The existence of two different functional receptors for 5-hydroxytryptamine (5-HT) was first proposed by Gaddum and Picarelli. Aided by the development of radioligand binding techniques, the heterogeneity of 5-HT receptors has become more apparent in the past ten years. There are three main types of 5-HT receptors: 5-HT1, 5-HT2 and 5-HT3. Moreover, 5-HT, is heterogenous and can be divided into 5-HT1A, 5-HT1B, 5-HT1C and 5-HT1D subtypes. 5-HT1B is probably related to the 5-HT autoreceptor controlling 5-HT release. Multiple 5-HT receptors are differentially distributed throughout the brain, and the agonist-receptor interaction is altered by physical parameters and chemicals, suggesting that the receptors may be physiologically relevant. Three 5-HT receptor subtypes, 5-HT1A, 5-HTIC and 5-HT2, have been cloned. All three receptors contain approximately 450 amino acids arrayed as seven transmembrane domains. 5-HT1 and 5-HT1A are coupled to adenylate cyclase positively and negatively, respectively, while 5-HTIC and 5-HT2 are coupled positively to phospholipase C. 5-HT1A is also coupled to the opening of K+ channels in hippocampal pyramidal cells. A number of 5-HT-induced physiological responses have been shown to correlate with the 5-HT receptor subtypes. Based on a number of pharmacological studies, it seems likely that the mode of action of certain psychotropic drugs is closely related to the activity of central 5-HT receptors.
Repeated administration of nicotine induces tolerance and/or reverse tolerance of spontaneous motor activity in rodents. These effects of nicotine on the spontaneous motor activity have been shown to be influenced by drug factors (e.g., doses, elapsed time after injection, period of treatment), circadian rhythm, age, sex, strain and species of animals. Although nicotinic acetylcholine receptors in the brain participate in the effects of nicotine, the development of tolerance and reverse tolerance is not sufficiently explained by changes in the receptor sites. Recently, neurochemical and behavioral studies have shown the possibility that reverse tolerance of nicotine on the spontaneous motor activity is probably concerned with the dopaminergic system through nicotinic acetylcholine receptors in the striatum or mesolimbic dopaminergic system of the rat brain. The present knowledge about the tolerance and reverse tolerance of nicotine on spontaneous motor activity is discussed in this review.
Bromhexine has been widely used as a mucolytic expectorant. Clinically, bromhexine is sometimes administered by inhalation. However, the effect of bromhexine by inhalation on bronchial musculature has not been documented. In the present study, the effect of inhaled bromhexine on bronchomotor tone in rats and guinea pigs was investigated. The bronchomotor tone was measured by a modified Konzett-Rössler method, and ventilation overflow (VO) was continuously recorded as an index of airway resistance. In rats, inhalation of bromhexine (0.1% and 0.2%, pH 5.3) caused no change in VO. At 0.2%, bromhexine slightly decreased systemic blood pressure (BP). In guinea pigs, bromhexine had no significant effect on VO at 0.2%, and it produced a significant but very slight increase at 0.1%. BP was slightly decreased by inhalation of bromhexine (0.1% and 0.2%, pH 5.3). N-Acetyl-L-cysteine, a cysteine-mucolytic (20%, pH 6.8), had no effect on VO and BP in either species. Inhalation of 0.1% bromhexine solution at pH 2.5, which was dissolved in tartaric acid solution, significantly increased VO, because of its acidity. From the above results, it is suggested that when the pH of the solution is considered, bromhexine has no or almost negligible effect on airway smooth muscles, and it may be useful as an effective mucolytic.