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M A . Gingras • A.R. Cools Different behavioral effects of daily or intermittent dexamphetamine administration in Nijmegen high and low responders

Received; 4 November 1996 / Final version: 22 January 1997

Abstract Outbred strains of Wistar rats contain both Introduction high responders to novelty (HR) and low responders to novelty (LR). Male HR and LR selected from the Nijme­ Exposure to stressors increases both the behavioral and gen outbred strain of Wistar rats differ in their sensitivity the biochemical responses to subsequent stimulant ad­ to acute administration of dexamphetamine (AMPH). ministration. For instance, a single exposure to stress en­ Sub-chronic administration of AMPH sensitizes rats to hances the behavioral response to dexamphetamine ad­ this agent, and this sensitization (SENS) increases when ministration (Antelman et al. 1980; Antelman and an intermittent, instead of continuous, regimen is used. Chiodo 1983; Herman et al. 1984; Robinson et al. 1985; Thus, the question arose whether HR and LR also differ Robinson and Becker 1986; Antelman 1988). As with in the development of sensitization to AMPH* AMPH stressors, corticosteroids are also necessary for the sensi­ (0.5 mg/kg SC) was given five times either each consec­ tization of dexamphetamine-induced locomotor activity utive day (daily: DAY) or each alternate day (intermit­ (Rivet et al. 1989; Cools 1991). tent: INT). Drug-induced changes in the spatio-temporal We have recently shown that mesolimbic otj adreno­ patterning of open field behavior were assessed for a pe­ ceptors are critically involved in the ability of corticoste­ riod of 45 min. Three sets of data were found: i) in the roids to sensitize the locomotor response to dexamphet­ AMPH-DAY conditions: total number of excursions with amine sensitization (Cools 1991). Since it is known that 0 stops increased in time; this SENS was far greater in mesolimbic a-adrenoceptors modulate the release and HR than in LR; ii) the effects under AMPH-DAY condi­ function of mesolimbic dopamine (Nurse et al. 1985; tions were far greater that those under AMPH-INT con­ Cools et al. 1991), it is not surprising that both mesolim­ ditions, especially in HR; iii) under AMPH-INT condi­ bic a-adrenoceptors and mesolimbic dopaminergic re­ tions a new phenomenon was observed: following a peri­ ceptors are important for dexamphetamine-induced sen­ od in which SENS occurred, a period marked by desensi­ sitization (Gold et al. 1988; Cools 1991). In short, there tization appeared which, in turn, was followed by a peri­ is evidence that corticosteroids, stress, mesolimbic a-ad- od with SENS being greater than the SENS seen during renergic, and mesolimbic dopaminergic receptors are the first time; this effect was far more pronounced in HR critically involved in dexamphetamine-induced sensitiza­ than in LR. It is concluded that AMPH-INT induces tion of locomotor activity. time-dependent changes marked by consecutive periods The behavioral and neurochemical responses to drugs of SENS and desensitization. This has far-reaching con­ of abuse such as dexamphetamine show considerable sequences for hypotheses about processes giving rise to variation between individual subjects (Deminière et al. the development of (1) SENS to psychostimulants and, 1989). For example, when low doses of psychostimulant consequently, (2) certain aspects of addiction to these drugs are used, only some rats acquire intravenous self­ drugs. administration (Piazza et al. 1989, 1990b, 1991). Previ­ ous experiments have demonstrated that drug-i indepen­ Key words Dexamphetamine • Sensitization • dent behavior such as locomotion in response to novelty Desensitization * Individual susceptibility ♦ Rats or sugar intake predicts individual differences in dexam­ phetamine self-administration behavior and in locomotor responses to psychomotor stimulant drugs such as dex­ M A . Gingras • A.R. Cools (S3) amphetamine and cocaine (Piazza et al. 1989, 1990 a,b; Department of Psychoneuropharmacology, University of Nijmegen, P.O. Box 9101, Hooks et al. 1991, 1992; Exner and Clark 1993; Sills and 6500 HB Nijmegen, The Netherlands Vaccarino 1994). The possibility of predicting individual Fax (+31) 24 354-0044 differences in the locomotor effect of dexamphetamine 189 on the basis of drug-independent behavior suggests that Selection procedure differences in structure and function of the brain of the Apparatus subjects may be an important factor in determining their sensitivity to drugs. However, the neurochemical mecha­ A 160 x 160 cm horizontal flat glass table, 95 cm high surrounded nisms determining these individual-specific differences by a white neutral background, served as open field. Behavior was in response to dexamphetamine are largely unknown. recorded with a computerized automated tracking system de­ Recently, we have studied the neurochemical and en­ scribed by Cools et al. (1990). docrinological differences between two fundamentally distinct types of rat which are normally present in unse- Selection lected, outbred populations of Wistar rats: so-called Ni­ jmegen high responders to novelty (HR) and Nijmegen Animals were placed on the open field for a period of 30 min. Ambulation was defined as the overall distance travelled (in low responders to novelty (LR). These two types of rat cm/30 min); exploratory behavior was defined as the portion of the are either selected from the outbred population of Nijme­ ambulation behavior which began after the rat was placed on the gen Wistar rats with the help of a special open field pro­ open field and ended when locomotor activity stopped for a period cedure (Cools et al. 1990, 1993a, b) or taken from partic­ of 1.5 min (habituation time). Distance travelled and habituation time were used as criteria to select the two types of rat (Cools et ularly outbred lines, namely the apomorphine-suscepti- al. 1993a). Rats which habituated in less than 480 s and locomoted ble rats (APO-SUS) being identical to H R and so-called less than 4800 cm/30 min were labeled LR, Rats which habituated apomorphine-unsusceptible rats (APO-UNSUS) being after a period of 840 s and covered more than 6000 cm/30 min identical to LR (for details see Cools et al. 1990, 1993a, were labeled H R (Cools et al. 1993a). Both variables, which have b). Studies on HR or APO-SUS and LR or APO-UNSUS been found to correlate fully in the Nijmegen Wistar rats (Cools et al. 1990), were used, since early postnatal handling that has been rats have revealed that the individual variation in behav­ found to alter the neurochemical structure and function of the ior of these two types of rat is the overall outcome of a brain (Rots 1995) enhanced the travelling distance without chang­ fundamentally different structure and function of the ing the habituation time, indicating that travelling distance per se brain, the neuroendocrine and the immune system (Cools is not always a reliable criterion (unpublished data; see also Rots 1995). et al. 1990, 1993a, b; Rots et al. 1995, 1996a, b). These Each animal was individually housed during 3 consecutive two types of rat can be used to elucidate mechanisms of days prior to the start of the selection period. Animals were trans­ behavioral sensitization. Thus, the goal of the present ported to the open field room 30 min prior to testing in order to al­ study was to establish whether these rats show differ­ low for environmental acclimatization. All testing took place be­ tween 0900 and 1700 hours. The selection procedure produced 15 ences in the development and expression of dexamphet­ HR [distance, mean ± SEM (cm/30 min): 8020 ± 333; habituation amine-induced sensitization of changes in spatio-tempo­ time, mean ± SEM (min): 21 ± 0.99] and 15 LR [distance, ral behavior. mean ± SEM (cm/30 min): 2440 ± 147; habituation time, Dexamphetamine-induced sensitization produced by mean± SEM (min): 3.5 ± 0.38], From the total number of rats test­ chronic intermittent (3- or 4-day interval) treatment is ed on the open field, 21 % were HR and 26% were LR; the remain­ ing 53% of the rats were not included in the experiment. greater than that produced by continuous treatment (Post 1980; Antleman and Chiodo 1981; Robinson and Becker 1986). Remarkably, there have been no studies compar­ Experiment 1: sub-chronic daily administration ing daily and intermittent administration of dexamphet­ of dexamphetamine in HR and LR amine. Given that mesolimbic a-adrenoceptors which Sixteen rats (eight HR and eight LR), weighing between 205 and are involved in dexamphetamine sensitization can 240 g at the start of the experiment, were randomly assigned to a change their “agonistic” state into an “antagonistic” sub-chronic daily treatment schedule of dexamphetamine. Each state, and vice versa, a situation lasting about 24 h animal was individually housed for 3 days following the selection period. ¿/-Amphetamine sulphate (0.5 mg/kg SC) obtained from (Cools et al. 1987), it was decided to use one schedule in RBI (Natick, Mass., USA) was dissolved in distilled water, and which dexamphetamine was administered daily for 5 fresh solutions were made for each test session. HR and LR were days, and one in which the drug was given five times given daily activity tests during a period of 45 min following dex­ with a 24 h interval. amphetamine injections for 5 consecutive days, Following an in­ jection of dexamphetamine, each animal was immediately placed in the center of the open field (described in Apparatus). Animals were pre-exposed to the novel open field for 30 min (during the Materials and methods selection procedure) which reduced locomotor activity at the start of the sensitization procedure. The animals were replaced in their Subjects home cages at the end of each test period.

Thirty male Wistar rats, bred and reared in the Central Animal Laboratory of the University of Nijmegen, were selected with the Experiment 2: sub-chronic intermittent administration help of the open field procedure described below. Animals were of dexamphetamine in HR and LR individually housed in standard plastic boxes (40 x 20 cm) and Fourteen rats (seven HR and seven LR), weighing between 205 maintained on a 12-h day and night cycle (lights on: 0700-1900 and 240 g at the start of the experiment, were treated on a sub­ hours). Standard lab chow and water was continuously available. chronic intermittent schedule. Animals were given an equal num­ All aniinal experiments were performed according to internation­ ber of treatments as in the daily condition (expt 1). Dexamphet­ al, national and institutional guidelines for animal experimenta­ amine (0.5 mg/kg SC) was administered every other day on the tion. basis of a 24-h interval. The open field and method of assessment were the same as in expt 1. 190

Behavioral analysis sions with zero, one and two stops. A decrease was seen after the third treatment, followed by a slight augmenta­ The computerized automated analysis was based on the definitions tion in the number of these excursions after the fourth of (a) home base, (b) excursions, and (c) stops as previously out­ lined (Eilam 1987; EJiam and Golani 1990; Golani et al. 1993). A treatment which subsequently peaked again following “home base” was defined as the place in which the rat remains for the fifth treatment. This consecutive series of increases the longest cumulative time and to which the number of visits is and decreases was especially evident for excursions with the highest. one stop (Ej). Indeed, the three-way ANOVA revealed An “excursion1’ or field trip was defined as the route starting immediately after leaving the home base and ending just before that there was a significant interaction effect in this case stopping again at the home base. Such an excursion could be ei­ [group x procedure x administration, E^ F(3,99, ther a “round trip”, being an excursion that starts and ends at the 111.6) = 2.86; j°<0.03]; no other significant interaction same base, or a “home trip”, being an excursion between two dif­ effects were found. Given this outcome, only the number ferent home bases (Golani et al. 1993). Once the computer pro­ gram defined the home base(s), it was able to track an excursion of Eq and E L was further analyzed with a two-way AN­ according to the above-mentioned definitions (Cools et al., sub­ OVA to evaluate HR-LR differences in the degree of sen­ mitted). The units of measurement were the number of excursions sitization per procedure (daily and intermittent, respec­ with zero, one and two stops, A “stop1' was defined as the inter­ tively). ruption of an excursion, during which the rat ceased to progress forward and froze in place, or ceased to progress forward and per­ formed lateral and/or vertical scanning movements with any or all parts of its trunk while staying in place. The computer program Sub-chronic daily administration traced the stop in two steps. First, the distance travelled between a of dexamphetamine in FIR and LR time interval of 1 s had to be less than 15 cm. Second, the distance between two successive stops had to be greater than 20 cm. When both conditions were fulfilled, the computer program labeled such Figure 1A shows that the daily administration of dexam­ an interruption as a “stop”. Finally, the excursions were classified phetamine increased the number of excursions with zero according to the number of stops. stops in HR to a far greater extent than it did in LR. This was confirmed by the outcome of two-way ANOVA that Statistics revealed a significant interaction [group (HR versus LR) x treatment (first to fifth administration), E0: F(3.10, A MANOVA for repeated measures by means of the SPSS pro­ 43.39 = 5.36; P<0.003]. This figure also shows that the gram was used to evaluate the data. P-values were calculated with daily administration of dexamphetamine resulted in a Averaged Tests of Significance, and the degrees of freedom were corrected with the Huynh-Feldt epsilon. First, a three-way AN- steadily increasing number of excursions with zero stops OVA for repeated measures was conducted (factor group: HR ver­ in HR [one-way ANOVA: treatment (first to fifth admin­ sus LR; factor procedure: daily versus intermittent; factor treat­ istration) E0: F(2.29, 16.02) = 11.09; P<0.001]; a far ment: first to fifth administration). If significant interaction was at­ smaller, but still significant increase was seen in LR tained, a two-way ANOVA for repeated measures was conducted [treatment (first to fifth administration), E0: F{4, (factor group: HR versus LR; factor treatment: first to fifth admin­ istration). If significant interaction was found, a one-way ANOVA 28) = 5.04; P<0.003]. for repeated measures was performed (factor treatment: first to Figure IB shows that the daily administration of dex­ fifth administration). A probability level of P<0.05 was taken as amphetamine also affected the number of excursions statistically significant. with one stop in HR and LR, but there was no significant interaction [two-way ANOVA: group (FIR versus LR) x treatment (first to fifth administration): NS], indi­ Results cating that HR and LR did not differ in this respect; moreover, the factor treatment (first to fifth administra­ General tion) was not significant, indicating that none of the rats developed sensitization in this case. The same holds true Figures 1A-F reveal that the occurrence of a slowly and for the effects of daily administration of dexamphet­ steadily developing sensitization was limited to the ef­ amine upon the number of excursions with two stops fects of daily administration of dexamphetamine upon (Fig. 1C). the number of excursions with zero stops (E0) in HR (Fig. 1A). Thus, the daily treated HR showed a far great­ er sensitization of E0 than the intermittently treated HR, Sub-chronic intermittent administration an effect that was not seen in LR (Fig. 1A and D). This of dexamphetamine in HR and LR was confirmed by the outcome of the three-way ANOVA that showed a significant interaction effect for E0 [group Figure 1D-F show that the intermittent administration of (HR, versus LR) x procedure (daily vs intermit­ dexamphetamine differentially affected HR and LR. tent) x treatment (first to fifth administration), E0: Two-way ANOVA revealed that this difference was only F(3.92, 109,9) = 3.53; PcO.OI], significant for the number of excursions with one stop Figures 1A-F also reveal that especially the intermit­ [group (HR versus LR) x treatment (first to fifth admin­ tent administration of dexamphetamine produced oscilla­ istration), E,: F(3.57, 49.94) = 3.99; P<0.009]. Fig­ tions in the number of excursions in HR. Thus, the sec- ure IE clearly shows that the intermittent administration ond treatment produced a peak in the number of excur- of dexamphetamine produced a consecutive series of in- 191

Daily Amphetamine Administration (0.5 mg/kg) Intermittent Amphetamine Administration (0.5mg/kg)

Fig 1 À-C Sub-chronic effects of daily administration of 0.5 creases and decreases in the number of excursions in HR mg/kg dexamphetamine on number of excursions with zero, one, that differed from that seen in LR. A subsequent one­ and two stops, respectively, in Nijmegen high (HR) and low (LR) way ANOVA per group revealed that this effect was sig­ responders on test days 1 through 5. The vertical bars represent ihe standard error of the mean. D-F Sub-chronic effects of inter­ nificant in FIR (first to fifth administration: jF(3.80, mittent administration of 0.5 mg/kg dexamphetamine of number of 26.57) = 4.23; PcO.Ol), but not in LR. excursions with zero, one, and two stops, respectively, in Nijme­ gen high (HR) and low (LR) responders on test days 1 through 9. The vertical bars represent the standard error of the mean Discussion

The goals of this study were to establish whether or not Nijmegen HR and LR differ in their behavioral response 192 to daily versus intermittent administration of dexamphet­ (Fig. IE). This alternating pattern of sensitization and amine and whether group-specific differences in the de­ desensitization probably explains why there was no sig­ velopment of sensitization to dexamphetamine exist be­ nificant difference in the number of excursions with one tween the groups. Given that drug-induced changes in stop between the first and last injection. In contrast, daily motor activity, as measured in standard locomotor boxes, dexamphetamine treated rats showed a steadily and were found to be insufficient in revealing major differ­ slowly developing sensitization when the number of ex­ ences between both groups (Gingras and Cools 1996), cursions with zero stops was analyzed. These two sets of we subsequently used a more subtle behavioral analysis data strongly suggest that excursions with one stop and allowing detailed examination of drug-induced changes excursions with zero stops are mediated by two different in the spatio-temporal programming of behavior. Using neurochemical mechanisms. this analysis, we recently found that HR are far more Sensitization, as seen in the daily treated rats (excur­ susceptible to the behavioral effects of acute administra­ sions with zero stops), involves progressive increases in tion of dexamphetamine than LR (Cools et al. 1997). behavioral responsiveness. Until now, studies on brain The present study, in which the rats’ progression was mechanisms of sensitization have focused almost exclu­ analyzed in terms of changes in the sequence of excur­ sively on dopaminergic systems (Robinson and Becker sions and stops, provides direct evidence that the HR are 1986; Kalivas and Stewart 1991). Indeed, it has been far more susceptible to the development of sensitization shown that the mesolimbic dopaminergic system is nec­ to the behavioral effects of dexamphetamine than LR. essary for a slowly developing dexamphetamine-induced Moreover, a new phenomenon was observed when the sensitization (Robinson et al. 1988; Perugini and Vezina dexamphetamine-daily and dexamphetamine-intermittent 1994; for reviews see Kalivas and Stewart 1991; Robin­ conditions were compared. These findings are discussed son and Becker 1996). It is therefore likely that the sen­ below. sitization seen in the number of excursions with zero In the first experiment, the slowly and steadily devel­ stops is at- least partly due to the effects of dexamphet­ oping sensitization to dexamphetamine was only seen amine on mesolimbic dopaminergic neurons. when the number of excursions with zero stops was tak­ The sensitization and desensitization seen in the num­ en as dependent variable (Fig. 1A): this effect was far ber of excursions with one stop can be at least partly ex­ greater in HR than in LR. There was no sensitization of plained by a noradrenergic homeostasis process that oc­ the number of excursions with one and two stops in ei­ curs at the level of receptor sites in the nucleus accumb- ther HR or LR (Fig. IB, C). Thus, the effects of dexam­ ens. First, it is known that noradrenergic receptors adapt phetamine vary across the dependent variables, viz. a their sensitivity inversely related to the level of stimula­ finding that underlines our previous conclusion in this tion by noradrenaline (Reisine 1981). That is, an in­ respect (Gingras and Cools 1996). In general, the greater creased level of noradrenaline release causes postsynap- sensitization seen in the ITR can partly be explained as tic binding sites to be sensitive to antagonists (or to be in follows. As mentioned in the Introduction, dexamphet­ an antagonistic state) but insensitive to agonists, whereas amine is interchangeable with stress and corticosteroids a decreased level of noradrenaline release causes post- that influence mesolimbic a-adrenoceptors. The meso- synaptic binding sites to be sensitive to agonists (or to be limbic adrenoceptors modulate the release of mesolimbic in an agonistic state) but insensitive to antagonists (for dopamine that, in turn, directs the sensitization of loco­ references see Cools et al. 1987). Second, it has been motor activity. HR show a significantly greater increase shown that a single injection of phenylephrine into the in corticosteroids in response to environmental or phar­ nucleus accumbens changes the noradrenergic receptor macological challenges than LR; HR also show a larger “state” for a period of about 24 h (Cools et al. 1987). behavioral response to stress than LR (Rots et al. 1995, Since dexamphetamine is known to release, among oth­ 1996a, b). These findings together may explain the ers, noradrenaline, it can be expected that dexamphet­ stronger and progressive developing sensitization of dex­ amine can influence the state of mesolimbic a-adreno- amphetamine-induced locomotor activity in HR. Our da­ ceptors as well Indeed, we have recently collected evi­ ta appear to be at variance with those of Hooks et al. dence that administration of dexamphetamine into the (1991, 1992), who have reported that the degree of sensi­ nucleus accumbens can reverse the “state” of mesolimbic tization to dexamphetamine does not differ between their a-adrenoceptors (Ellenbroek and Cools 1993). Third, HR and LR. However, both the procedure used to select unchallenged HR have mesolimbic a-adrenoceptors in HR and LR and the treatment protocols differ in all re­ the “agonist” state, whereas unchallenged LR have me­ spects between the present study and those of Hooks and solimbic a-adrenoceptors in the “antagonistic” state (El­ colleagues. Because of these differences, the outcome of lenbroek and Cools 1993; Roozendaal and Cools 1994). the present study cannot be compared with those of the These findings together imply that the mesolimbic a- studies of Hooks and colleagues. adrenoceptors of HR are not only more sensitive to dex­ Apart from the overall difference in sensitization to amphetamine-induced release of mesolimbic noradrena­ dexamphetamine between HR and LR, the present data line, but also more susceptible to noradrenaline-depen­ revealed a new phenomenon. The intermittent dexam­ dent changes in the “state” of the mesolimbic a-adreno­ phetamine treatment led to a sequence of increases and ceptors than do LR. It is therefore postulated that the pat­ decreases in the number of excursions with one stop tern of sensitization and desensitization of the excursions 193 with one stop, viz. a phenomenon that was clearly pres­ Cools AR, van den Bos R, Ploeger G, Ellenbroek B (1991) Gating ent in HR, is primarily due to the effects of dexamphet­ function of noradrenaline in the ventral striatum: its role in be­ amine on mesolimbic a-adrenoceptors. havioural responses to environmental and pharmacological challenges. In: Willner P, Scheel-Kriiger J (eds) The mesolim­ As mentioned, the successive periods of sensitization bic dopamine system: from motivation to action. Wiley, New and desensitization seen during intermittent administra­ York, pp 141-173 tion of dexamphetamine is a new phenomenon. However, Cools AR, Ellenbroek B, Heeren D, Lubbers L (1993a) Use of a comparable phenomenon has been described for co­ high and low responders to novelty in rat studies on the role of the ventral striatum in radial maze performance: effects of in- caine that is known to produce oscillations in the magni­ tra-accumbens injections of sulpiride. Can J Physiol Pharma­ tude or direction of the organism’s responsiveness to suc­ col 71: 335-342 cessive administrations of cocaine (Antelman et al, Cools AR, Rots NY, Ellenbroek B, de Kloet ER (1993b) Bimodal 1995). According to Antelman and colleagues (1995), shape of individual variation in behavior of Wistar rats: the overall outcome of a fundamentally different make-up and re­ this capacity of cocaine is due to its stressful aspect rath­ activity of the brain, the endocrinological and immunological er than to its specific pharmacological properties. Given system. Neuropsychobiology 28: 100-105 the concept of the interchangeability of stressors and Cools AR, Ellenbroek A, G in gras MA, Engbersen A, Heeren D psychostimulants such as dexamphetamine and the role (1997) Differences in vulnerability to dexamphetamine in Ni­ of noradrenaline in this interchangeability (Antelman et jmegen high responders to novelty and Nijmegen low respond­ ers to novelty: a dose-effect analysis of spatio-temporal pro­ aL 1980, 1983, 1995), the present study shows that An- gramming of behaviour. Psychopharmacology 132: 18 l- l 87 telman’s concept about cocaine and its oscillations can Deminière JM, Piazza PV, Le Moal M, Simon H (1989) Experi­ be generalized to other psychostimulants as well. mental approach to individual vulnerability to psychostimulant In sum, the present study shows that the development addiction. 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