Recent Investigations on the Mechanism of Action of
Nomifensine

Schacht, Ulrich; Leven, M.; Hj, Gerhards; Hunt, Peter; Jp, Raynaud

doi:10.1159/000468599

Cited by 24 publications

(14 citation statements)

References 27 publications

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“…Recovery efficiency for NE was 6.5 ± 0.6% ( n = 5). On the morning of self‐administration day 12, 1–2 h before the onset of the self‐administration session, a probe was inserted through PVN guide cannula and perfused at 2 μL/min with a solution of artificial CSF (140 mM NaCl, 2.5 mM KCl, 1.2 mM MgCl 2 , 1.4 mM CaCl 2 , 5 mM glucose, pH 7.2–7.4) containing 5 μM nomifensine (NE reuptake blocker) (Schacht et al. 1982).…”

Section: Methodsmentioning

confidence: 99%

Nicotine self‐administration diminishes stress‐induced norepinephrine secretion but augments adrenergic‐responsiveness in the hypothalamic paraventricular nucleus and enhances adrenocorticotropic hormone and corticosterone release

Sharp

2010

Journal of Neurochemistry

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J. Neurochem. (2010) 112, 1327–1337. Abstract Chronic nicotine self‐administration augments the thalamo‐pituitary‐adrenal (HPA) responses to stress. Altered neuropeptide expression within corticotropin‐releasing factor (CRF) neurons in the hypothalamic paraventricular nucleus (PVN) contributes to this enhanced HPA response to stress. Herein, we determined the role of norepinephrine, a primary regulator of CRF neurons, in the responses to footshock during nicotine self‐administration. On day 12–15 of self‐administration, microdialysis showed nicotine reduced PVN norepinephrine release by footshock (< 50% of saline). Yet, the reduction in footshock‐induced adrenocorticotropic hormone and corticosterone secretion because of intra‐PVN prazosin (α1 adrenergic antagonist) was significantly greater in rats self‐administering nicotine (2‐fold) than saline. Additionally, PVN phenylephrine (α1 agonist) stimulated adrenocorticotropic hormone and corticosterone release to a similar extent in unstressed rats self‐administering nicotine or saline. Nicotine self‐administration also decreased footshock‐induced c‐Fos expression in the nucleus of the solitary tract‐A2/C2 catecholaminergic neurons that project to the PVN. Therefore, footshock‐induced nucleus of the solitary tract activation and PVN norepinephrine input are both attenuated by nicotine self‐administration, yet PVN CRF neurons are more responsive to α1 stimulation, but only during stress. This plasticity in noradrenergic regulation of PVN CRF neurons provides a new mechanism contributing to the HPA sensitization to stress by nicotine self‐administration and smoking.

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Section: Methodsmentioning

confidence: 99%

Nicotine self‐administration diminishes stress‐induced norepinephrine secretion but augments adrenergic‐responsiveness in the hypothalamic paraventricular nucleus and enhances adrenocorticotropic hormone and corticosterone release

Sharp

2010

Journal of Neurochemistry

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“…To test this prediction experimentally, extracellular dopamine was quantified with voltammetric microelectrodes that provide micrometer‐scale spatial resolution. Extracellular dopamine was measured during electrical stimulation of the medial forebrain bundle (MFB) before and after the administration of drugs that decrease the rate of dopamine uptake (nomifensine) (Schact et al, 1982; Wightman et al, 1988), increase the rate of evoked dopamine release [L‐3,4‐dihydroxyphenylalanine (L‐DOPA)] (Wightman et al, 1988; Snyder and Zigmond, 1990; Koshimura et al, 1992; Pothos et al, 1996), and decrease the rate of evoked dopamine release [α‐methyl‐ p ‐tyrosine (α‐MPT)] (Kuhr et al, 1986; Stamford et al, 1988). For comparison, stimulation responses were also recorded with voltammetric electrodes 400 μm in length, which provide spatially averaged rather than spatially discrete information.…”

mentioning

confidence: 99%

Changes in the Kinetics of Dopamine Release and Uptake Have Differential Effects on the Spatial Distribution of Extracellular Dopamine Concentration in Rat Striatum

Peters

Michael

2000

Journal of Neurochemistry

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Abstract:The objective of this study was to examine whether the limited diffusion distance of dopamine in rat striatum produces spatial heterogeneity in the extracellular dopamine concentration on a dimensional scale of a few micrometers. Such heterogeneity would be significant because it would imply that the concentration of dopamine at a given receptor depends on the receptor's ultrastructural location. Spatially resolved measurements of extracellular dopamine were performed in the striatum of chloral hydrate-anesthetized rats with carbon fiber microdisk electrodes. Dopamine was monitored during electrical stimulation of the nigrostriatal pathway before and after administration of drugs that selectively affect the kinetics of evoked dopamine release and dopamine uptake. The effects of nomifensine (20 mg/kg), L-DOPA (250 mg/kg), and ␣-methyl-p-tyrosine (250 mg/kg) on the amplitude of the stimulation responses were examined. The outcome of these experiments was compared with predictions derived from a mathematical model that combines diffusion with the kinetics of release and uptake. The results demonstrate that the extracellular dopamine concentration is spatially heterogeneous on a micrometer scale and that changing the kinetics of dopamine release and uptake has different effects on this spatial distribution. The impact of these results on brain neurochemistry is considered. Key Words: Dopamine -Heterogeneity-Electrical stimulation-In vivo voltammetry-Microelectrodes-Striatum.

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“…On the day of the experiment, the probe was perfused with a solution of Kreb's Ringer Buffer (147 mm NaCl, 4.0 mm KCl, and 3.4 mm CaCl 2 in polished water; 0.2 m filter sterilized and degassed) containing 5 m nomifensine (NE uptaker blocker) (32). The recovery rate of individual probes was determined by in vitro dialysis in a solution containing 200 pg NE/16 l for 40 min at 22 C; triplicate 20-min samples were obtained, and the average recovery rate was 8.4% Ϯ 0.9 (n ϭ 30).…”

Section: In Vivo Microdialysismentioning

confidence: 99%

Adrenocorticotropin Response and Nicotine-Induced Norepinephrine Secretion in the Rat Paraventricular Nucleus Are Mediated through Brainstem Receptors*

Matta

Valentine

et al. 1997

Endocrinology

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Nicotine is a potent stimulus for the secretion of ACTH, and norepinephrinergic neurons originating in the brainstem are involved. Prior reports using in vivo microdialysis in alert rats have shown that nicotine, administered i.p. or into the fourth ventricle, stimulated the release of norepinephrine (NE) into the hypothalamic paraventricular nucleus (PVN), the site of neurons containing CRH. In the present studies, rats received an i.v. infusion of nicotine into the jugular vein on alternate days during their active (dark) phase; therefore, direct correlations between the levels of NE microdialyzed from the PVN and plasma ACTH could be made in each animal. Nicotine administered i.v. (0.045-0.135 mg/kg) elicited dose-dependent increases in both NE and ACTH (P < 0.01). A significant correlation was found between nicotine-stimulated NE release in the PVN and ACTH secretion (r = 0.91, P < 0.01). To address whether the site(s) of action of nicotine was on presynaptic receptors on NE terminals in the PVN or on receptors on neurons in brainstem regions accessible from the fourth ventricle, the nicotinic cholinergic antagonist, mecamylamine (0.1-4.8 microg), was microinjected directly into the PVN or into the fourth ventricle before nicotine infusion. Fourth-ventricular administration of mecamylamine (1.6 microg) or higher, before i.v. nicotine (0.09 mg/kg), completely blocked both NE release in the PVN (IC50 = 0.64 microg) and ACTH secretion (IC50 = 0.40 microg) (P < 0.01, compared with vehicle before nicotine), whereas it was ineffective when injected directly into the PVN. The results demonstrate that the nicotinic cholinergic receptors in the brainstem, rather than presynaptic receptors within the PVN itself, mediate nicotine-stimulated PVN NE release and ACTH secretion.

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Recent Investigations on the Mechanism of Action of Nomifensine

Cited by 24 publications

References 27 publications

Nicotine self‐administration diminishes stress‐induced norepinephrine secretion but augments adrenergic‐responsiveness in the hypothalamic paraventricular nucleus and enhances adrenocorticotropic hormone and corticosterone release

Nicotine self‐administration diminishes stress‐induced norepinephrine secretion but augments adrenergic‐responsiveness in the hypothalamic paraventricular nucleus and enhances adrenocorticotropic hormone and corticosterone release

Changes in the Kinetics of Dopamine Release and Uptake Have Differential Effects on the Spatial Distribution of Extracellular Dopamine Concentration in Rat Striatum

Adrenocorticotropin Response and Nicotine-Induced Norepinephrine Secretion in the Rat Paraventricular Nucleus Are Mediated through Brainstem Receptors*

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