate triethylammonium salt. Furthermore, in dissociated striatal cultures which lack midbrain and cortical pre-synaptic inputs, H3 phospho-acetylation was induced by glutamate, L- Robertson et al. 1991;Nguyen et al. 1992;Deutch et al. 1996) followed by increased transcription of neuropeptides, second and third messenger molecules, receptors, ion channels and other neurotransmission-related molecules (Merchant and Dorsa 1993;Fox et al. 1994;Delfs et al. 1995;Fitzgerald et al. 1995;Laprade and Soghomonian 1995;Schoots et al. 1995;Doucet et al. 1996;Moratalla et al. 1996;Eastwood et al. 1997;Healy and Meador-Woodruff 1997;Mijnster et al. 1998; Atkins et al. Abbreviations used: cAMP-PKA, cAMP-dependent protein kinase A; Rp-cAMPs, Rp-Adenosine 3c¢,5c¢-cyclic monophosphorothioate triethylammonium salt; Sp-cAMPs, Sp-Adenosine 3c¢,5c¢-cyclic monophosphorothioate triethylammonium salt.

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Lithium (Li) is frequently used in the treatment of bipolar disorder (BPD), a debilitating condition that is increasingly diagnosed in children and adolescents. Because the symptoms of BPD in children are different from the typical symptoms in adulthood and have significant overlap with other childhood psychiatric disorders, this disorder is notoriously difficult to diagnose. This raises the possibility that some children not affected by BPD are treated with Li during key periods of brain development. The objective of this investigation was to examine the long-term effects of Li on the developing brain via a series of behavioral and molecular studies in rats. Rat pups were reared on Li chow for 3 weeks. Parallel groups were tested while on Li chow or 2 and 6 weeks after discontinuation of treatment. We found increased measures of anxiety-like behavior at all times tested. Gene microarray studies of the amygdala revealed that Li affected the expression of gene transcripts of the synapse and the cytoskeleton, suggesting that the treatment induced synaptic adjustments. Our study indicates that Li can alter the trajectory of brain development. Although the effects of Li on the normal brain seems unfavorable, effects on the abnormal brain cannot be determined from these studies alone and may well be therapeutic. Our results indicate that Li administration to the normal brain has the potential for lasting adverse effects.

Dopamine (DA) receptor-mediated signal transduction and gene expression play a central role in many brain disorders from schizophrenia to Parkinson's disease to addiction. While trying to evaluate the role of L-type Ca 2+ channels in dopamine D 1 receptor-mediated phosphorylation of the transcription factor cyclic AMP response element-binding protein (CREB), we found that activation of dopamine D 1 receptors alters the properties of L-type Ca 2+ channel inhibitors and turns them into facilitators of Ca 2+ influx. In D 1 receptor-stimulated neurons, L-type Ca 2+ channel blockers promote cytosolic Ca 2+ accumulation. This leads to the activation of a molecular signal transduction pathway and CREB phosphorylation. In the absence of dopamine receptor stimulation, L-type Ca 2+ channel blockers inhibit CREB phosphorylation. The effect of dopamine on L-type Ca 2+ channel blockers is dependent on protein kinase A (PKA), suggesting that protein phosphorylation plays a role in this phenomenon. Because of the adverse effect of activated dopamine receptors on L-type Ca 2+ channel blocker action, the role of L-type Ca 2+ channels in the dopamine D 1 receptor signal transduction pathway cannot be assessed with pharmacological tools. However, with antisense technology, we demonstrate that L-type Ca 2+ channels contribute to D 1 receptor-mediated CREB phosphorylation. We conclude that the D 1 receptor signal transduction pathway depends on L-type Ca 2+ channels to mediate CREB phosphorylation.