Temporal changes of light-induced proteins in the SCN following treatment with the serotonin mixed agonist/antagonist BMY7378

Abstract

The 5-HT1A mixed agonist/antagonist BMY7378 has been shown to greatly potentiate photic phase advances in hamsters. The underlying mechanism and intracellular changes in the suprachiasmatic nucleus (SCN) by which this potentiation is accomplished have yet to be fully determined. Here, we examine the effect of BMY7378 on temporal activation patterns of a number of proteins and enzymes in the SCN following light exposure in the late subjective night. BMY7378 administration increased the amount of several photo-inducible proteins in the SCN at specific time points following light exposure in the late subjective night. Relative to animals given saline before a light pulse, the number of cells immunoreactive for cFos, JunB and PER1 was all significantly greater 360 min following the light pulse in BMY7378 pretreated animals, indicating an extended action of these light-induced proteins in the SCN following BMY7378 pretreatment. Aside from a modest, nonsignificant increase in P-ERK levels at 60 min, BMY7378 did not affect light-induced P-ERK levels. The levels of light-induced P-CREB were similarly unaffected by BMY7378. Also unaffected by BMY7378 treatment were cFos expression and JunB expression at 120 and 180 min following light exposure. These findings suggest that BMY7378 may potentiate photic phase shifts at least partly by prolonging the activity of some, but not all, light-induced proteins and biochemical pathways involved in coupling the light signal to the output of the circadian clock, particularly those which are active many hours after the light signal reaches the SCN.

Relationship between locomotor activity rhythm and corticosterone levels during HCC development, progression, and treatment in a mouse model

“…As readouts for a functional circadian system, rhythms in spontaneous locomotor activity and serum corticosterone levels were determined before and after therapeutic irradiation. In addition, p‐ERK immunohistochemistry was used as a marker for rhythmic SCN neuronal activity under light/dark conditions 28‐30 …”

Chronic BMY7378 treatment alters behavioral circadian rhythms

“…The 5‐HT 1A receptor mixed agonist/antagonist 8‐[2‐[4‐ (2‐Methoxyphenyl)‐1‐piperazinyl] ethyl]‐8‐azaspiro [4.5] decane‐7, 9‐dione dihydrochloride (BMY7378, Sigma Aldrich, Oakville, ON, USA) was dissolved in physiological saline and administered through osmotic mini pumps. Previously, we had examined the acute effects of this drug (Smith et al ., ,c) at a dose of 5 mg/kg. Here, we elected to use this same dose but spread over the full 24 h day (i.e., 5 mg/kg/day).…”

Serotonergic enhancement of circadian responses to light: role of the raphe and intergeniculate leaflet

“…The 5‐HT 1A receptor is required for this potentiation (Smith et al ., ). In the SCN, light‐induced expression of c‐Fos, JunB, and PER1 (Recio et al ., ; Smith et al ., , ) and phosphorylation of cAMP response element‐binding protein (Smith et al ., ) are altered by NAN‐190 or BMY7378 pre‐treatment. It has been suggested that systemic administration of these drugs might enhance circadian responses to light by decreasing 5‐HT release from the raphe, while simultaneously disinhibiting the retinal terminals in the SCN, leading to greater neurotransmitter release following a light pulse (Gannon, ).…”

“…These drugs bind to the 5-HT 1A receptor and are thought to act as agonists at raphe autoreceptors and as antagonists at post-synaptic receptors (Rydelek-Fitzgerald et al, 1990;Claustre et al, 1991;Gannon, 2003). When these drugs are given prior to a light pulse the resulting phase advances can be up to 250% greater than to light alone (Rea et al, 1995;Moriya et al, 1998;Takahashi et al, 2002;Gannon, 2003;Gannon & Millan, 2006;Sterniczuk et al, 2008;Smith et al, 2010Smith et al, , 2015b. Interestingly, both BMY7378 and have been shown to enhance photic shifts when administered even up to 6 h after a light pulse (Kessler et al, 2008;Lungwitz & Gannon, 2009).…”

“…The 5-HT 1A receptor is required for this potentiation (Smith et al, 2010). In the SCN, light-induced expression of c-Fos, JunB, and PER1 (Recio et al, 1996;Smith et al, 2010Smith et al, , 2015b and phosphorylation of cAMP response elementbinding protein (Smith et al, 2010) are altered by It has been suggested that systemic administration of these drugs might enhance circadian responses to light by decreasing 5-HT release from the raphe, while simultaneously disinhibiting the retinal terminals in the SCN, leading to greater neurotransmitter release following a light pulse (Gannon, 2003). Although this probably accounts for some of the effect, we have previously shown that systemic changes how the SCN responds to intra-SCN injections of agonists for neurotransmitters involved in photic signalling to and within the SCN .…”