Gen. Pharmac. Vol. 29, No. 2, pp. 265-267, 1997 Copyright @ 1997 Elsevier Science Inc. Printed in the USA.
ISSN 0306-3623/97 $17.00 + .00 PII S0306-3623(96)00414-4 All rights reserved ELSEVIER
Repeated Administration Intensifies the Reinforcing Effect of Fencamfamine in Rats R. DeLucia, 1. C. S. Planeta, 2 M. L. Aizenstein I and C. Scavond 1DEPARTAMENTO DE FARMACOLOGIA, INSTITUTO DE CIF.NCIAS BIOMI~DICAS,UNVIERSIDADE DE SAO PAUL©, 05508-900, Sa.o PAUL©, BRAZIL [FAx: (55 011) 8130845] A N D 2DEPARTAMENTODE PRINCfPIOS ATIVOS NATURALS E TOXICOLOGIA,FACULDADEDE CI~.NCIAS FARMACF:UTICAS, UNIVERS1DADEESTADUALPAULISTA, 14801-902, ARARAQUARA,S~o PAUL©, BRAZIL
ABSTRACT. 1. In the present study, we evaluated the role of repeated administration on conditioning place preference (CPP) induced by fencamfamine (FCF) in male rats. 2. Repeated FCF (3.5 mg/kg) or saline once or daily for ten consecutive days enhanced sniffing duration and decreased locomotion and rearing duration. 3. At the 3.5 mg/kg dose, FCF produced a significant place-preference effect. 4. Repeated exposures to FCF intensified its reinforcing properties. 5. These results suggest that repeated FCF administration sensitizes its rewarding effects, as with other addictive substances, tEN eHAm~Ac 29;2:265-267, 1997. © 1997 Elsevier Science Inc. KEY WORDS. Fencamfamine, psychostimutant, sensitization, place conditioning, reinforcing effect INTRODUCTION Fencamfamine (FCF) is a psychostimulant drug classified as an indirect dopamine agonist (DeLucia et al., 1984). The pharmacological profile of FCF is similar to amphetamine and cocaine (Aizenstein et al., 1995). Abuse of FCF has been reported among athletes (Delbeke and Debackere, 1981) and students (DeLucia and Planeta, 1989). Some reports suggest that, in the United States, FCF is a cocaine substitute in the illicit drug market (Gorodetzky et al., 1984). Recently, we reported that FCF could act as a positive reinforcer and that dopamine D1 and opioid I* receptors are related to the reinforcing effect of FCF (Planeta et al., 1995b). In addition, it was demonstrated that FCF caused signs of withdrawal similar to those of other psychostimulant drugs (Planeta et al., 1994). The repeated use of stimulant drugs results in an altered behavioral response to the subsequent administration of the drug. This altered-response profile is frequently referred to as sensitization or augmentation. For instance, FCF develops sensitization to stereotyped behavior (DeLucia et al., 1987). Because dopaminergic mechanisms play a crucial role in the behavioral effect of FCF, a variety of potential dopaminergic mechanisms underlying FCF-induced sensitization have been considered (Aizenstein et al., 1990); Planeta et al., 1989). Besides, repeated exposures to drugs with a rewarding effect, such as amphetamine, cocaine and morphine, might produce the behavioral sensitization (Aizenstein eta/., 1990; Joyce and Iversen, 1979; Segal and Mandell, 1974) and enhance the rewarding effects produced by these drugs (Giardi et al., 1991; Horger et al., 1990; Lett, 1989). The conditioning place preference (CPP) is a method extensively used to assess reinforcing actions of drugs. It has demonstrated that the human abuse of substances usually induces CPP. For example, CPP has been demonstrated for FCF, cocaine, amphetamine, morphine and ethanol (Acquas et al., 1989; Aizenstein et al., 1993; Bozarth, 1990; Hembey et al., 1992; Planeta et al., 1995a; Shippenberg * To whom correspondence should be addressed. Received 13 February 1996; revised 15 August 1996, accepted 9 September 1996.
et al., 1989). Because FCF has intrinsic reinforcing properties that could lead to abuse, we studied the role of repeated administration of FCF on the drug-induced rewarding effect as measured by CPP. MATERIAL A N D METHODS Subjects Adult male Wistar rats weighing between 250 and 300 g were maintained at 22-+2°C on a 12-hr-light-12-hr-dark cycle, with lights on at 07:00 hr for 9 weeks before the start of the experiments. Food and water were freely available except during behavior observation periods, when food and water were withdrawn. Behavioral tests were conducted during the light period. Drugs Fencamfamine hydrochloride (Merck) was dissolved in 0.9% saline and administered in a volume of 1 ml/kg. All doses are expressed as weight of salt. Experimental
design
Two experiments were performed. In experiment I, behavioral sensitization produced by repeated administration of FCF was studied. In experiment II, sensitization to the rewarding effect produced by repeated exposures to FCF was studied. EXPERIMENT L Animals (n= 16) divided into two groups (n=8) were treated with FCF (3.5 mg/kg) or saline (1 ml/kg) intraperitoneally (IP) daily for ten consecutive days and used in the behavioral sensitization procedure. Thirty minutes after the last FCF or saline injection, the rats were observed in their home cages, and locomotion (all four legs moving), rearing (both front feet off the floor) and sniffing (with all feet on the cage floor) durations were recorded for a period of 60 sec every 15 min for a total of 90 min. The observer was not aware of the treatments.
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Sniffing
EXPERIMENT I1. Animals (n=16) used in the CPP procedure were divided into two groups (n=8). For ten consecutive days, rats were injected with either FCF (3.5 mg/kg, IP) or saline and then were placed in the apparatus used to evaluate the reinforcing properties of FCF. The apparatus consisted of a rectangular shuttle box [90 (length) × 15 (width) × 22 (height) cm] divided into two equal-size con> partments by a guillotine door. One compartment had white walls and grid floor, and the other black walls and smooth floor. The experimental procedure consisted of three phases:
1. Preconditioning: In this phase, the animals were placed in one side of the shuttle box (initial compartment) for three consecutive days, and each rat was allowed to explore the two compartments for 15 min. The time spent in each compartment was recorded on the third day. 2. Conditioning phase: For four consecutive days, the animals were injected with FCF (3.5 mg/kg, IP) or saline on alternate days and confined for 15 min, respectively, to the white or black compartment. 3. Postconditioning (test): On the fifth day, doors were opened and the rats were placed in the initial compartment and allowed to freely move inside the apparatus. The time spent in each compartment was recorded for 15 min in a drug-free situation.
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Statistical analyses In the sensitization behavioral experiments, data for each behavioral parameter were submitted to the Student t-test. Data from CPP experiments were analyzed by two-way analysis of variance (ANOVA). The Newman-Keul method was used for differences between means with F-ratio.
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RESULTS As shown in Fig. 1, the repeated administration of FCF induced a significant increase in sniffing, rearing and locomotion compared with the saline group, both on day 1 and on day 10 of treatment. Animals treated with FCF or saline have distinct profiles of sniffing, rearing and locomotion when these behavioral parameters are viewed separately. The rats showed a significant increase in sniffing duration and simultaneous decreases in rearing and locomotion duration. No significant changes were found for saline groups when comparing days 1 and 10 of treatment. Figure 2 summarizes the mean time (±SEM) spent in the drugpaired compartment during the pre- and postconditioning phases for animals treated with FCF or saline. When post- and preconditioning phases are compared, time spent in the drug-paired compartment was significantly higher for the group injected with 3.5 mg/kg of FCF for ten consecutive days, indicating that repeated exposures intensified the reinforcing effect of FCF. DISCUSSION The present experiments, with the use of behavioral techniques, showed that repeated exposures to FCF augment the drug-induced rewarding effect of FCF-induced behavioral sensitization. To better characterize the development of behavioral sensitization with FCF, we observed changes of acute behavioral effects of FCF after treatment with 3.5 mg/kg for ten consecutive days. The comparison of animals after acute and repeated FCF administration revealed that a significant increase in sniffing duration and simultaneous decreases in locomotion and rearing duration were selected for repeated administration. Because these behaviors are mutually
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FIGURE 1. Effect of repeated fencamfamine administration on the duration of sniffing, rearing and locomotion. The height of bars represents the mean duration of each behavioral parameter recorded 90 min after last injection of treatment with FCF (3.5 mg/kg; IP) or saline ( 1.0 ml/kg; IP). Vertical lines represent SEM (standard error of the mean). *P
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SAL TRE.ATHENT F I G U R E 2. Effects of pretreatment with fencamfamine or saline on FCF-induced conditioning place preference. T h e animals ( n = 8 ) were treated with (3.5 mg/kg; IP) or saline (1 ml/kg; IP) daily for ten consecutive days. Histograms represent m e a n -+ SEM of rats observed in shuttle box during 15-min interval. * P < 0 . 0 5 pre- versus postconditioning; +P<0.05 post- versus postcondi-
tioning (Newman-Keuls): crosshatched column, preconditioning; open column, postconditioning.
other stimulants. Neurons of the dorsal (caudate-putamen) and ventral {nucleus accumbens) striatum take part in the development and expression of behavioral sensitization {Kalivas and Stewart, 1991). However, the exact neural mechanisms producing this effect have not been identified. It has been proposed that psychostimulants and other additive substances derive their reinforcing effects by stimulating the dopaminergic mesocorticolimbic system that also mediates psychomotor activities (Wise and Bozarth, 1987). Indeed, Wise and Bozarth have argued that the rewarding and the behavioral sensitization effects are mediated by a c o m m o n mechanism. Thus, to evaluate the role or repeated exposures to FCF on the drug-induced rewarding effect, animals were treated with FCF at 3.5 mg/kg for ten consecutive days. Our present data showed that repeated exposures to FCF enhanced the place-preference effect. In agreement with the view, repeated exposures intensified the rewarding effects of amphetamine, cocaine and morphine (Giardi et al., 1991; Horger et al., 1990; Lett, 1989). All these data suggest that repeated administration of FCF and other drugs of abuse sensitize the central reward mechanism, so the drugs taken produce a progressively greater reinforcing effect (Lett, 1989). In conclusion, our results suggest that repeated exposures to FCF sensitized its reinforcing effect as assessed by CPP in a similar manner to other addictive substances. This research project was supported by grants from Conselho Nacional de Pesquisa (CaPq). The authors wish to thank Dr. Silvana Chiavegatto for help with the illustrations.
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