Changes in Tyrosine Hydroxylase mRNA Expression in the Rat Locus Coeruleus Following Acute or Chronic Treatment with Valproic Acid

Abstract

Valproate has proven effective in treating bipolar disorder. Though some biochemical effects of valproate are rapid, mood-stabilizing effects can take weeks, suggesting that regulatory changes in gene expression in brain neurotransmitter systems may be involved. Given a presumed role for norepinephrine (NE) in bipolar disorder, as well as the actions of mood-stabilizing drugs, we examined changes in mRNA expression for tyrosine hydroxylase (TH), the NE transporter (NET) andIt has long been hypothesized that dysregulation of central norepinephrine (NE) neuronal systems might be involved in the expression if not the development of major affective disorders, including depression and mania (Schatzberg and Schildkraut 1995;Schildkraut 1965). The noradrenergic neurons of the locus coeruleus (LC), situated in the dorsal pons, project widely throughout the central nervous system, representing the source of noradrenergic terminals innervating many forebrain and limbic regions such as the amygdala, hippocampus, hypothalamus and neocortex (Moore and Bloom 1979). As such, these neurons are ideally poised to exert global modulatory or state-related changes in brain activity. Central NE, and the LC in particular, is hypothesized to play an important role in attention, arousal and behavioral activation (Aston-Jones et al. 1991;Charney et al. 1990;Foote et al. 1983;Puumala et al. 1997;Siegel and Rogawski 1988), all of which may be severely disrupted in mood disorders, especially those involving a manic component such as bipolar affective disorder. Thus, the noradrenergic neurons of the LC may represent potential targets for mood stabilizing drug treat- Effective therapeutic agents have been developed for the treatment of bipolar disorder. Lithium has been the primary treatment for bipolar disorder, although its side effects are many and often severe, and its mechanism of action is still relatively unknown (Bowden et al. 1994). Recently, certain classes of antiepileptic agents, including valproic acid (VPA), have proven to be as effective as lithium in the treatment of mania and bipolar disorder, and possess a more benign adverse effect profile and a broader therapeutic margin of safety (Bowden et al. 1994;Loscher 1993). The mechanism of action of VPA for the treatment of affective disorders is largely unknown. By contrast, the mechanisms by which it acts as an antiepileptic have been more extensively examined. The biochemical effects of VPA occur rapidly, and include the inhibition of GABA transaminase (and thus inhibition of GABA catabolism) and a decrease in sodium channel activity (Van den Berg et al. 1993). Similarly, the antiepileptic effects of VPA are observed quickly, whereas the antimanic effects of VPA require a much longer course of treatment, as long as 2-3 weeks (Bowden et al. 1994). Because of this, the mechanisms of action underlying the antimanic action of VPA may be distinct from those underlying its antiepileptic effects. Thus, it would be informative to investigate the induction of long-term regulatory, react...

The Effect of Perinatal Hypoxic/Ischemic Injury on Tyrosine Hydroxylase Expression in the Locus Coeruleus of the Human Neonate

“…The combination of a longer postnatal survival time with the administration of anticonvulsants might have positive effects on the recovery of TH expression in the LC. Antiepileptic drugs can modify gene expression, including TH [62] and neurotrophic/neuroprotective proteins, via the regulation of specific transcriptional factors and/or through epigenetic modifications [63,64,65,66,67,68,69]. The antiepileptic drugs carisbamate and lamotrigine increase the levels of brain-derived neurotrophic factor (BDNF) in the frontal cortex and hippocampus, and subchronic lamotrigine treatment restores the stress-induced downregulation of BDNF expression in these brain areas [70,71].…”

Valproic Acid–Induced Gene Expression through Production of Reactive Oxygen Species

“…In fact, the findings by Takai et al (50) that its antiproliferative activity in HEC-1B endometrial cancer cells, as well as its antitumor activity in nude mice, which occurs without any major side effects, prompted the authors to suggest that VPA may become a useful adjuvant therapy for endometrial cancers. In addition to its antiproliferative effects, VPA has also been shown to induce the expression of a variety of genes in various cell types (10)(11)(12). Although the mechanism of this effect has been elusive, it seems to involve the interaction of AP-1 transcription factors at AP-1 response elements (17,18) and/or Sp1 transcription factor interaction at Sp1-binding sites (11), depending on the gene promoter.…”

“…1-3). VPA induces histone acetylation (4-7), DNA demethylation (8), chromatin decondensation (9), and the expression of a variety of genes (10)(11)(12). It has antiproliferative effect on cells, and is known to induce differentiation of cell lines derived from myeloid leukemia (4,7), teratocarcinoma, glioma, and neuroblastoma (13).…”

Regulatory Effects of Reboxetine Treatment Alone, or Following Paroxetine Treatment, on Brain Noradrenergic and Serotonergic Systems

“…In situ hybridization was conducted as described previously (Sands et al, 2000a). The 275 nt TH probe was transcribed from cDNA templates provided by Dr Stanley Watson (University of Michigan), with addition of a-35 S-UTP (New England Nuclear) to a specific activity of 2 Â 10 9 cpm/mg.…”