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Serotonin is involved in a wide range of physiological and patho-physiological mechanisms. In particular, 5-HT1A receptors are proposed to mediate stress-adaptation. The aim of this research was to investigate in adolescent rats: first, the consequences of perinatal exposure to 5-metoxytryptamine (5MT), a 5-HT1/5-HT2 serotonergic agonist, on behavioural-stress reactivity in elevated plus maze, open field and forced swim tests; secondly, whether the behavioural effects induced by perinatal exposure to 5MT on open field and forced swim tests were affected by the selective 5-HT1A receptor agonist LY 228729, a compound able to elicit a characteristic set of motor behaviours on these experimental models, and by the co-administration of the selective and silent 5-HT1A antagonist WAY 100635. Results indicate that a single daily injection of 5MT to, pregnant dams from gestational days 12 to 21 (1mg/kg s.c.), and to the pups from postnatal days 2 to 18 (0.5mg kg s.c.), induce in the adolescent rat offspring: an increase in the percentage of entries and time spent on the open arms in the elevated plus maze; a reduction in locomotor activity and rearing frequency, and an increase in the time spent on the central areas in the open field test; a decrease in immobility and an increase in swimming in the forced swim test. Acute administration of LY 228729 (1.5mg/kg s.c.) strongly decreases rearing frequency and increases peripheral activity in the open field test, and decreases immobility and increases swimming in the forced swim test both in perinatally vehicle and 5MT-exposed offspring. Co-administration of WAY 100635 (0.25mg/kg s.c.) abolishes the effects exerted by LY 228729. These results suggest that, in the adolescent rat, perinatal exposure to 5MT enhances the stress-related adaptive behavioural responses, presumably through a predominant action on presynaptic 5-HT1A receptors and does not deteriorate the functional response of 5-HT1A receptors to selective agonist and antagonist compounds.

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The objective of this study was to compare the long‐term safety of a fixed combination of fenoterol hydrobromide (50 μg) and ipratropium bromide (20 μg) delivered using a metered dose inhaler (MDI) formulated with a non‐chlorinated propellant, hydrofluoroalkane134a (HFA‐MDI), with delivery using the conventional chlorofluorocarbon propellant (CFC‐MDI, Berodual®/Bronchodual®). The study was designed according to Safety Assessment of Marketed Medicines (SAMM) guidelines, to reflect as far as possible the use of MDIs under normal prescribing conditions. Two thousand and twenty‐seven patients with chronic airways obstruction (CAO) were enrolled from 99 centres in France, 95 centres in Germany and 24 centres in Italy. Following a 2‐week run‐in period, patients were randomized on a 2:1 basis (1,348 patients to HFA‐MDI, 679 patients to CFC‐MDI) to receive a flexible dose regimen of the combination (2 puffs, 2–4 times a day, as prescribed by the investigator) during a 12‐week open label phase. The overall incidence of adverse events was comparable between both groups. In addition, the incidence of respiratory side effects was also similar, with CAO exacerbations or bronchitis the most frequently recorded events. The safety profile of the HFA formulation was comparable to those of the marketed CFC‐MDIs used in Germany and France/ltaly. No clinically significant differences were detected between HFA134a or CFC driven inhalers on the switch from CFC‐ to HFA‐MDI (2 weeks before randomisation versus 2 weeks after randomization). There was a trend for taste complaints to be reported more frequently by patients in the HFA‐MDI group (0.7% before randomization versus 3.4% after randomization). This, however, was an expected finding as the HFA134a formulation does have a different taste to the CFC formulation. No difference between formulations was observed in the incidences of coughing or paradoxical bronchospasm. The incidence of falls in FEV1 >15% within 15 min following inhalation at each of the clinic visits was 1.2% for both CFC‐ and HFA‐MDIs. In conclusion, administration of a fenoterol/ipratropium bromide combination via hydrofluoroalkane‐metered dose inhaler is as safe as delivery by the currently available chlorofluorocarbon‐metered dose inhaler, in an extended population of patients with CAO under normal prescribing conditions.

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