Pharmacological Analysis of the Effects of Benzodiazepines On
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Short report 81 Pharmacological analysis of the effects of benzodiazepines on punished schedule-induced polydipsia in rats Ricardo Pello´ n, Ana Ruı´z, Esmeralda Lamas and Cilia Rodrı´guez Food-deprived Wistar rats were exposed to a fixed-time rate-increasing effect of 0.3 mg/kg of diazepam, but at 60-s food delivery schedule until they developed schedule- 17.0mg/kg partially blocked such antipunishment effect. induced polydipsia. Every fifth lick was then followed by an Overall, the present results extend the similarities of electric shock during two, signalled, 5-min periods, which the effects of benzodiazepine compounds on adjunctive ran concurrently with the food delivery schedule. Shock and operant patterns of behaviour by showing similar intensities were adjusted to reduce licking to 60–70% of interactions within the benzodiazepine receptor the unpunished licking rates. The benzodiazepine full complex. Behavioural Pharmacology 18:81–87 c 2007 agonists, diazepam (0.3–3.0 mg/kg), chlordiazepoxide Lippincott Williams & Wilkins. (0.3–10.0 mg/kg), oxazepam (0.3–3.0 mg/kg) and the benzodiazepine partial agonist, RU-32698 (3.0–17.0 Behavioural Pharmacology 2007, 18:81–87 mg/kg), led to increases in punished responding at Keywords: benzodiazepine-receptor compounds, chlordiazepoxide, intermediate doses and decreases at the highest doses diazepam, flumazenil, oxazepam, punishment, rat, RU-32698, RU-34000, tested. All benzodiazepine agonists brought about dose- schedule-induced polydipsia dependent decreases in unpunished schedule-induced Animal Behaviour Laboratories, Department of Basic Psychology I, Faculty of polydipsia, with doses required to reduce drinking proving Psychology, National University for Distance Education (Universidad Nacional de higher than doses required to increase punished schedule- Educacio´ n a Distancia), Madrid, Spain. induced polydipsia. The antipunishment effect of 0.3 mg/kg of diazepam was dose-dependently antagonized by Correspondence to Dr Ricardo Pello´ n, PhD, Departamento de Psicologı´a flumazenil and the benzodiazepine inverse agonist, Ba´sica I, Facultad de Psicologı´a, Universidad Nacional de Educacio´ n a Distancia, C/ Juan del Rosal 10, Ciudad Universitaria, 28040-Madrid, Spain. RU-34000. Flumazenil effects, however, could reflect E-mail: [email protected] actions of flumazenil as a partial inverse agonist at GABAA receptors. RU-32698 at 10.0 mg/kg further facilitated the Received 26 May 2006 Accepted as revised 30 October 2006 Introduction receptor (see Rudolph et al., 2000). Such mediation can Benzodiazepines are highly effective compounds in the be investigated by blocking GABAA receptors with treatment of anxiety disorders (see Nutt, 2005). One of benzodiazepine antagonists, and then testing the absence the best documented behavioural effects of benzodiaze- or diminution of a previously observed effect by the pines is their anxiolytic action in conflict procedures. The targeted benzodiazepine agonist. In this connection, the operant response rate reduced by the simultaneous antipunishment effect of benzodiazepines and related occurrence of a schedule of positive reinforcement and compounds can be attenuated by previous administration a punishment schedule is selectively increased by of the benzodiazepine receptor antagonist, flumazenil substances with anxiolytic activity, notably benzodiaze- (e.g. Barrett et al., 1986; Witkin et al., 1997). pines (see Houser, 1978; Millan, 2003). Compared with the research undertaken on operant The antipunishment effect of benzodiazepines and other behaviour, very few studies have addressed the effects of anxiolytics depends on the intensity and frequency of the drugs on punished adjunctive behaviour. The term electric shocks that are used as punitive stimuli and ‘adjunctive behaviour’ refers to any behaviour that occurs determine the punished response rate; low unpunished during reinforcement schedules without any apparent operant response rates are not increased by anxiolytic drugs contingent relationship with the reinforcer, and would (McMillan, 1973; Jeffrey and Barrett, 1979; Dworkin correspond to behavioural patterns adjunctive to the et al., 1989). The degree of the antipunishment effect of operant behaviour needed to obtain the reinforcer. The benzodiazepines is linked to their clinical efficacy, with best studied adjunctive behaviour is schedule-induced positive correlations reported in studies with pigeons polydipsia in rats, that is, when an animal is deprived of (Kleven and Koek, 1999), rats (Cook and Davidson, food and is subjected to an intermittent reinforcement 1973) and rhesus monkeys (Rowlett et al., 2006). schedule of food presentation, then, if it is given access to water at the same time, it will drink great amounts of Behavioural effects of benzodiazepines appear to be liquid concurrently with its performance under the mediated by actions at different subtypes of GABAA reinforcement schedule (Falk, 1961). Schedule-induced 0955-8810 c 2007 Lippincott Williams & Wilkins Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 82 Behavioural Pharmacology 2007, Vol 18 No 1 polydipsia is adjunctive behaviour because the animals doses of the inverse benzodiazepine agonist, RU-34000 are neither thirsty nor do they have any need to drink to (Gardner and Budhram, 1991). The study of the obtain the food reinforcer. Despite formal distinctions pharmacological mediation of actions of benzodiazepines between adjunctive and operant behaviour, operant on punished schedule-induced polydipsia should provide contingencies have been postulated to be involved in further comparisons of adjunctive and operant behaviour the maintenance of schedule-induced polydipsia and to advance the understanding of the mechanisms adjunctive behaviour in general. Such thinking is derived involved in the development and maintenance of in part from studies showing similarities in the effects of adjunctive behaviour. drugs on adjunctive and operant patterns of behaviour (Pello´n and Flores, 2006). Methods Flores and Pello´n (1998) showed that adjunctive drinking Subjects reduced by contingent presentation of electric shocks Six experimentally naive, male Wistar rats, obtained from could be increased after administration of the benzo- IFFA-CREDO (Lyon, France), were used. They were diazepine, diazepam, but not after administration of approximately 90 days old and had a mean free-feeding weight of 414 g (range: 380–432 g) at the start of the buspirone or D-amphetamine. Moreover, this effect depended on the intensity of shock used, and was not experiment. The rats were individually housed and seen in animals that received noncontingent electric placed in a room with controlled environmental condi- 1 shocks upon licking. In a later study, Flores and Pello´n tions (ambient temperature 22 C, 60% relative humidity (2000) observed that the more adjunctive drinking was and an 08.00/20.00 h light/dark cycle). After a 10-day reduced by the use of electric shocks of different period of habituation to the living conditions, and before intensity, the greater was the antipunishment effect of training, the rats were gradually reduced to and main- diazepam. The procedure used by Flores and Pello´n tained at 80% of their ideal free-feeding weight through (2000) consisted of inducing adjunctive drinking in rats food restriction. Clean, fresh water was freely available in by means of a schedule that dispensed a food pellet every all animals’ home cages. These procedures were in 60 s regardless of the animals’ behaviour [a fixed-time accordance with European Union Directive 2003/65/EC (FT) schedule], and alternating this schedule with and Spanish Royal Decree 1201/2005 governing the another which, in addition to food, dispensed electric protection of animals used for experimental purposes. shocks contingent on every fifth lick. Indeed, this procedure, based on the presentation of alternate punish- Apparatus ment and nonpunishment components, was the one The experiment was conducted in six, identical 29 Â followed in the present experimental series. 24.7 Â 35.5 cm, LI-836 rodent conditioning chambers (Letica Instruments, Barcelona, Spain) with grid floors. The chambers were enclosed in a soundproofed housing. Unlike the punishment studies outlined above, moderate The front panel of each chamber was made of aluminium, doses of benzodiazepine increase unpunished adjunctive the right-hand wall of black Plexiglas, and the remaining drinking, though mainly in terms of water intake rather sides and roof of transparent Plexiglas. Scrambled than licking (Bacotti and Barrett, 1976; Sanger and electric shocks were administered via each chamber’s Blackman, 1976; Pello´n et al., 1992), a finding that grid floor, by six independent LI 200–20 generators, suggests that benzodiazepines might alter the topography (Letica Instruments, Barcelona, Spain). A calibrated of drinking. water bottle was attached to the external side of the right wall of each chamber, with its spout accessible to This study sought to investigate the pharmacological the rat through a 3.2 Â 3.9 cm aperture, located 20 cm mechanisms of action of benzodiazepines on punished from the front wall and 7 cm above the floor. The spout schedule-induced polydipsia, by the comparative study of was positioned 2 cm behind the aperture, in such a way different benzodiazepine agonists and the possible that the rat could lick, but not maintain permanent antagonism through the blockade of benzodiazepine