Effects of JL 3, a putative antidepressant, on rat noradrenergic and serotonergic systems

Using in vivo electrophysiological procedures, we confirm the inhibitory ef fect of 10-(4-methylpiperazin-1-yl)pyrido[4,3-b][1,4]benzothiazepine (JL 3) , on dorsal raphe serotonergic (IC50 = 14 mu M) and noradrenergic neurons ( IC50 = 4.5 mu M). The effect on dorsal raphe neurons was reduced by N-[2-[4 -(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-cyclohexanecarboxamid e (WAY-100635), suggesting the importance of 5-HT1A receptor stimulation. Y ohimbine, and ritanserin, to a lesser extent, blocked the inhibitory effect of JL 3 on locus coeruleus neurons indicating that alpha(2)-adrenoceptors and 5-HT2A receptors may be implicated in the effects. Because of its negli gible alpha(2)-adrenoceptor affinity, the effect of JL 3 on locus coeruleus neurons, would have to be indirect. JL, 3 may interfere with the norepinep hrine transporter site (IC50 = 0.34 mu M). JL 3 tended to reinforce the hyp ertensive effect of norepinephrine, while it strongly inhibited the hyperte nsive effect of tyramine, further indicating an interaction at the norepine phrine transporter site level. (C) 1999 Elsevier Science B.V. All rights re served.