Basal levels of monoamines and DHEA in four main limbic brain regions were measured in prepubertal Wistar Kyoto (WKY) rats (a putative animal model of childhood depression). Basal levels of “Brain-Derived Neurotrophic Factor (BDNF)” were also determined in two regions in the hippocampus, compared with Wistar strain controls. In the second phase, we examined the responsiveness of prepubertal WKY rats to different types of chronic antidepressant treatments: Fluoxetine, Desipramine, and dehydroepiandrosterone sulfate (DHEAS). WKY prepubertal rats exhibited different monoamine levels in the limbic system, reduced DHEA levels in the VTA and lower levels of BDNF in the hippocampus CA3 region compared to controls. In prepubertal WKY rats, only treatment with DHEAS produced a statistically significant decrease in immobility, compared to saline-administered controls in the forced swim test. Wistar controls were not affected by any antidepressant. The results imply that DHEA(S) and BDNF may be involved in the pathophysiology and pharmacotherapy of childhood depression.

O. Malkesman

T. Asaf

L. Shbiro

A. Goldstein

R. Maayan

A. Weizman

N. Kinor

E. Okun

B. Sredni

G. Yadid

A. Weller

Monoamines, BDNF, Dehydroepiandrosterone, DHEA-Sulfate, and Childhood Depression—An Animal Model Study

Ethanol-induced folate deficiency is due to effects of ethanol on folate metabolism and absorption. We have already shown by using different methods that ethanol interferes with reabsorption of folate from the proximal tubule. In this study, we have used the folate analogue, the fluorescein methotrexate (FL-MTX), in order to evaluate effects of ethanol on FL-MTX uptake by the human proximal tubular (HPT) cells by using a confocal microscope and fluoroskan microplate reader. Since endothelins (ETs) play a major role in a number of diseases and also in the damage induced by a variety of chemicals, we have used endothelin-B (ET-B) and protein kinase-C (PKC) inhibitors to evaluate the role of endothelin in ethanol-mediated FL-MTX uptake by using fluoroskan microplate reader. Confocal microscope and fluoroskan studies reveal that cellular absorption of FL-MTX is concentration-dependent. Moreover, ethanol concentration has an impact on FL-MTX uptake. Fluoroskan studies reveal that the ethanol-induced decrease in FL-MTX uptake is reversed by adding the ET-B receptor antagonist (RES-701-1) or PKC-selective inhibitor (BIM). Thus, we can conclude that ethanol may act via ET and ET in turn may act via ET-B receptor and the PKC signaling pathway to impair FL-MTX transport.

Sivakumar JT Gowder

Kenneth E. McMartin

Methods to Evaluate the Effect of Ethanol on the Folate Analogue: Fluorescein Methotrexate Uptake in Human Proximal Tubular Cells

In the in vivo experiments on anaesthetized sheep, it was presently examined whether
muscarinic receptor antagonists with diverse selectivity affect the release of VIP in response to electrical stimulation of the parasympathetic chorda tympanic nerve differently, and if the changes in the release could be associated to altered secretory and vasodilator responses. The location of the muscarinic receptor subtypes was examined also. In the experiments, blood
was collected out of the submandibular venous drainage before and during electrical stimulation of chorda tympani nerve in the absence and presence either of pirenzepine or methoctramine. While metchoctramine increased the output of protein, pirenzepine inhibited flow of saliva and increased protein output, vasodilatation, and VIP output. In morphological examinations, the inhibitory muscarinic M4 receptor occurred interacinarily in the gland. It is concluded that prejunctional muscarinic receptors, most likely of the M4 subtype, exert inhibitory modulation of the parasympathetic release of VIP in the ovine submandibular gland.

Anders T. Ryberg

Ondrej Soukup

Gunnar Tobin

Characterization of Prejunctional Muscarinic Receptors: Effects on the Release of VIP and Functional Responses and Receptor Expression in the Ovine Submandibular Gland

We hypothesized that agonist-induced contraction correlates with the phospho-cofilin/cofilin (P-CF/CF) ratio in
pulmonary artery (PA) rings and cultured smooth muscle cells (PASMCs). PA rings were used for isometric contractions and along with PASMCs for assay of P-CF/CF by isoelectric focusing and immunoblotting. The P-CF/CF measured 22.5&#x25; in PA and differentiated PASMCs, but only 14.8&#x25; in undifferentiated PASMCs. With comparable contraction responses in PA, endothelin-1 (100&#x2009;nM) and norepinephrine (1&#x2009;<svg     style="vertical-align:-3.56265pt;width:9.5625px;" id="M1" height="12.175" version="1.1" viewBox="0 0 9.5625 12.175" width="9.5625"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,7.675)"><path id="x1D707" d="M538 96q-38 -45 -84 -76.5t-71 -31.5q-44 0 -15 117q12 49 18 89h-2q-99 -128 -163 -178q-36 -28 -70 -28q-26 0 -44 38h-2q-16 -69 -16 -129q0 -43 11 -75.5t24 -42.5l1 -6q-7 -12 -24.5 -23t-37.5 -11q-40 0 -40 76q0 52 35 202l94 407l78 24l5 -5q-32 -122 -72 -310&#xA;q-7 -33 0 -55t25 -22q36 0 105.5 75t107.5 145l32 146l75 26h10q-50 -197 -78 -347q-7 -38 6 -38q7 0 31 17t47 39z" /></g>

		
	
</svg>M) induced a 2-fold increase of P-CF/CF, while angiotensin II (1&#x2009;<svg     style="vertical-align:-3.56265pt;width:9.5625px;" id="M2" height="12.175" version="1.1" viewBox="0 0 9.5625 12.175" width="9.5625"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,7.675)"><use xlink:href="#x1D707"/></g>

		
	
</svg>M) induced none. All agonists activated Rho-kinase and LIMK2, and activation was eliminated by inhibition of Rho-kinase. Microcystin LF (20&#x2009;nM) potentiated the angiotensin II, but not the 5-hydroxytryptamine (1&#x2009;<svg     style="vertical-align:-3.56265pt;width:9.5625px;" id="M3" height="12.175" version="1.1" viewBox="0 0 9.5625 12.175" width="9.5625"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,7.675)"><use xlink:href="#x1D707"/></g>

		
	
</svg>M)-mediated increase of P-CF/CF. In conclusion, all tested agonists activate the Rho-kinase-LIMK pathway and increase P-CF/CF. Angiotensin II activates PP2A and counteracts the LIMK-mediated CF phosphorylation. CF phosphorylation stabilizes peripheral actin structures and may contribute to the maximal contraction of PA.

Yan-Ping Dai

Shaner Bongalon

Violeta N. Mutafova-Yambolieva

Ilia A. Yamboliev

Distinct Effects of Contraction Agonists on the Phosphorylation State of Cofilin in Pulmonary Artery Smooth Muscle

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Advances in Pharmacological and Pharmaceutical Sciences publishes original research articles and review articles in all areas of experimental and clinical pharmacology, pharmaceutics, medicinal chemistry and drug delivery.

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Advances in Pharmacological and Pharmaceutical Sciences

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Advances in Pharmacological and Pharmaceutical Sciences