Antagonism of the nicotine-induced changes of the striatal dopamine metabolism in mice by mecamylamine and pempidine

Summary The ability of nicotinic receptor blockers, mecamylamine and pempidine, to antagonize the changes in striatal dopamine (DA) metabolism induced by repeated nicotine administration was studied. The contents of DA and its metabolites 3-methoxytyramine (3-MT), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured. Mice kept at 20–22°C were given nicotine, 3 mg/kg, s.c., four times, at 30 min intervals, and sacrificed 20 min after the last dose. Hexamethonium, 10 mg/kg, i.p., was administered at 30 min before the first nicotine dose in order to prevent the peripheral effects of nicotine. Mecamylamine, 0.6 or 10 mg/kg, i.p., and pempidine, 0.6 or 20 mg/kg, i.p., were given at 60 min before sacrifice.Mecamylamine and pempidine decreased clearly the striatal 3-MT content, which suggests that the nigrostriatal dopaminergic neurons are physiologically controlled by a stimulatory nicotinic mechanism. The repeatedly administered nicotine caused deep hypothermia, and increased the striatal DOPAC content but decreased the 3-MT and HVA contents. The small dose of mecamylamine, which was the only dose found to effectively antagonize the nicotine-induced hypothermia, antagonized the decrease of HVA content. The large but not the small doses of mecamylamine and pempidine antagonized the nicotine-induced increase of DOPAC content but none of the doses studied antagonized the decrease of 3-MT content. Thus it seems that nicotine decreases the 3-MT content by a mechanism distinct from the mechanism mediating the increase of the DOPAC content. The decreased 3-MT content most probably results from desensitization of nicotinic cholinergic receptors (nAChR) and following decrease of cholinergic regulation of nigrostriatal dopaminergic neurons. The changed conformation of nAChR explains the inability of mecamylamine and pempidine to antagonize the nicotine-induced decrease of 3-MT content.This research was supported by the Research Council for Medicine of the Academy of Finland Send offprint requests to H. Haikala at the above address     

Different changes in striatal dopamine metabolism induced by nicotine in mice kept at different ambient temperatures

Summary Further information about the nicotine-induced changes in striatal dopamine metabolism in hypothemic mice was searched by measuring the contents of dopamine and its metabolites (3,4-dihydroxyphenylacetic acid, DOPAC; 3-methoxytyramine, 3-MT; and homovanillic acid, HVA) after blocking the synthesis of dopamine by-methyl-p-tyrosine (-MT). This method gave a possibility to study the effect of nicotine on the metabolism of dopamine in two pools (the cytoplasmic newly-synthesized dopamine and the granular dopamine). 3 mg/kg of (–)nicotine was given s.c. four times, at 110, 80, 50 and 20 min, and-MT (250 mg/kg i.p.) at 60 min before sacrifice. To prevent the peripheral effects of nicotine all mice were given hexamethonium (10 mg/kg i.p.) at 140 min before sacrifice. Hexamethonium did not alter striatal dopamine metabolism. Experiments were performed at 20–22°C at which temperature nicotine induced hypothermia or at 32–34°C.The-MT-induced proportional decrease of 3-MT content was clearly less than that of dopamine content. On the contrary the-MT treatment decreased the DOPAC content proportionally more than the dopamine content. Thus DOPAC could not be solely formed from the same dopamine pool as 3-MT. These results indicate that 3-MT reflects best the metabolism of the granular dopamine and DOPAC that of the newly-synthesized dopamine.In hypothermic mice nicotine administration reduced the-MT-induced depletion of the dopamine content. Nicotine also decreased the 3-MT content and this effect was not altered by-MT. These results indicate that nicotine prevents the metabolism and release of the granular dopamine. The nicotine-induced decrease of the HVA content did not occur in-MT treated mice, which suggests that nicotine also diminished the release of the newly-synthesized dopamine.In mice kept at 32–34°C nicotine tended to enhance the-MT-induced depletion of the dopamine content and nicotine alone did not decrease the 3-MT content. Thus in these mice nicotine tended to increase the release of the granular dopamine. The nicotine-induced increases of HVA and DOPAC contents in these mice were reduced by-MT, which indicates that nicotine increased also the metabolism and probably the release of the newly-synthesized dopamine.     

Impairment of left atrial mechanics does not contribute to the reduction in stroke volume after active ascent to 4559 m

Hypoxia challenges left ventricular (LV) function due to reduced energy supply. Conflicting results exist whether high‐altitude exposure impairs LV diastolic function and thus contributes to the high altitude‐induced increase in systolic pulmonary artery pressure (sPAP) and reduction in stroke volume (SV). This study aimed to assess LV diastolic function, LV end‐diastolic pressure (LVEDP), and LA mechanics using comprehensive echocardiographic imaging in healthy volunteers at 4559 m. Fifty subjects performed rapid (<20 hours) and active ascent from 1130 m to 4559 m (high). All participants underwent echocardiography during baseline examination at 424 m (low) as well as 7, 20 and 44 hours after arrival at high altitude. Heart rate (HR), sPAP, and comprehensive volumetric‐ and Doppler‐ as well as speckle tracking‐derived LA strain parameters were obtained to assess LV diastolic function, LA mechanics, and LVEDP in a multiparametric approach. Data for final analyses were available in 46 subjects. HR (low: 64 ± 11 vs high: 79 ± 14 beats/min, P < 0.001) and sPAP (low: 24.4 ± 3.8 vs high: 38.5 ± 8.2 mm Hg, P < 0.001) increased following ascent and remained elevated at high altitude. Stroke volume (low: 64.5 ± 15.0 vs high: 58.1 ± 16.4 mL, P < 0.001) and EDV decreased following ascent and remained decreased at high altitude due to decreased LV passive filling volume, whereas LA mechanics were preserved. There was no case of LV diastolic dysfunction or increased LVEDP estimates. In summary, this study shows that rapid and active ascent of healthy individuals to 4559 m impairs passive filling and SV of the LV. These alterations were not related to changes in LV and LA mechanics.     

Nicotine antagonizes the effects of reserpine on the striatal metabolism of dopamine, 5-hydroxytryptamine and noradrenaline in hypothermic but not in normothermic mice

Summary Our previous studies indicate that repeated nicotine administration inhibits the release of striatal dopamine in hypothermic mice. To study if similar inhibition occurs in noradrenergic and serotoninergic neurons mice were given (–)-nicotine (3 mg/kg, s.c.) repeatedly at 110, 80, 50, and 20 min before sacrifice. The interactions of nicotine with reserpine were also investigated. Reserpine (5 mg/kg, i.p.) was administered after the second nicotine dose at 60 min before sacrifice. To prevent the effects of nicotine on autonomic ganglia all mice were given hexamethonium (10 mg/kg, i.p.). Experiments were carried out at 20–22°C at which ambient temperature nicotine induced deep hypothermia or at 32–34°C to prevent the drug-induced hypothermia. The changes in striatal metabolism of dopamine, noradrenaline and 5-hydroxytryptamine (5-HT) weNicotine had temperature dependent effects on the dopamine metabolism which indicates a block of dopaminergic neurons as suggested in our earlier studies. Reserpine per se increased the homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) contents and decreased the 3-methoxytyramine (3-MT) and dopamine contents at both ambient temperatures. In hypothermic but not in normothermic, nicotine-treated mice reserpine's effect on dopamine metabolism was almost totally vanished. Nicotine and reserpine per se increased the 3-methoxy-4-hydroxyphenylethylglycol (MOPEG) content and decreased the noradrenaline content at both ambient temperatures. In hypothermic but not in normothermic mice nicotine antagonized the reserpine-induced decrease of noradrenaline content. Nicotine tended to decrease the 5-hydroxy-indoleacetic acid (5-HIAA) content in hypothermic mice but increased it in normothermic ones. Reserpine decreased the 5-HT content and increased the 5-HIAA content at both ambient temperatures. In hypothermic but not in normothermic, nicotine-treated mice the reserpine-induced effects on 5-HT metabolism were clearly reduced. These results indicate that in hypothermic mice repeatedly administered nicotine blocks the release of striatal dopamine and 5-HT and perhaps also noradrenaline. The nicotine-induced antagonism of the effects of reserpine is temperature-dependent as the nicotine-induced blockade of the neurons and thus the main mechanism behind both of these phenomena could be the sustained depolarization of the monoaminergic neurons. Send offprint requests to H. Haikala at the above address     

Depression and Associated Factors in Coronary Heart Disease

Objective - To investigate whether depression was associated with cardiac status and socio-demographic factors in patients with coronary heart disease (CHD). Methods - The sample consisted of 144 symptomatic patients with CHD. For screening depression the Beck Depression Inventory was administered on the day before elective coronary angiography. Results - Twenty-four per cent of patients had probable depressive disorder, but none of them had been previously identified as suffering from depression, or been treated for depression. Alexithymia and dissatisfaction with life were common in depressed patients. Logistic regression analysis showed that neither the cardiac status nor sociodemographic factors were associated with depression. Conclusion - Depression is a common finding and should be looked for independently of other risk factors in patients with CHD.     

Depression is associated with the long-term outcome of lumbar spinal stenosis surgery: a 10-year follow-up study

Background Context

Depression is associated with greater postoperative disability in patients with lumbar spinal stenosis (LSS). No previous studies have reported the association in a 10-year follow-up.