Repeated electroconvulsive shock produces long-lasting increases in messenger RNA expression of corticotropin-releasing hormone and tyrosine hydroxylase in rat brain. Therapeutic implications.

Abstract

Electroconvulsive shock (ECS) is a highly effective therapy for the treatment of major depression, but its mechanisms of action are not known. We report that repeated ECS in rats produces enduring changes in two clinically relevant stress-responsive brain systems: (a) the hypothalamic-pituitary-adrenal axis regulated by corticotropin-releasing hormone (CRH) in the paraventricular nucleus; and (b) the NE system in the locus coeruleus regulated by tyrosine hydroxylase (TH). CRH and TH mRNA levels in these brain regions were assessed by in situ hybridization histochemistry. A single interaural ECS elevated TH but not CRH mRNA measured 24 h later. Repeated daily treatments (3, 7, or 14) elevated both mRNAs, maximally with 7, correlating with the time course of clinical efficacy. The elevations persisted for 3 (CRH) or 8 wk (TH) after the ECS. No other therapeutic treatment is known to produce such longlasting changes in central nervous system gene expression. The time course of events (delayed onset, long duration) implicate CRH as a principal mediator of the antidepressant effects of ECS. The locus coeruleus-NE system may be important in initiating the central nervous system response. (J. Clin. Invest. 1994.94:1263-1268

Neuronal activity regulates expression of tyrosine hydroxylase in adult mouse substantia nigra pars compacta neurons

“…1999, 2006); and from electroconvulsive shock in noradrenergic cells of the locus coeruleus (Kapur et al. 1993; Brady et al. 1994).…”

“…Indeed, SNc neurons would be exceptional amongst catecholaminergic cells if electrical activity did not feed into pathways regulating TH expression (Zigmond 1980;Dreyfus et al 1986;Stone et al 1991;Stachowiak et al 1994;Menezes et al 1996). Increases in translatable TH mRNA result from nicotinic receptor-mediated depolarization of chromaffin (Stachowiak et al 1986(Stachowiak et al , 1988Fossom et al 1991a,b;Craviso et al 1992), superior cervical ganglion (Stachowiak et al 1988) and PC12 cells (Kilbourne and Sabban 1990;Gueorguiev et al 1999Gueorguiev et al , 2006; and from electroconvulsive shock in noradrenergic cells of the locus coeruleus (Kapur et al 1993;Brady et al 1994). Camouflage behaviour in tadpoles depends on recruitment and loss of DAergic (TH+) neurons in the ventral suprachiasmatic nucleus, regulated by retinal afferents relaying information about the level of ambient light (Dulcis and Spitzer 2008).…”

Electroconvulsive Treatment: Hypotheses about Mechanisms of Action

“…The increases are abrupt and appear to normalize to baseline levels within 1 h post-treatment in the human studies (61, 62). More invasive rodent studies indicate a longer lasting increase in ACTH, with sustained elevated levels at least 24 h post-treatment (63). The increased ACTH and cortisol levels are more pronounced with high as compared to low intensity stimulation, particularly with the degree to which stimulus intensity exceeds the individual seizure threshold (61).…”

Stress, norepinephrine and depression

“…Several studies have reported that long-term treatment with a variety of antidepressants attenuates stress-induced changes in TH by 40%-70%. [18][19][20][21] Others have also found a decrease in levels of tetrahydrobiopterin, a natural cofactor for TH, in depressed patients. [22][23][24][25] This evidence seems to indicate that adaptive changes in TH and the onset of action of various antidepressants are linked.…”