Psychopharmacology (2000) 151:291–298
© Springer-Verlag 2000
O R I G I N A L I N V E S T I G AT I O N
A.R. Zavala · A. Nazarian · C.A. Crawford S.A. McDougall
Cocaine-induced behavioral sensitization in the young rat
Received: 30 August 1999 / Accepted: 21 December 1999
Abstract Rationale: Repeated psychostimulant treatment has been shown to sensitize the locomotor activity of young rats, but there is conflicting evidence suggesting that this sensitized response will persist across only a few drug abstinence days. Objective: The purpose of the present study was to determine whether: (a) young rats are capable of expressing a sensitized locomotor response after an extended drug abstinence period, and (b) the longevity of the sensitized response is critically affected by either the number of drug pretreatment days or environmental conditioning factors. Methods: Young rats were pretreated with saline or cocaine (15 mg/kg or 30 mg/kg, i.p.) for either five or ten consecutive days [i.e., on postnatal days (PD) 16–20 or PD 11–20]. After each daily injection, rats were placed in activity chambers, and locomotion was measured for 30 min. To assess environmental conditioning factors, some rats were injected with saline prior to being placed in the activity chambers and then injected with cocaine prior to being returned to the home cage. After one or seven abstinence days (i.e., on PD 22 or PD 28), rats received a challenge injection of saline or cocaine (15 mg/kg) in the activity chamber and locomotion was assessed. Results: Young rats exhibit cocaine-induced locomotor sensitization after either a short (1-day) or long (7-day) drug abstinence period. When a long abstinence period was used, locomotor sensitization was only apparent when cocaine pretreatment lasted for 10 days. Conditioning factors were also important for determining whether locomotor sensitization was expressed, because young rats pretreated with cocaine in the home cage did not show a sensitized locomotor response after seven abstinence days. Conclusions: Young rats are capable of showing cocaine-induced locomotor sensitization after an extended abstinence period. Both the number of drug pretreatment days and the environmental context in which cocaine was givA.R. Zavala · A. Nazarian · C.A. Crawford · S.A. McDougall (✉) Department of Psychology, California State University, San Bernardino, CA 92407, USA e-mail:
[email protected], Tel.: +1-909-8805581, Fax: +1-909-8807003
en (i.e., the activity chamber or home cage) influenced the longevity of cocaine-induced locomotor sensitization. Keywords Behavioral sensitization · Cocaine · Young rat · Locomotor activity
Introduction Repeated exposure to psychostimulant drugs (e.g., amphetamine and cocaine) results in an augmented behavioral response called behavioral sensitization (Robinson and Becker 1986; Kalivas and Stewart 1991). In adult animals, behavioral sensitization has been studied very intensively because it is believed to be important for the incentive-motivational components of addiction (Robinson and Berridge 1993). Chronic psychostimulant treatment is capable of sensitizing various behaviors, including locomotor activity, stereotyped sniffing, and repetitive head movements (Shuster et al. 1977; Rebec and Segal 1980; Segal and Kuczenski 1987; Patrick et al. 1991; Crawford et al. 1998). In adult rats and mice, behavioral sensitization can be induced by as little as one drug exposure and can be detected for months after final psychostimulant treatment (Shuster et al. 1977; Leith and Kuczenski 1982; Robinson et al. 1982; Castro et al. 1985; Weiss et al. 1989; Paulson et al. 1991). Comparably few studies have assessed behavioral sensitization in young animals, although the relevance of these studies for early human psychostimulant use is clear (McDougall et al. 1999). Interestingly, young rats do not appear to show adult-like behavioral sensitization. More specifically, young rats will exhibit a sensitized response after one or two abstinence days (McDougall et al. 1994; Bowman et al. 1997; Duke et al. 1997; Tirelli and Ferrara 1997; Wood et al. 1998); however, behavioral sensitization is typically not observed after a more extended abstinence period (Fujiwara et al. 1987; Kolta et al. 1990; McDougall et al. 1994; Ujike et al. 1995). Two exceptions to this pattern of results have been reported,
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as young rats given repeated injections of a high dose of methylphenidate (20 mg/kg) exhibited long-term maintenance of a sensitized sniffing response (McDougall et al. 1999). More importantly, Spear and colleagues have shown that chronic exposure to cocaine during the preweanling period will produce a sensitized locomotor response that can be detected for at least 3 weeks after final drug treatment (Snyder et al. 1998). It is uncertain why only one research group has found that young rats will maintain a sensitized locomotor response across an extended abstinence period, but any number of procedural differences might be responsible. Among the most likely possibilities are the number of drug pretreatment days, size of the testing apparatus, type and dose of psychostimulant used, and the different ways in which locomotor activity is quantified. Spear and colleagues hypothesized that the number of drug pretreatment days may be critical, as they administered cocaine across seven pretreatment days, while previous studies often used only four or five pretreatment days (Snyder et al. 1998). Regardless, it now appears that chronic psychostimulant treatment during the preweanling period is capable of producing sensitized behavioral responses that persist across an extended abstinence period (Snyder et al. 1998; McDougall et al. 1999). The purpose of the present study was threefold: first, to confirm that cocaine produces long-term locomotor sensitization in young rats; second, to discover whether the number of drug pretreatment days is a critical factor determining the longevity of the sensitized response; and, third, to determine whether environmental conditioning factors are necessary for cocaine-induced locomotor sensitization (Post et al. 1981; Badiani et al. 1995; Anagnostaras and Robinson 1996; Browman et al. 1998). In order to assess the importance of conditioning factors, some rats were injected with saline prior to being placed in the activity chambers and then injected with cocaine prior to being returned to the home cage. In addition, a second experiment was conducted in which both cocaine-induced conditioned activity and behavioral sensitization were assessed. It was predicted that the number of drug pretreatment days (either 5 days or 10 days) would not differentially affect expression of locomotor sensitization after a short (1-day) abstinence period, but that ten drug pretreatment days would be necessary to maintain locomotor sensitization across a longer (7-day) abstinence period.
group. The colony room was maintained at 22–24°C and kept under a 12-h/12-h light/dark cycle. Subjects were treated according to the National Institutes of Health guidelines for the care and use of laboratory animals (Principles of Laboratory Animal Care, NIH Publication #85–23). Apparatus Behavioral testing was done in commercially available (Coulbourn Instruments, Allentown, Pa.) activity monitoring chambers (25.5×25.5×41 cm), consisting of Plexiglas walls, a plastic floor, and an open top. Each chamber included an X–Y photobeam array, with 16 photocells and detectors, which was used to determine distance traveled (horizontal locomotor activity). Drugs (–)-Cocaine hydrochloride was dissolved in saline and injected i.p. at a volume of 5 ml/kg. Cocaine was generously provided by the National Institute on Drug Abuse (Research Triangle Park, N.C.).
Experiment 1: behavioral sensitization Materials and methods Procedure During the pretreatment phase, rats were habituated to the activity chambers for 5 min each day. After the habituation period, separate groups of rats were given daily injections of saline or cocaine (15 mg/kg or 30 mg/kg, i.p.) on either postnatal days (PD) 16–20 or PD 11–20. Rats were immediately placed back in the activity chambers and distance traveled was measured. After 30 min of behavioral assessment, rats initially given cocaine (15 mg/kg or 30 mg/kg) were injected with saline and immediately returned to their home cages, whereas rats initially given saline were injected with saline or cocaine (15 mg/kg or 30 mg/kg, i.p.) and returned to their home cages. Distance traveled was not measured in the home cage. In summary, the pretreatment phase lasted either 5 days or 10 days (i.e., for PD 16–20 or PD 11–20, respectively), and the following injection sequences were given prior to placement in the activity chamber and home cage (activity chamber–home cage): saline–saline, 15 mg/kg cocaine–saline, 30 mg/kg cocaine–saline, saline–15 mg/kg cocaine, and saline–30 mg/kg cocaine. Thus, one group of rats was given only saline injections; two groups of rats were injected with cocaine (15 mg/kg or 30 mg/kg) before being placed in the activity chambers, and two groups of rats were injected with cocaine (15 mg/kg or 30 mg/kg) before being placed in the home cage. The test day occurred after either one or seven drug abstinence days (i.e., at PD 22 or PD 28). On the test day, all rats received a challenge injection of cocaine (15 mg/kg, i.p.) 5 min after being placed in the activity chambers. Distance traveled was measured for 30 min.
General methods
Statistical analyses
Subjects
Behavioral data from the pretreatment phase were analyzed using 5×5 or 5×10 (pretreatment condition × day) repeated-measures analyses of variance (ANOVAs); whereas, test day data were analyzed using one-way (pretreatment condition) ANOVAs. Litter effects were controlled by treating litter as a random factor in all analyses (Hughes 1979; Tirelli and Jodogne 1990). Preliminary analyses showed the lack of statistically reliable gender effects, so this variable was removed from subsequent analyses. Post-hoc analysis of the behavioral data was made using Dunnett tests (P
