Psychopharmacology (1994) 113:463-470 Psychopharmacology © Springer-Verlag 1994 Acute and chronic treatment with 5-HT reuptake inhibitors differentially modulate emotional responses in anxiety models in rodents Guy GriebeP, Jean-Luc Moreau 2, Francois Jenck 2, Ren6 Misslin 1, James R. Martin z 1 Laboratoire de Psychophysiologie, 7 rue de l'Universit~, F-67000 Strasbourg, France 2 Pharma Division, Prectinical Research, F. Hoffmann-La Roche Ltd, CH-4002, Basel, Switzerland Received March 17, 1993 /FinaI version May 24, 1993 Abstract. This study investigated behavioural effects of 1992). However, several studies reported intriguing ob- very potent 5 HT reuptake inhibitors after acute treat- servations early in treatment (Saletu and Gfiinberger ment (cianopramine and citalopram), as well as after 1985; Gorman et al. 1987; Van Praag 1988 ;.Westenberg chronic treatment (cianopramine), in two behavioural and den Boer 1988; Humble et al. 1989; Giesecke 1990; models of anxiety: 1) the light/dark choice procedure in Montgomery 1991; Westenberg 1992). These authors mice and 2) the elevated plus-maze test in rats. In addi- noted activating effects at the beginning of treatment tion, the responses of mice to novelty in a free explora- with a 5-HT reuptake blocker, described as racing tion paradigm were assessed after acute administration thoughts, anxiety, nervousness, tremor, insomnia, jitteri- of both drugs. A single injection of cianopramine or ness, emotional discomfort and agitation; this effect dis- citalopram increased neophobic reactions in the free ex- appeared with subsequent treatment. It is hypothesized ploration test. Furthermore, these drugs increased the that the acute increased availability of 5-HT resulting avoidance reaction to a brightly illuminated chamber in from reuptake inhibition would initially produce an- the light/dark choice procedure as well as to open arms xiogenic-like effects until adaptive changes of the 5-HT in the elevated plus-maze test. In contrast, after chronic receptors occurred, thereby eliminating such effects treatment (10 mg/kg IP, once daily for 21 days) ofciano- (Westenberg and den Boer 1988). pramine, anxiogenic-like effects were no longer produced Acute administration of established antidepressants in the light/dark choice paradigm whereas in the elevated in animals has been reported to produce anxiogenic-like plus-maze test, anxiolytic-like effects appeared. These effects in some studies (File 1985; Linnoila et al. 1987; results shed more light on the 5-HT hypothesis of anxi- Bodnoff et al. 1989; Handley and McBlane 1992) and no ety, insofar as the increased availability of 5-HT result- specific effects in others (Chopin and Briley 1987), or has ing here from reuptake inhibition seems to initially result even elicited anxiolytic-tike responses (Handley and in an increased emotional reactivity which, however, McBlane 1992). In addition, they have been found to subsequently disappears during chronic treatment. produce anxiolytic-like effects following repeated ad- ministration (Bodnoff et al. 1988, 1989; Fontana et al. Key words: Cianopramine - Citalopram - 5-HT reup- 1989; Cadogan et al. 1992). take inhibitors -Light/dark choice procedure -.Elevated The present experiments address this issue by assess- plus-maze test - Anxiety - Neophobia - Acute and ing the role of two potent 5 HT reuptake inhibitors, chronic treatments cianopramine (a dibenzapine derivative) (Da Prada et al. 1982) and citalopram (a bicyclic phthalane derivative) (Hyttel 1977) in regulating emotional responses in rodent models of anxiety. Their effects were evaluated using the Serotonin (5-HT) reuptake blockers constitute a novel light/dark choice procedure in mice and the elevated class of psychoactive drugs for which the clinical efficacy plus-maze test in rats. In these paradigms, several ben- in depressive disorders is now well established (•sberg et zodiazepines and non-benzodiazepine anxiolytics have al. 1986). There is also growing evidence for possible been shown to reduce anxiety-like responses towards beneficial therapeutic effects in other psychiatric disor- aversive stimuli (Belzung et al. 1987; Treit 1991; Griebel ders, such as obsessive-compulsive disorder (Insel et al. et al. 1992), while benzodiazepine receptor inverse ago- 1985; Goodmann et al. 1986), panic disorder (Westen- nists and direct 5-HT receptor agonists potentiated these berg and den Boer 1988) and social phobia (Westenberg responses (Belzung et al. 1987; Petlow et al. 1987; Griebel et al. 1990, 1991): Both drugs were given acutely Correspondence to. G. Griebel (cianopramine and citatopram) in one experiment and 464 cianopramine was administered chronically in another within a period of 5 min. At different times after drug administra- experiment. In addition, a free-exploration test was used tion, animals were placed on the rotarod and inability to remain on to evaluate neophobia in mice after acute treatment with the rod for 1 rain was scored as a sign for sedative/myorelaxant activity. cianopramine and citalopram. In this procedure, psycho- In the HWT, a training trial was also performed before injection stimulant drugs (Misslin and Ropartz 1981), as well as to allow the mice to become familiarized with the test situation. At some 5-HT receptor agonists (Griebel et al. 1990, 1991), different times after drug administration, the animals were tested have previously been shown to enhance neophobia. Fi- again for HWT performance directly after ROT testing; inability nally, the motor impairing effects of cianopramine and to grasp the wire with the forepaws or inability to actively grasp, citalopram were evaluated on mice using a locomotor the wire within 3 s with at least one hindpaw is used as a criterion for sedative and/or myorelaxant effects of the substance. Groups of activity test and forced motor performance tests. six mice were used to evaluated each dose over time at 2, 5, 10, 15, 30, 45, 60 and 120 rain following injection. Doses of 1, 3.2, 10 and 32 mg/kg IP were tested for cianopramine and citalopram. EDso Materials and methods values were calculated by probit analysis for each time point. Animals Experiment 2: effects of a single acute Male Swiss albino mice (Ibm: MoRo), 10 weeks old at time of injections of cianopramine and citalopram testing, were used in the free exploration test, in the light/dark in the free exploration test in mice choice procedure, in the animal activity monitor and in the forced motor performance tests. In the elevated plus-maze test, male Wis- Apparatus. The apparatus consisted of a polyvinylchloride box tar rats (Ibm: RoRo) weighing 110-200 g at time of testing were (30 x 20 x 20 cm) covered with Plexiglas and subdivided into six used. All animals were housed in groups of five and maintained equal square exploratory units, which were all interconnected by under standard laboratory conditions (21-23 ° C, relative humidity small doors. It could be divided in half lengthwise by closing three 55%) with free access to food and water. They were kept on a temporary partitions. 12: 12-h light - dark cycle with light onset at 6 p.m. and 6 a.m. for mice and rats, respectively. Animals were bred and provided by Procedure. Approximately 24 h before testing, each subject was Biological Research Laboratories (Ffillinsdorf, 4414, Switzerland). placed in one half of the apparatus with the temporary partitions in place, in order to be familiarized with it. The floor of this half was covered with sawdust and the animal was given unlimited Drugs access to food and water. Next day, the subject was exposed to both familar and novel compartments by removal of the temporary Cianopramine and citalopram (Hoffmann-La Roche, Basel, Swit- partitions. It was then observed, under red light, for 10 rain via a zerland) were dissolved in physiological saline and administered closed circuit TV camera by an observer located in an adjacent intraperitoneally in a volume of 10 ml/kg and 5 ml/kg body weight room. The time spent in the novel half (novelty preference), the in mice and rats, respectively. In acute treatments, drugs were number of units entered (locomotion) and the number of rears made injected 30 min before testing was begun. by the animals were recorded. Mice were randomly allocated into the following groups: a) cianopramine experiment: vehicle control (saline; n= 10) and drug (1, 3.2, 10, 30 mg/kg in saline; n= 10 per Experiment 1 : effects of a single acute injection of group); b) citalopram experiment: vehicle control (saline; n = 10) cianopramine and citaIopram in a locomotor activity test and drug (3.2, 10, 30 mg/kg in saline; n = 10 per group). Testing was and in forced motor performance tests in mice carried out between 2 p.m. and 5 p.m. Locomotor activity. The apparatus (Model RXYZCM(16); Om- nitech Electronics, Inc.) consisted of a polyvinylchloride box Experiment 3: effects of acute treatment of (20 x 20 x 30 cm) equipped with sensors fbr monitoring horizontal and vertical activity. cianopramine and citalopram in the light~dark test The subjects were individually tested under red light in 10-rain in mice and the elevated plus-maze test in rats sessions in the apparatus described above. All mice were initially placed in the centre of the area at the start of the test session. Total Light~dark test. The apparatus consisted of two polyvinylchtoride distance (era) travelled (indicator of ambulatory activity), move- boxes (20 x 20 × 14 cm) covered with Plexiglas. One of these boxes ment time (seconds spent ambulating) and the number of rearing was darkened. A light from a 100 W desk lamp, 25 cm above the movements were recorded. Mice were randomly allocated to the other box, and four neon tubes fixed on the ceiling provided the experimental groups: a) cianopramine experiment: vehicle control room illumination. The light intensity on the centre of the illumi- (saline; n = 16) and drug (1, 3.2, 10 and 30 mg/kg in saline; n = 8 per nated box was 4400 lux.