Role of dose interval in the acquisition of tolerance to methylphenidate

Nrurophormacology Vol. 20, pp Printed in Great Br~tam

ROLE

995

lo 1002.

0028.3908!81:100995-08502.OWO Pergamon Press Ltd

1981

OF DOSE INTERVAL IN THE ACQUISITION TOLERANCE TO METHYLPHENIDATE

OF

M. W. EMMETT-OGLESBY and K. E. TAYLOR Department

of Pharmacology, Texas College of Osteopathic Fort Worth, TX 76107, U.S.A. (Accepted

17

April

Medicine,

1981)

Summary-Two experiments were performed to test the role of dose interval in the development of tolerance to methylphenidate. Rats were trained to consume sweetened milk and then were given methylphenidate in a dose that decreased milk intake by approx. 50%. For the next 23 sessions they received either saline: methylphenidate daily, immediately post-session; or pre-session methylphenidate, either daily, every-other-day, or every-four-days. The next session, all groups received methylphenidate pre-session. The 3 groups treated on a chronic basis with methylphenidate pre-session returned to baseline levels of milk intake and differed significantly from the daily saline and daily post-session methylphenidate groups, which did not become tolerant. In a second experiment, rats injected presession daily or every fourth day with 15 mg/kg methylphenidate developed tolerance to the disruption of milk consumption. As compared to rats treated chronically with saline, the 2 groups given methylphenidate showed a shift of their dose-effect curves to the right and cross-tolerance to d-amphetamine. These results demonstrate that tolerance can occur to the disruptive effects of amphetamine-type drugs even when three drug-free days intervene between administrations. This tolerance is characterized by a shift in the dose-effect curve as well as cross-tolerance to a drug with similar pharmacological properties.

Repeated administration of amphetamine-type drugs frequently alters the magnitude of drug effects observed upon acute administration. Supersensitivity to the induction of stereotyped behavior has been found (Browne and Segal, 1977; Randrup and Munkvad, 1974), and tolerance to many of their behavioral effects has been reported (see reviews by Kalant LeBlanc and Gibbins, 1971; Corfield-Sumner and Stolerman, 1978; Woolverton and Schuster, 1977). Most experiments dealing with tolerance have used at least once-daily drug administration, perhaps because frequent administration is thought to provide optimal conditions for producing tolerance (Seevers and Deneau, 1963); such is certainly the case for some effects of the opiates (Goldstein and Sheehan, 1969), and probably the case for sedative-hypnotics (LeBlanc, Gibbins and Kalant, 1976). Although it has been suggested that intermittent administration of amphetamines will delay or avoid the development of rolerance (Winsberg, Bialer and Tobias, 1972), no study has evaluated the relationship between the interval between amphetamine administrations and the development of tolerance. The results of several experiments suggest that tolerance is not a simple function of having amphet;amines chronically present in the organism; rather, drug-behavior interactions may largely determine the development or absence of tolerance. For example, in several experiments, the drug was administered daily either before or after a behavioral test, and tolerance developed only in the group receiving the drug preKey words: methylphenidate, anorexia, intermittent dosing.

amphetamines,

tolerance,

995

session den,

(Carlton 1973;

and Wolgin,

Woolverton,

Even

though

unless

the subjects

1971; Campbell

Kandel

and

Schuster,

and

Sei-

1978).

identical doses were administered, performed the task while under the influence of the drug, no tolerance occurred. These results demonstrate that daily administration per se does not produce tolerance to amphetamine-type drugs unless an opportunity occurs to adapt to the disruptive effect of the drug. Is daily administration a necessary condition for producing tolerance’? Although this question has never been tested systematically for amphetaminetype drugs, evidence obtained during dose-effect testing suggests that tolerance can occur even when several days separate successive administrations. Smith and McKearney (1977) trained pigeons to peck a key under a schedule of reinforcement that generated low-rates of responding, and then d-amphetamine was administered twice weekly. Initially, d-amphetamine increased the rate of responding in a dose-related manner, but in subsequent replications of the dose-effect curve, the rate-increasing effects of d-amphetamine diminished with repeated injection. In this laboratory, comparable results were obtained in rats trained under a differential-reinforcement-of-lowrate (DRL) schedule. When doses of methylphenidate were given repetitively during dose-effect testing, the second and third administration of each dose produced diminished rate-increases compared to results obtained during the initial dose-effect testing (Brewin and Emmett-Oglesby, 1978). In the present experiment, methylphenidate was used to study the development of tolerance to amphetamine-type drugs as a function of the dose interval.

996

M. W. EMMETT-OGLESBY and K.E. TAYLOR

Methylphenidate has behavioral effects essentially interchangeable with those of d-amphetamine (Seiden, Andresen and MacPhail, 1979); when given daily, cross-tolerance between methylphenidate and d-amphetamine has been shown for their effects in rats on milk consumption and differential-reinforcement-of-low-rate of responding (Pearl and Seiden, 1976). Methylphenidate is also a typical amphetaminelike drug in terms of increasing the metabolism of brain catecholamines when administered acutely (Ferris, Tang and Maxwell, 1972; Moore, 1978; Weiden, et al., 1979). On the other hand, the pharmacokinetic properties of methylphenidate confer advantages over d-amphetamine when the role of the dose interval in the production of tolerance is tested. The half-life of methylphenidate in rats is less than 1 hr whereas the half-life of d-amphetamine is more than 2 hr (Segal, Cunningham, Dayton and Israili, 1976). Thus, as compared to d-amphetamine, rats given methylphenidate will be drug-free for longer intervals when administration is intermittent. In addition, d-amphetamine is metabolized to p-hydroxynorephedrine in rats (Brodie, Cho and Gessa, 1970); this compound replaces a portion of norepinephrine in adrenergic nerve terminals, and several days are required after d-amphetamine is terminated before norepinephrine concentrations return to normal (Lewander, 1971). Methylphenidate, however, does not modify norepinephrine concentrations (Pearl and Seiden, 1976). The present experiment tested the role of interval of administration in producing tolerance to the disruptive effects of methylphenidate on sweetened-milk consumption. Specifically, this experiment addressed the following questions: (1) Does tolerance occur after daily post-session administration of methylphenidate? (2) Does tolerance occur with pre-session administration of methylphenidate when the dose interval is greater than once daily? (3) Does the rate of development of tolerance vary as a function of the dosing interval‘? (4) If tolerance develops to a fixed dose of methylphenidate administered once every four days, does this produce shifts in the dose-effect curve and cross-tolerance to other amphetamine-type drugs? (5) Is tolerance to the disruption of sweetened-milk intake associated with tolerance to the disruption of solid food intake?

METHODS

Subjects

Male, Sprague-Dawley rats (Holtzman Co., Madison, WI), initially 60 days old, were used in both experiments. They were housed individually and received ad libitum food (Purina Rat Chow) and water in their home cage until they weighed 320g. Subsequently the body weights were reduced and maintained at 300 + 5 g by adjusting the daily quantity of food received.

Drugs

Methylphenidate.HCl was a gift of Ciba-Geigy (Summit, NY). d-Amphetamine sulfate was obtained from Sigma Chemical Co. (St Louis, MO). The drugs were dissolved in 0.9% saline and injected intraperitoneally (i.p.) in a volume of 1 ml/kg body weight. All doses are expressed in terms of the respective salts. Procedure

A modification of the milk drinking procedure used by Carlton and Wolgin (1971) was employed. Sweetened-milk was made from powdered milk prepared to package specifications with corn syrup substituted for 20% of the water volume. Twenty-five ml portions of the milk solution were measured volumetrically into 50ml graduated centrifuge tubes capped with rubber stoppers fitted with a metal spout having a 2.5 mm diameter opening at the end. Milk consumed during the session was determined volumetrically to the nearest ml. In the first experiment, the rats were housed in plastic cages, 44 x 24 k 14 cm, covered with metal-bar lids. The spout was presented through the bars from above the animal. In the second experiment, the rats were housed in metal cages suspended from a housing rack (Suburban Surgical, Chicago, IL), and the spout was presented from the front at a height of approx. 8 cm above the floor of the cage. In the first experiment, 49 rats received 30-min daily access to 25 ml of sweetened milk, 7 days per week. Water was available ad libitum except during the milk-drinking period when the water bottle was replaced with a milk bottle. Weights were maintained by food pellets given 2 hr post-session, and all rats were approx. 20-hr food deprived when tested the next day. Within 7 days of training, all rats consumed 25 ml of sweetened milk in approx. 10 min. Following five consecutive sessions of saline, injected 20-min pre-session, they were given methylphenidate 15 mg/kg, 20-min pre-session. This day is noted as day I in Table 1. Subsequently, rats were assigned to one of five groups, and for the next 23 days, each group received one of five treatments as described in Table 1 under days 2 through 24. Following the chronic treatment phase (day 25, Table l), all rats again received methylphenidate, 15 mg/kg, 20 min pre-session. In the second experiment, 85 rats were housed and trained to drink sweetened milk as described above. After 7 days of saline injections they were given methylphenidate, 15 mg/kg, 20-min pre-session; subsequently, they were assigned to one of three groups: saline (N = 28); daily methylphenidate, daily 15 mg/kg 20-min pre-session (N = 28); or methylphenidate, 15 mg,kg every-fourth-session, 20-min presession (N = 29). These conditions were maintained for 84 sessions (21 exposures to MP for the onceevery-fourth-session group). On sessions 85, 89 and 93, dose-response functions were determined for

Tolerance Table

1. Treatment

997

to methylphenidate groups

for experiment

Experimental 4 5

one

day

Group

I

Saline

B

MP post-session

B

A

A

A

A

..

A

A

B

pre-session

B

B

B

B

B

..

B

B

B

MP pre-session

B

B

..

B

B

...

2

3

23

24

.

25 B

MP

B

B

MP pre-session

B

B

All groups received pre-session saline injections for 5 sessions prior to day 1. On days 1 and 25, all groups received methylphenidate (MP), 15 mg/kg, 20 min pre-session (B = before session). On days Z-24, one group received saline, daily, pre-session; one group received methylphenidate (MP), 15 mg/kg, daily, immediatety post-session (A = after session); the remaining three groups received methylphenidate, 15 mg/kg, pre-session, either daily, every-other-day, or every-fourth-day. Open spaces represent pre-session saline.

methylphenidate, d-amphetamine and methylphenidate, respectively. For each dose-response determirats from daily treatment groups were nation, assigned randomly to one of three doses of drug (N = 9 or 10 per subgroup from each of the daily treatment groups). Session 85 tested the effect of 12, 24 and 34 mg/kg of methylphenidate on milk-intake; session X9 tested the effect of 1.5, 3.0 and 4.2 mg/kg ~~-amphetamine on milk-intake; and session 93 tested the effect of 12, 24 and 34mgikg of methylphenidate on rat-chow intake. Statistic:; In experiment one, a repeated measures analysis of variance (Winer, 1971) was used to compare milk consumption in all groups after pre-session methylphenidate on days 1 and 25. Because a significant interaction effect was obtained, direct tests on main effects were performed using two one-way analysis of variance for the effects of methylphenidate on milk consumption on days 1 and 25. Group differences after significant main effects were assessed by NewmanKeuls statistic (Winer. 1971). In experiment 2, differences in dose-effect curves were determined by a twofactor (3 groups x 3 doses) analysis of variance. .P < 0.05 are reported as significant.

RESULTS In experiment one, initial exposure to 15 mg/kg of methylphenidate reduced average milk consumption by approx. 50%; however, this effect was not uniform. Of the 49 rats, 19 consumed 20ml or more and 20 consumed fewer than 10ml of milk. The rats were assigned to treatment groups to balance this effect. During chronic administration (days 2-24), all the rats receiving saline either daily or interspersed between methylphenidate, consumed 25 ml of milk.

Thus, intervening saline days produced a baseline intake for the groups receiving methylphenidate on an every-other-day or every-fourth-day basis. Rats receiving daily post-session injection of methylphenidate also consumed all the milk during the next day’s session, indicating that (1) methylphenidate did not disrupt food intake 24 hr after injection, and (2) daily administration of methylphenidate did not produce a cumulative or toxic effect. Rats receiving pre-session injection of methylphenidate, whether daily, everyother-day or every-fourth-day, developed tolerance to the disruptive effects of methylphenidate. For days I and 25 when all groups received pre-session injection of methylphenidate (Fig. l), a 5 x 2 (treatment groups x days) repeated measures analysis of variance showed a significant interaction effect (F = 3.22; d.f. = 4,44). Therefore, two one-way analyses of variance were performed for the effects of methylphenidate on milk consumption for days 1 and 25. For day 1 there were no significant group effects; for day 25, group effects were significant (F = 5.96; d.f, = 4,44), and the three groups receiving chronic pre-session injection of methylphenidate differed significantly from the groups receiving either saline or daily postsession drug. No other differences were significant. In experiment two, an initial dose of 15mg/kg of methylphenidate given pre-session, produced effects similar to those in experiment one. The rats were again assigned to treatment groups such that group averages for means and standard deviations were comparable, and chronic treatment conditions were maintained for 84 sessions. Not all rats in the daily and every-fourth-day group returned to their pre-drug baseline of milk intake during chronic administration, and the longer delay in the development of toierance in this experiment as compared to the first experiment may be due to the housing conditions of the subjects. Methylphenidate

998

M. W. EMMETT-OGLESBYand K. E. TAYLOR 25

SA

POST

DAILY

TWO

FOUR

Fig. 1. Milk consumption for days 1 (light bars) and 25 (dark bars) when methylphenidate (MP) 15 mg/kg, was given pm-session to all groups. Ordinate: milk intake in ml. Abscissa: chronic treatment conditions (days 2-24): SA = saline: POST = methylphenidate, daily, post-session; DAILY = methylphenidate, daily pre-session; TWO = methylphenidate every other day, pre-session; FOUR = methylphenidate every four days, pre-session. Lines depict one SEM. N = 9 for the daily group; N = 10 for the other groups,

I

I

1

2

I

I

I

3 4 5 Exposures lo YP (15 mg/kg)

I

6

I

7

Fig. 2. Milk consumption after pre-session injection of methylphenidate (MP), 15 mg/kg, for rats treated with this dose daily (0) or every day (A). Ordinate: milk intake in ml; 25 ml maximum possible. Abscissa: exposure to methylphenidate, where each point represents the average of three consecutive exposures. All 21 exposures for the everyfour-day group are included. The first 21 exposures for the daily group are included. By the time of cross-tolerance testing the daily group averaged over 24ml per session. N = 28 for the daily group; N = 29 for the every-four-day group. Each point on the graph represents average milk consumption; vertical bars show one SEM.

25 produced

stereotyped

ing, gnawing served

and

to bring

behavior rearing.

rats

into

in the first experiment

The contact

where

characterized rearing, with the milk

by sniff-

in particular, the metal was

In the second experiment, rearing decreased the probability of contacting the spout, which was presented from the front of the cage; however, tolerance clearly developed in both groups. Prior to dose-effect testing, the once-every-four day group received 21 injections of 15 mgjkg of methylphenidate, and the daily group received 84 injections. To compare the rate at which tolerance developed in the two groups, results from the first 21 injections in the daily group were tested against results from the once-every-four day group. The 21 injections were summarized in 7 blocks of three injections each (Fig. 2), and in a 2 x 7 (groups x exposures) repeated measures analysis of variance, tolerance occurred across exposures (F = 11.4; d.f. = 6,330); there were no significant differences between the groups and no significant interaction effect. Tolerance to the disruptive effect of methylphenidate on the consumption of milk was shown further during dose-effect testing on the eighty-fifth day of this experiment (Fig. 3). A 3 x 3 (groups x doses) analysis of variance showed a significant effect of both daily treatment (F = 10.5; d.f. = 2,76) and test dose from

above

the

20.

spout

presented

f

subject.

z

15.

+ -L r 10.

5.

I

I

I

12

24

34

Meihylphenldale

imq kg)

Fig. 3. The effects of varying doses of methylphenidate on milk consumption. On day 85 of chronic treatment, rats in all chronic treatment groups were assigned randomly to one of three doses of methylphenidate given 20-min prior to milk access. N = 9 or 10 for each point. A represents the group treated chronically with methylphenidate every fourth day; 0 represents the group treated chronically with methylphenidate on a daily basis; * represents the group treated chronically with saline. Each point on the graph represents average milk consumption in ml; vertical bars show one SEM. No bar represents a SEM less than the symbol size.

999

Tolerance to methylphenidate (F = 5.9; d.f. = 2,76); the interaction effect was not significant. Compared to daily saline treatment, daily or every-fourth-day treatment with methylphenidate resulted in a significantly decreased effect of the drug. There is no evidence that rats receiving daily injections of methylphenidate were more tolerant than rats receiving the drug every fourth day. On the eightyninth day, cross-tolerance to the disruptive effect of d-amphetamine for doses of 1.5, 3.0 and 4.2mg/kg was tested. A 3 x 3 (groups x doses) analysis of variance showed a significant effect of both daily treatment (F = 4.8; d.f. = 2,76) and test dose (F = 5.9; d.f. = 2,76); the interaction effect was not significant (Fig. 4). Compared to daily saline treatment, daily or every-fourth-day treatment with methylphenidate resulted in cross-tolerance to d-amphetamine. Tolerance transferred from the disruption of milk-intake to the disruption of rat-chow intake (Fig. 5). A 3 x 3 (groups x doses) analysis of variance showed a significant effect of both daily treatments (F = 4.3; d.f. = 2,76) and test dose (F = 23.4; d.f. = 2,76); the interaction effect was not significant. Compared to

1’2

214

*

34

Methyiphentdate imgfkg)

Fig. 5. The effects of varying doses of methylphenidate on solid food consumption. On day 93 of chronic drug treatment, rats in ail chronic treatment groups were assigned randomly to one of the doses of methylphenidate given 20min prior to unlimited access to rat-chow pellets for 30min. N = 9 or 10 per group. A represents chronic administration of methylphenidate every-fourth-day; l rep resents chronic administration of methylphenidate on a daily basis; * represents chronic saline. Each point on the graph represents the average amount of rat-chow consumed in g; vertical bars shown one SEM.

?5_

20.. F w % 15.. E f f

daily saline treatment, daily or every-fourth-day treatment with methylphenidate resulted in a significantly decreased effect of the drug on food intake.

10..

DISCUSSION

5..

I

I

/

15

30

42

@-amphetamine

Img Cgi

Fig. 4. The effects of varying doses of d-amphetamine on milk consumption. On day 89 of chronic treatment, rats in ail chronic-treatment groups were assigned randomly to one of three doses of d-amphetamine. N = 9 or 10 per group. Ail rats were injected 20-min pre-session. LL represents chronic administration of methyiphenidate every fourth day; l represents chronic daily injection of methylphenidate; * represents chronic saline. Each point on the graph represents average milk consumption in ml; vertical bars show one SEM. No bar represents a SEM less than the symbol size except for the point representing the subgroup (iv = 10) treated chronically with daily administration of methyiphenidat~ and tested with 4.2mg/kg d-amphetamine. Standard error for this point is 3.5 and the bar is omitted due to an overlap with the other symbols at this dose.

These results demonstrate that tolerance occurred to disruption of milk drinking when methylphenidate was given pre-session on an infrequent basis such as once every four days. Milk consumption was chosen for study because tolerance readily develops to the disruption of milk intake caused by the acute administration of CNS stimulants (Carlton and Wolgin, 1971; Pearl and Seiden, 1976). Tolerance in this paradigm is not necessarily confined to tolerance to the anorexigenic action of CNS stimulants; in addition to providing a major portion of the daily calorie consumption, the milk also provided a large portion of the daily fluid consumption. Thus adipsic as well as anorexic effects of methylphenidate may be part of the stimuli which resulted in tolerance. The results of daily administration confirm the results of Pearl and Seiden (1976) and extend them to include djs~ption of solid food intake. The results of once-every-four-day administration show: (I) a decreased effect of a fixed dose with repeated administration; (2) a shift in the dose-effect curve to the right;

1000

M. W. EMMETT-OGLESBY and K. E. TAYLOR

and (3) cross tolerance to the effects of d-amphetamine. In addition, on a per exposure basis, the rate of development of tolerance in the every-four-day group did not differ significantly from the group receiving methylphenidate daily. Thus, daily or more frequent administration is not a prerequisite for the development of tolerance to methylphenidate. Pearl and Seiden (1976) showed that no methylphenidate or metabolites could be found in rat brain 24 hr after a radiolabelled, 20mg/kg, dose of methylphenidate was given intraperitoneally. Their data agree well with those of Faraj, Israili, Perel, Jenkins, Holtzman. Cucinell and Dayton (1974) who found that 30 min after a 20mg/kg (i.p.) dose of radiolabelled methylphenidate, most of the compound was present in plasma as ritalinic acid, a polar compound that is effectively excluded from the brain. Thus, the half-life of methyiphenidate and its metabolites is brief in rats, being less than one hour for the parent compound (Segal er ai., 1976). In the present experiment. t5 mg/kg produced readily apparent stereotyped behavior that was no longer detectable at approx. 3 hr after injection. At 24 hr after administration of methylphenidate, no behavioral effects were noted on milk-intake in either the daily post-session, the every-other-day or the once-every-four-day group. These observations, plus the kinetic data available in the literature, strongly suggest that no drug was present during the three intervening saline days in the group receiving methylphenidate once-every-four days. Thus, mechanisms mediating tolerance to the amphetanlines develop even when these drugs are given with at least 3 drug-free days intervening. Post-session administration of methylphenidate for 23 consecutive days produced no evidence of tolerance. Similar observations have been obtained with milk drinking procedures when d-amphetamine was administered post-session for seven sessions (Carlton and Wolgin, 1971) or cocaine was administered postsession for 75 days (Woolverton et al., 1978). With an operant task, no tolerance was found to d-amphetamine in rats after 26 days of post-session injection (Campbell and Seiden, 1973). Thus, frequent postsession administration of an amphetamine-ty~ drug is not an adequate condition for producing tolerance, and it appears that the behavioral paradigm plays a critical role in the development of tolerance. One potential variable that could confound the interpretation of results from the post-session group is the phenomenon of conditioned taste aversion (Stolerman and D’Mello, 1978). In a conditioned taste aversion paradigm, a novel appetitive stimulus is followed by drug administration, and, over the course of several such pairings, subjects cease to consume the distinctively flavored substance. In the present experiment, no evidence for conditioned test aversion was found because the post-session group continued to consume the milk during all test sessions. In general, taste aversion is obtained onIy with novel appetitive stimuli, and in the present experiment the rats were

given substantial training on the milk-consumption task before drug injections began. Data from paradigms involving ethanol administration (LeBlanc, Gibbins and Kalant, 1973; LeBlanc, Poulas and Chappell, 1977), have been instrumental in supporting the hypothesis that tolerance is primarily a function of drug in the organism, and this tolerance is behaviorally augmented by the conditions of the test procedure. However, the present authors are unaware of any evidence showing that tolerance occurs to the behavioral effects of amphetamine-type drugs simply as a function of drug administration. Rather, it appears that tolerance occurs to these drugs only for behaviors that are practiced under the drug condition, Thus, for the amphetamines, it may be the case that tolerance is behaviorally determined rather than behaviorally augmented. Two findings in the present experiment support this alternate hypothesis. First, 23 days of post-session administration produced no indication of tolerance. Second, if tolerance is only augmented by behavioral procedures, then lengthening the interval between administration allows the subject to become drug free, which should produce decreased manifestations of tolerance (Kalant rt 01.. 1971). This was not the case in the present experiments because once-every-four-day administration produced tolerance and cross-tolerance that did not differ significantly from that obtained with daily administration. Why does tolerance occur with pre-session but not with post-session administration? Chen (1968) attributed this phenomenon to “learning” to be tolerant to the disruptive effects of the drug, which occurs only with pre-session administration. However, learning is an intervening variable that is difficult to test in terms of a physiological basis for tolerance (Kalant et ul., 1971). Schuster, Dockens and Woods (1966) first suggested that tolerance occurs to drug effects on behavior when the drug decreases reinforcement density, i.e. if a drug modifies behavior in such a way as to cause reinforcements to be lost, then the behavior will return toward baseline. Although the generality of this hypothesis has been questioned (Corfield-Sumner and Stolerman, 1978), it does apply to many instances of tolerance, and it focuses attention on the critical nature of drug-behavior interactions with reference to biochemical events occurring during reinforcement. Particularly because the acute effects of amphetamines are related to their effects on catecholamine metabolism, it is interesting that presentation of a reinforcing stimulus modifies brain catecholamine metabolism (Albert, Emmett-Oglesby and Seiden, 1977; Emmett-Oglesby, Lewy, Albert and Seiden, 1978). Although such a drug-behavior interaction cannot explain why tolerance develops, it may be useful for explaining why certain behavioral paradigms are compatible with tolerance whereas others are not. Tolerance to the disruptive effects of methylphenidate on milk intake was associated with tolerance to the disruptive effects on solid-food intake. This may

1001

Tolerance to methylphenidate not be surprising in that both behaviors are consumatory and required no conditioned behavior. As far as is known, however, there are no previous studies demonstrating that tolerance to amphetamines transfers from one behavioral situation to another. Comparison of Figures 3 and 5 suggests that the degree of tolerance was not as great for food consumption, perhaps reflecting the fact that milk consumption involves substantial fluid intake, and solid food consumption was associated with significantly different stimuli such that tolerance did not transfer completely. Both tolerance (Pear1 and Seiden, 1976) and sensitization, particularly to stereotyped behavior (Browne and Segal, 1977) have been reported after chronic administratl,on of methylphenidate. The present authors also observed stereotyped behavior, and although these data were not scored and recorded, some observations may be noteworthy. First, tolerance does not imply a complete return to baseline. Under saline conditions all milk was consumed during the first 1Omin of the 30min access period; however, after pre-session administration of drug, milk consumption was not complete for most rats until approx. 20min into the session. This phenomenon has also been described lor the effect of d-amphetamine on water intake (MacPhail and Seiden, 1976). Second, when dose-effect testing occurred at the end of the experiment, particularly for large doses, it was not possible to distinguish between rats in the three groups during the 20 min prior to milk access; all rats gnawed on the metal wires of the cage and showed sniffing and head-bobbing signs. When milk was presented, the rats in the chronic saline or post-session groups continued to show these signs, whereas rats in the chronic pre-session groups showed a decrease in stereotyped behavior signs and immediately approached the milk spout. Thus, tolerance to methylphenidate is not simply a decreased drug effect, but rather it may be related to the development of specific behaviors that compensate for the disruption associated with druginduced stereotypies. A number of studies have shown decreased effects of amphetamines when doses are repeated during dose-effect testing (Orloff and Stretch, 1975; Smith and McKearney, 1977; MacPhail and Seiden, 1976; Downs and Woods, 1975). Recently, tolerance has been shown after doses of phencyclidine spaced 8 days apart (Ruffing and Domino, 1980), and longlasting tolerance following a single injection of a narcotic has been reported (Cochin and Kornetsky, 1964). Thus, the phenomenon of tolerance developing during intermittent administration has been demonstrated frequently and for a variety of drug classes, but few studies have examined this variable systematically. The present study has shown that: (1) tolerance to methylphenidate is not a simple consequence of daily injection; (2) pre-session injection of methylphenidate either daily, every-other-day or everyfourth-day produced tolerance; (3) tolerance

produced by every-fourth-day administration was comparable to that produced by daily injection; it produced shifts in the dose-effect curve for methylphenidate and cross-tolerance to d-amphetamine; (4) tolerance transferred to the disruptive effects of methylphenidate on solid-food intake. These findings emphasize the critical role behavioral variables play in producing tolerance, and with respect to amphetamine-type drugs, these results suggest that tolerance may be behaviorally determined. Ackno~ledyements-Supported by Texas College of Osteopathic Medicine faculty research grant 34520. We thank F. Gage and H. La1 for their comments on the manuscript.

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