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ABSTRACT: Acetylcholinesterase inhibitors (AChE-Is), galantamine, physostigmine and tacrine, enhance central levels of synaptic acetylcholine. Galantamine and physostigmine, but not tacrine, exhibit allosteric potentiation ligand (APL) properties on nicotinic acetylcholine receptors. The purpose of this study was to investigate whether AChE-Is with nicotinic acetylcholine receptor-positive allosteric modulator properties generalize to the discriminative stimulus effect of nicotine in rats. A two-lever operant conditioning paradigm was used in which rats were trained to discriminate nicotine (0.2 mg/kg/ml intraperitoneally) from saline. After training, generalization tests were carried out with galantamine (1, 3 or 5 mg/kg intraperitoneally), physostigmine (0.05, 0.1 or 0.2 mg/kg subcutaneously) or tacrine (0.625, 1.25 or 2.5 mg/kg subcutaneously) given as a single presession administration. Galantamine, physostigmine or tacrine produced a partial generalization of 62.2%, 55.1% or 43.6% , respectively, on the nicotine-appropriate lever compared with 100% partial generalization induced by the nicotine-training dose. High doses of galantamine, physostigmine or tacrine produced small but significant decreases in operant response rate, suggesting a possible underestimation of the degree of generalization. Our study showed that these three AChE-Is partially generalized to the nicotine stimulus without a significant distinction between AChE-Is with or without APL properties. These findings suggest that the APL property is not necessary for inducing nicotine-like effects in vivo in this behavioural paradigm.
Behavioural pharmacology 11/2010; 22(1):1-6. · 2.85 Impact Factor
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ABSTRACT: The objective of this study was to describe an optimised neurobehavioural observation battery in the beagle dog and to demonstrate that it can be used for an integrated assessment of cardiovascular and neurobehavioural functions within a single Safety Pharmacology study.
A standardised and detailed observation battery was established based on the direct examination of 44 signs, including behavioural responses and a full, systematic neurological examination, using clearly defined numerical scores. To complete the neurobehavioural assessment the remote observation of animals by video recording was also performed. Results from two studies, where cardiovascular and neurobehavioural parameters were assessed using drugs that either showed or did not show cardiovascular effects, are presented to show the influence of the direct neurobehavioural exam on the telemetrically acquired cardiovascular parameters.
Heart rate and systolic blood pressure were affected by the handling required for the neurobehavioural procedure for a total of approximately 25 min, consisting in 20 min needed for the sequential neurobehavioural observation of four dogs (requiring approximately 5 min each) and approximately 5 min to return to baseline. Drug related cardiovascular effects were not affected by the changes associated with these neurobehavioural observations. More evident cardiovascular changes were observed with other routine procedures such as feeding.
The direct neurobehavioural examination caused fluctuations of the telemetric cardiovascular parameters for no more than 5 min from the end of the procedure and this did not alter or jeopardise the analysis and interpretation of the cardiovascular parameters. These results confirmed that this optimised neurobehavioural observation battery can be used in the beagle dog for a reliable integrated assessment of neurobehavioural and cardiovascular changes during the course of Safety Pharmacology evaluations.
Journal of pharmacological and toxicological methods 06/2009; 60(2):198-209. · 2.32 Impact Factor
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ABSTRACT: Unwanted effects of drugs on neurobehavioural and cardiovascular functions are normally assessed in separate studies and using different animals. A new model using dogs which allows for the integration of these assessments into a single study was established and validated, adopting the most sophisticated technologies for both monitoring behaviour by video recordings and cardiovascular parameters by telemetry.
Conscious male beagle dogs (n=4) were given single oral doses of vehicle, and D-amphetamine (0.25, 0.75, 1.5 mg/kg) or acepromazine (0.05, 0.3, 2 mg/kg) within two different studies. Blood pressure, heart rate, electrocardiogram (EKG), body temperature, motor activity and behaviour (by video) were monitored continuously for 24 h post-dose. Animals underwent a full neurobehavioural examination the day before dosing, at the time to the maximal plasma concentration (Tmax) and 24 h post-dose.
D-Amphetamine: a dose-dependent increase in arterial blood pressure was noted at all doses and was generally associated with an increase in the QA interval, an index of cardiac contractility. Heart rate also increased but only at the 1.5 mg/kg dose. A dose-dependent general excitatory state of the nervous system was observed, characterised mainly by hyper-reactivity, and stereotyped activities. Acepromazine: a decrease in systolic blood pressure was detected at 0.3 and 2 mg/kg generally associated with a decrease in pulse pressure reflecting a negative inotropic effect. A dose-related increase in heart rate accompanied this effect. Dose-dependent general depression of the nervous system was noted; mainly characterised by half-closed eyes, subdued behaviour and impaired posture. In both studies, all dogs completely recovered at approximately 16 h after treatment.
Cardiovascular and neurobehavioural changes expected from the pharmacology of test substances were accurately detected. No significant fluctuations of the telemetric parameters recorded were noted as a consequence of the handling associated with the direct neurobehavioural examination. These results confirm the validity of this combined model capable of providing a reliable neurobehavioural and cardiovascular assessment of drugs.
Journal of Pharmacological and Toxicological Methods 56(2):265-75. · 2.32 Impact Factor
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ABSTRACT: Unwanted effects of drugs on neurobehavioural and cardiovascular functions are normally assessed in separate studies and using different animals. The purpose of this study was to validate, in the monkey, a model that incorporates the neurobehavioural assessment into the Safety Pharmacology cardiovascular study, allowing for an integrated evaluation of these two physiological systems.
Conscious male cynomolgus (Macaca fascicularis) monkeys (n=4) were given single oral doses of vehicle, D-amphetamine (0.5, 1 and 2 mg/kg) or diazepam (0.5, 1 and 2.5 mg/kg) in a dose-escalation study design. Blood pressure, heart rate, electrocardiogram (ECG), body temperature, locomotor activity and behaviour (by video) were monitored continuously for 24h post-dose. Animals underwent a standardised neurobehavioural test battery which allowed the direct examination of 31 signs, including behavioural responses and neurological examinations, conducted the day before dose, at maximal plasma concentration time (T(max)), and 24 h post-dose. The study was carried out in a first phase with telemetric cardiovascular recording only, and a second phase with telemetric cardiovascular recording and neurobehavioural observations. Results from the second phase of the study were used to evaluate the influence of the direct neurobehavioural examination on the telemetrically acquired cardiovascular parameters.
The expected cardiovascular and neurobehavioural changes, based on the pharmacological properties of the compounds tested, were accurately detected. In the second phase of the study the direct neurobehavioural examination caused fluctuations of the telemetric cardiovascular parameters for no more than 20 min from the end of the procedure and this did not alter or jeopardize the analysis and interpretation of the cardiovascular parameters.
These results confirm the validity of this combined model capable of providing in the cynomolgus monkey a reliable and reproducible neurobehavioural and cardiovascular assessment of candidate drugs during the course of safety pharmacology evaluations.
Journal of pharmacological and toxicological methods 62(2):95-106. · 2.32 Impact Factor
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Journal of pharmacological and toxicological methods 58(2):167. · 2.32 Impact Factor
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ABSTRACT: Identifiable in pre-clinical species, there is therefore a continuous need to improve the prediction performance in this area refining the methodologies used. A behavioural test was first introduced by Irwin as a psychotropic screening procedure in mice. Following modifications Functional Observational Batteries (FOBs) were developed for rats and more recently adapted in the most common non-rodent species. When assessing neurobehaviour it is important to carefully control and standardise all factors involved in the test (the animal, the observer, the observation battery and environmental conditions) to make the data collected objective and reproducible, and therefore predictive of safety liabilities. In our laboratories, detailed neurobehavioural observation batteries have been developed for use in most pre-clinical species: rodents, dogs, mini-pigs and non-human primates. The rodent FOB assesses home cage and open field activities, stimulus reactivity and neuromuscular functions. The dog and mini-pig FOBs have been developed based on that used for rodent but apply different levels of handling. The monkey FOB is considered the most suitable assessment when effects on higher-level cognitive and behavioural processes are to be assessed. In conclusion, it is possible to perform a reliable neurobehavioual assessment in all the major pre-clinical species, using a standard observation battery, but the procedure has to be adapted and optimised to the species.
Journal of pharmacological and toxicological methods 58(2):151. · 2.32 Impact Factor
