Anatomical study of serotonergic innervation and 5-HT(1A) receptor in the human spinal cord.

Serotonergic innervation of the spinal cord in mammals has multiple roles in the control of motor, sensory and visceral functions. In rats, functional consequences of spinal cord injury at thoracic level can be improved by a substitutive transplantation of serotonin (5-HT) neurons or regeneration under the trophic influence of grafted stem cells. Translation to either pharmacological and/or cellular therapies in humans requires the mapping of the spinal cord 5-HT innervation and its receptors to determine their involvement in specific functions. Here, we have performed a preliminary mapping of serotonergic processes and serotonin-lA (5-HT(1A)) receptors in thoracic and lumbar segments of the human spinal cord. As in rodents and non-human primates, 5-HT profiles in human spinal cord are present in the ventral horn, surrounding motoneurons, and also contact their presumptive dendrites at lumbar level. 5-HT(1A) receptors are present in the same area, but are more densely expressed at lumbar level. 5-HT profiles are also present in the intermediolateral region, where 5-HT(1A) receptors are absent. Finally, we observed numerous serotonergic profiles in the superficial part (equivalent of Rexed lamina II) of the dorsal horn, which also displayed high levels of 5-HT(1A) receptors. These findings pave the way for local specific therapies involving cellular and/or pharmacological tools targeting the serotonergic system.

A randomized controlled trial of oral selegiline plus nicotine skin patch compared with placebo plus nicotine skin patch for smoking cessation.

OBJECTIVES: To compare the effect of oral selegiline plus nicotine patch with placebo plus nicotine patch on smoking cessation rates. DESIGN: Randomized double-blind placebo-controlled trial. SETTING: Three community-based clinics. PARTICIPANTS: One hundred and nine male and female smokers aged 18-55 years, who smoked at least 15 cigarettes/day. INTERVENTIONS: Oral selegiline, 2.5 mg, or placebo twice/day initiated 1 week before the quit day, followed by 5 mg oral selegiline or placebo twice daily for 26 weeks, plus active nicotine skin patch to all participants for the first 8 weeks only. Measures of continuous abstinence rates up to 52 weeks, withdrawal symptoms, blood pressure and adverse events incidence. FINDINGS: Twenty-five per cent (14 of 56) were continuously abstinent for 52 weeks in the selegiline plus nicotine group compared with 11% (6 of 53) in the placebo plus nicotine group (P = 0.08). Craving for cigarettes was lower in the selegiline plus nicotine group 4 weeks after quit day (P = 0.02). CONCLUSIONS: Adding selegiline to nicotine patch was associated with a doubling of the 52-week continuous abstinence rate, but this difference was not statistically significant. Selegiline significantly reduced craving for cigarettes and appeared to mitigate the need for nicotine replacement therapy. The results suggest that selegiline is a promising drug for future smoking cessation research.

Rosiglitazone (PPARgamma-agonist) attenuates atherogenesis with no effect on hyperglycaemia in a combined diabetes-atherosclerosis mouse model.

BACKGROUND: The administration of peroxisome proliferator-activated receptor gamma (PPARgamma) agonists to low-density lipoprotein (LDL)-receptor-deficient mice resulted in a reduction in the atherosclerotic lesion area in male mice, but not in female mice. The male mice also exhibited reduction in insulin resistance while the female mice did not. To further examine the relationship between PPARgamma agonists, insulin resistance and atherosclerosis, we used the model of accelerated atherosclerosis in male apolipoprotein E (apoE)-deficient mice rendered diabetic by low-dose streptozotocin (STZ). METHODS: Male, apoE-deficient mice (n = 48) were randomly divided into four groups. To induce diabetes, two groups received low-dose STZ and two groups served as controls. After diabetes induction, rosiglitazone (a PPARgamma agonist) was administered by oral gavage to one of the diabetic and one of the non-diabetic groups. RESULTS: Rosiglitazone reduced significantly the atherosclerotic aortic plaque area in both diabetic and non-diabetic apoE-deficient mice: 340 +/- 54 vs. 201 +/- 27 micromol2 (p = 0.001) in diabetic mice; 243 +/- 22 vs. 158 +/- 27 micromol2 (p = 0.001) in non-diabetic mice. Also, rosiglitazone reduced the correlation coefficient between plasma glucose and the degree of atherosclerosis (p < 0.0025) without affecting plasma glucose levels. The rosiglitazone-treated mice, both diabetic and non-diabetic, had higher lipid levels. CONCLUSIONS: Rosiglitazone-treated animals showed less atherosclerosis despite higher lipid levels and similar glucose levels. These data suggest a direct anti-atherogenic effect of rosiglitazone on the arterial wall.