Linda Naes

Preferential stimulation of ventral tegmental area dopaminergic neurons by nicotine

The effect of intravenous (i.v.) nicotine on the single unit activity of midbrain dopamine (DA) neurons was studied in rats under either local or general anesthesia. Nicotine (50-500 micrograms/kg) produced a dose-related increase in the firing rate of nigral pars compacta DA cells (A9), up to 25% above baseline, irrespective of the preparation. The same range of doses was more than three times as effective on ventral tegmental area DA cells (A10) in rats paralyzed and given a local anesthetic. By contrast, the majority of these cells were temporarily depressed in deeply anesthetized animals. All of the above effects were reversed and prevented by i.v. mecamylamine suggesting the involvement of nicotine cholinergic receptors. Moreover, after nicotine-induced stimulation, low doses of i.v. apomorphine inhibited the firing rate similar to controls indicating that dopamine receptors are not directly involved in the nicotinic action. The results suggest that acute nicotine shares with other drugs of abuse the characteristic of being more effective in stimulating A10 than A9 neurons.

Inhibition of periarterial nerve stimulation-induced vasodilation of the mesenteric arterial bed by CGRP (8-37) and CGRP receptor desensitization.

We provide the first functional evidence that calcitonin gene-related peptide (8-37) induces a direct vasoconstriction and reversibly antagonizes vasodilation of the mesenteric arterial bed induced by calcitonin gene-related peptide (CGRP) suggesting that CGRP (8-37) is a competitive antagonist of vascular CGRP receptors. Vasodilation induced by periarterial nerve stimulation was inhibited both by CGRP (8-37) and by desensitization of CGRP receptors. These results further support the evidence that the periarterial nerve stimulation-induced nonadrenergic noncholinergic vasodilation of the mesenteric vasculature is mediated by endogenous CGRP and its receptors.

Prejunctional and postjunctional effects of neuropeptide Y at the noradrenergic neuroeffector junction of the perfused mesenteric arterial bed of the rat

Summary: The effect of neuropeptide Y (NPY) on periarterial nerve stimulation-induced release of norepinephrine (NE) and increase in perfusion pressure in the perfused mesenteric arterial bed of the rat was examined. Perfusate effluents were continuously collected and assayed for endogenous NE by high-pressure liquid chromatography (HPLC) coupled to electrochemical detection. Perfusion pressure was continuously monitored by means of a pressure transducer. Periarterial nerve stimulation (8 or 16 Hz, 60 V, 2-ms duration for 30 s) resulted in a readily detectable increase in NE release and perfusion pressure that was attenuated by the prior administration of tetrodotoxin (TTX) (10−5 M) or guanethidine (5 × 10−5 M). NPY exerted both prejunctional and post-junctional effects on noradrenergic neurotransmission in this preparation. The peptide produced a concentration-dependent reduction in the release of NE over a concentration range of 10−10-10−7 M. A similar inhibition effect occurred at 8. 10. and 16 Hz. In contrast, low concentrations (10−10 and 10−9 M) decreased the effect of nerve stimulation on perfusion pressure, whereas higher concentrations (10−7 M) produced a marked potentiation. The α2-adrenoceptor antagonist, yohimbine, did not alter the inhibitory effect of NPY on evoked NE release or the effect on perfusion pressure. Prazosin similarly did not alter the inhibitory effect of NPY on NE release but prevented the increase in perfusion pressure. We conclude that NPY modulates noradrenergic neurotransmission in the mesenteric arterial bed by decreasing the evoked release of NE and producing a concentration-dependent bi-phasic response on vascular smooth muscle. The inhibition of NE produced by low concentrations of NPY results in a decrease in perfusion pressure whereas high concentrations produce a marked increase in perfusion pressure.

Direct evidence for the role of neuropeptide Y in sympathetic nerve stimulation-induced vasoconstriction

Neuropeptide Y (NPY) is a vasoconstrictor peptide and a cotransmitter with norepinephrine (NE) in sympathetic nerve terminals and is thought to be involved in sympathetic nerve stimulation (SNS)-induced vasoconstriction. Using BIBP-3226, a Y1 receptor selective antagonist, we examined this hypothesis in the isolated and perfused mesenteric vascular bed. SNS produced a frequency-dependent increase in perfusion pressure and concomitant overflow of NPY immunoreactivity in the perfusate. [Leu31,Pro34]NPY potentiated NE-induced and ATP-induced vasoconstriction, indicating the presence and biological action of Y1 receptors in this vascular bed. The potentiation effect of [Leu31,Pro34]NPY of the increase in perfusion pressure by NE, ATP, or SNS was prevented by BIBP-3226. In addition, SNS-induced vasoconstriction at both high and low frequencies was significantly attenuated by BIBP-3226 at a concentration that completely blocked the [Leu31,Pro34]NPY-induced potentiation of the NE- or ATP-induced vasoconstrictor effect. These results suggest that approximately 30% of vasoconstriction produced by SNS depends on NPY in the mesenteric vascular bed.Neuropeptide Y (NPY) is a vasoconstrictor peptide and a cotransmitter with norepinephrine (NE) in sympathetic nerve terminals and is thought to be involved in sympathetic nerve stimulation (SNS)-induced vasoconstriction. Using BIBP-3226, a Y1 receptor selective antagonist, we examined this hypothesis in the isolated and perfused mesenteric vascular bed. SNS produced a frequency-dependent increase in perfusion pressure and concomitant overflow of NPY immunoreactivity in the perfusate. [Leu31,Pro34]NPY potentiated NE-induced and ATP-induced vasoconstriction, indicating the presence and biological action of Y1 receptors in this vascular bed. The potentiation effect of [Leu31,Pro34]NPY of the increase in perfusion pressure by NE, ATP, or SNS was prevented by BIBP-3226. In addition, SNS-induced vasoconstriction at both high and low frequencies was significantly attenuated by BIBP-3226 at a concentration that completely blocked the [Leu31,Pro34]NPY-induced potentiation of the NE- or ATP-induced vasoconstrictor effect. These results suggest that ∼30% of vasoconstriction produced by SNS depends on NPY in the mesenteric vascular bed.

Role of Neuropeptide Y in Cold Stress-Induced Hypertension

Chronic cold stress (4 degrees C) produced a sustained increase in mean arterial pressure in both normotensive and borderline hypertensive rats (BHR). The high blood pressure in BHRs was significantly reversed by a neuropeptide Y (NPY) Y1 receptor antagonist suggesting that NPY is involved in mediating stress-induced hypertension. Corresponding increases in adrenal NPY messenger RNA and NPY immunoreactivity were found during the stress; furthermore, chronic cold stress also potentiated the pressor response of rats to a subsequent acute stress test in which NPY has been shown to play a role. These results suggest that chronic cold stress-induced hypertension is mediated by elevated NPY release and vascular tone as a result of increased NPY gene expression and storage.

Chapter 17 Regulation by nicotine of midbrain dopamine neurons

Publisher Summary This chapter discusses the regulation of midbrain dopamine neurons by nicotine. The chapter summarizes the results of recent studies where two approaches are used to study the action of nicotine on midbrain dopamine neurons. The first was a neurochemical approach where the effect of nicotine on the release of dopamine in vitro using isolated slices and in vivo utilizing push-pull perfusion of rat striatum in freely moving unanesthetized rats is examined. The second approach is electrophysiological where the firing rates of dopamine and nondopamine cells is measured in the substantia nigra and ventral tegmental area of Tsai following systemic injection of nicotine following injection of the alkaloid into the terminal regions of these dopamine neurons, namely the caudate nucleus and nucleus accumbens. There is growing evidence that the so-called nigro-striato-nigral loop consists not only of the striatonigral projection and dopaminergic neurons which project back to the striatum, but also involves the nondopaminergic pars reticulata (SNR) neurons which have been demonstrated to influence other brainstem and thalamic nuclei with a tonic inhibition.

The effect of opioid drugs on the release of dopamine and 5-hydroxytryptamine from rat striatum following activation of nicotinic-cholinergic receptors

The effect of (Met5)enkephalin, (D-Ala2,D-Met5)enkephalin, (Leu5)enkephalin, (D-Ala2,D-Met5)enkephalin and morphine on the release of [3H]dopamine, endogenous dopamine and [3H]5-hydroxytryptamine produced by the nicotinic-cholinergic agonist, dimethylphenyl piperazinium iodide (DMPP), was examined in rat striatal slices. The DMPP-induced release of [3H]dopamine and endogenous dopamine was reduced by the presence of (Met5)enkephalin, (D-Ala2,D-Met5)enkephalin (1-10 microM) or morphine (10 microM) but not by (Leu5)enkephalin or (D-Ala2,D-Leu5)enkephalin. The DMPP-induced release of [3H]5-hydroxytryptamine was reduced by (Leu5)enkephalin, (D-Ala2,D-Leu5)enkephalin, (Met5)enkephalin, (D-Ala2,D-Leu5)enkephalin (1-10 microM), and morphine (10 microM). All three opioids failed to alter the release of [3H]dopamine induced by field stimulation or potassium depolarization (30 microM). The inhibitory effects of opioid peptides and morphine demonstrated in the present study appear to be due to an initial interaction with nicotinic-cholinergic receptors in the striatum.

Elevated Neuropeptide Y Gene Expression and Release During Hypoglycemic Stress

Our previous studies show that neuropeptide Y (NPY) is involved in mediating sympathetic nerve stimulation-induced vasoconstriction. Insulin hypoglycemia is known to produce increased sympathetic output and elevated arterial pressure. The present study examined the role of NPY in the hypertensive response to insulin by examining the effects of insulin on NPY gene expression, tissue content and release. Subcutaneous injection of insulin produced an immediate increase in plasma NPY immunoreactivity (NPYir) and delayed increases in adrenal and neuronal NPY mRNA and adrenal NPYir in rats. These results suggest that NPY may play a role in insulin-induced hypertension.

Influence of cold stress on neuropeptide Y and sympathetic neurotransmission

Chronic cold stress of rats (4 degrees C; 1-3 weeks) induced a marked increase in gene expression (adrenal medulla; superior cervical ganglia), tissue content (mesenteric arterial bed) and nerve stimulation-induced overflow of NPY-immunoreactivity (NPYir) from the perfused mesenteric arterial bed. In contrast increased NPY neurotransmission was offset by an apparent decrease in the evoked overflow of norepinephrine (NE) due to a presumed deactivation of NE by nitric oxide (NO), despite increased sympathetic nerve activity. The net effect of these offsetting system was no change in basal or the evoked increase in perfusion pressure (sympathetic tone). It is concluded that differences in NPY and NE transmission act as an important compensatory mechanism preventing dramatic changes in arterial pressure when sympathetic nerve activity is high during cold stress.

Presynaptic Peptide Receptors and Hypertension

Vascular smooth muscle is subject to control from a variety of neuronal, hormonal, and autacoidal influences. Among the various chemical mediators that exert important actions on the cardiovascular system are a variety of vasoactive peptides stored and released from perivascular nerves or from components of blood vessels such as smooth muscle and endothelium. Two peptides of great interest include neuropeptide Y (NPY) which has been shown to be colocalized and coreleased with norepinephrine from noradrenergic nerves’,’ and calcitonin gene-related peptide (CGRP) located in a variety of sensory and perivascular nerves.’.‘‘ The purpose of this paper is to summarize recent studies on the preand postjunctional actions of NPY and CGRP at the vascular neuroeffector junction of normotensive and the spontaneously hypertensive rat (SHR). The perfuscd mesenteric arterial bed of the rat has bccn utilized as a model of the vascular neuroeKector junction.