Nicotinic receptors

Regulation of normal or abnormal behaviour is critically controlled by the central serotonergic systems. Recent evidence has suggested that serotonin (5-HT) neurotransmission dysfunction contributes to a variety of pathological conditions, including depression, anxiety, schizophrenia and Parkinson’s disorders. There is also a great amount of evidence indicating that 5-HT signalling may affect the reinforcing properties of drugs of abuse by the interaction and modulation of dopamine (DA) function. This chapter is focused on one of the more addictive drugs, nicotine. It is widely recognised that the effects of nicotine are strongly associated with the stimulatory action it exhibits on mesolimbic DAergic function. We outline the role of 5-HT and its plethora of receptors, focusing on 5-HT2 subtypes with relation to their involvement in the neurobiology of nicotine addiction. We also explore the novel pharmacological approaches using 5-HT agents for the treatment of nicotine dependence. Compelling evidence shows that 5-HT2C receptor agonists may be possible therapeutic targets for smoking cessation, although further investigation is required.peer-reviewe

Metabolic modulation of sympathetic vasoconstriction in human skeletal muscle: role of tissue hypoxia

Sympathetically evoked vasoconstriction is modulated by skeletal muscle contraction, but the underlying events are incompletely understood. During contraction, intramuscular oxygenation decreases with increasing exercise intensity. We therefore hypothesized that tissue hypoxia plays a crucial role in the attenuation of sympathetic vasoconstriction in contracting skeletal muscle.In 19 subjects, near-infrared spectroscopy was used to measure decreases in muscle oxygenation (ΔtHbO2+MbO2) as an estimate of the vasoconstrictor response to reflex sympathetic activation with lower body negative pressure (LBNP) in the microcirculation of resting and contracting forearm muscles. Oxygen delivery to the muscles was reduced by decreasing (a) arterial O2 content by breathing 10 % O2, or (b) muscle perfusion by applying forearm positive pressure (FPP, +40 mmHg).In resting forearm, reflex sympathetic activation decreased muscle oxygenation by 11 ± 1 %. Handgrip alone at 5 and 20 % of maximal voluntary contraction (MVC) decreased muscle oxygenation by 4 ± 1 and 28 ± 4 %, respectively. When superimposed on handgrip, LBNP-induced decreases in muscle oxygenation were preserved during handgrip at 5 % MVC, but were abolished during handgrip at 20 % MVC. Oral administration of aspirin (1 g) did not restore the latter response.When the decrease in forearm muscle oxygenation elicited by handgrip at 20 % MVC was mimicked by either (a) systemic hypoxia plus 5 % handgrip (ΔtHbO2+MbO2, −32 ± 3 %), or (b) hypoperfusion of resting muscle by FPP (ΔtHbO2+MbO2, −26 ± 6 %), LBNP-induced decreases in muscle oxygenation were greatly attenuated.These data suggest that local tissue hypoxia is involved in the metabolic attenuation of sympathetic vasoconstriction in the microcirculation of exercising human skeletal muscle. The specific underlying mechanism remains to be determined, although products of the cyclo-oxygenase pathway do not appear to be involved