Cocaine: a microstructural analysis of its effects on feeding and associated behaviour in the rat

45

Brain Research, 608 (1993) 45-51 © 1993 Elsevier Science Publishers B.V. All rights reserved 0006-8993/93/$06.00

BRES 18682

Cocaine: a microstructural analysis of its effects on feeding and associated behaviour in the rat S t e v e n J. C o o p e r a n d Glynis A. v a n d e r H o e k School of Psychology, University of Birmingham, Birmingham (UK) (Accepted 27 October 1992)

Key words: Anorexia; Cocaine; Locomotion; Rearing; Grooming; Microstructural analysis

Cocaine (5.6-30 mg/kg, i.p.) was administered to nondeprived male rats trained to eat a palatable sweetened mash. Over a 60-min period, their behaviour was observed and recorded for a microstructural anaylsis. Cocaine suppressed feeding in a dose-dependent manner (significantly at 10 mg/kg and greater), and this was due in the main to a reduction in the frequency of eating bouts. In contrast, the mean duration of eating bouts was unaffected, except at the highest dose, 30 mg/kg. In addition, the rate of eating was not significantly affected by cocaine at any dose. Time-course data revealed that cocaine, at anorectic doses (10-30 mg/kg), initially suppressed feeding completely, and the duration of this suppression was proportional to the dose. In effect, cocaine delayed the initiation of feeding, thus bringing about the reduction in the number of eating bouts. Cocaine caused some stimulation of locomotor activity and rearing to the side of the observation tank, but did not affect rearing away from the centre, or immobility. Grooming proved to be very sensitive to cocaine's suppressant effect, with substantial inhibition occurring at 5.6 mg/kg (a sub-anorectic dose). These data are compared with previously published work with D-amphetamine and are contrasted with results for selective D I and D 2 dopamine receptor agonists.

INTRODUCTION In contrast to the long-standing interest in the effects of amphetamine and its derivatives on food intake, comparatively little detailed attention has been paid to cocaine's effects on appetite and feeding responses. Van Rossum and Simons reported that cocaine (9.6 mg/kg) reduced food intake in rats by 33% in a 2-hour test 25. In the same study, D-amphetamine (0.4 mg/kg) reduced food intake by 43%. In another early study, intravenous injection of cocaine (3 mg/kg) reduced food intake in food-deprived rats by 65% in a 30-min period immediately after drug administration x2. Balapoule and colleagues showed that the effect of cocaine (10-25 mg/kg, i.p.) on food intake was relatively transient, occurring only in the first hour post-injection 1. Dose-related reductions in food consumption were produced by cocaine (3.45-27.6 mg/kg i.p.) in food-deprived rats 2. Heffner et al. reported dose-dependent reductions in food intake following the administration of cocaine (4-24 mg/kg, i.p.) to food-deprived rats ~3. As an alternative to using food-deprived ani-

mals, Foltin and co-workers found that cocaine (4-32 mg/kg, i.p.) produced dose-dependent reductions in the consumption of sweetened milk by non-deprived rats ~1. Similar dose-related reductions in consumption were produced by D-amphetamine (0.5-4 mg/kg), i.p.) 11. We have observed transient (< 15 min) depression of sucrose sham-feeding following the administration of cocaine (5.6 and 10 mg/kg, i.p.) 7. Although an anorexigenic effect of cocaine has been documented, therefore, none of these reports provide behavioural data with which to understand the mechanisms by which cocaine affects feeding activity. Feeding behaviour is not continuous in rats, but occurs in discrete bouts. A microstructural approach to the study of feeding has been developed, and has contributed substantially to characterizing the different means by which drug treatments affect feeding responses 4,s. The main aim of the present study was to provide microstructural data for the changes in feeding that occur following cocaine administration (5.6-30 mg/kg). Since the feeding-suppressant effect of cocaine may be dopamine-mediated 19, we were also interested in corn-

Correspondence: S.J. Cooper, School of Psychology, University of Birmingham, Birmingham B15 2TT, UK. Fax: (44) (21) 414 3338.

46 paring cocaine's effects with those described previously for the selective dopamine

D 1 receptor agonist SK&F

383936 a n d t h e s e l e c t i v e D 2 r e c e p t o r a g o n i s t N - 0 4 3 7 2~. Several authors

have noted

that cocaine increases

a c t i v i t y m e a s u r e s a t d o s e s w h i c h a r e e f f e c t i v e in r e d u c ing f o o d i n t a k e 2'25. N e v e r t h e l e s s , s u c h i n c r e a s e s i n activity w e r e d e t e r m i n e d

s o l e l y in t e r m s o f p h o t o b e a m

interruptions, and so provide little detail of the characteristics of cocaine's reported mg/kg,

that

stimulant

action. Scheel-Kruger

a relatively large dose of cocaine

i.p.) p r o d u c e d

(25

a strong effect on locomotor

activity and rearing which began a few minutes post-injection and lasted 45-60

m i n 23. A f u r t h e r a i m o f t h e

present study was to provide a microstructural analysis n o t o n l y o f c o c a i n e ' s e f f e c t s o n f e e d i n g b u t a l s o o f its effects on a range of typical behavioural

r e s p o n s e s in

t h e rat, i n c l u d i n g l o c o m o t i o n , r e a r i n g a n d g r o o m i n g . MATERIALS AND METHODS

Animals The subjects were 35 adult male hooded rats (general strain, bred in our laboratory), weighing 310-450 g. They were individually housed with free access to standard laboratory pellets and water. They were maintained on a 12 h light/12 h dark cycle (lights on at 8.00 h). All animals were familiarised with handling and weighing. Drugs Cocaine hydrochloride was obtained from May and Baker Ltd. It was dissolved in isotonic saline, and administered intraperitoneally at doses of 5.6, 10, 17.8 and 30 mg/kg (i.e. in quarter-log units). It was injected 5 min prior to the feeding observation test. Procedure The animals were first adapted to eating a palatable, sweetened mash. The formula was 50 ml sweetened condensed milk, 150 ml

20

powdered Chow (No. 1 ground rat maintenance diet, Special Diet Services Ltd., Essex. UK), and 200 ml tap water, mixed thoroughly and allowed to stand for several minutes. In the first phase (6 days), the rats were given daily access to the sweetened mash in the home cage. They were then adapted to eating the mash in the individual clear-plastic observation boxes (47 × 24 × 19 cm) in a separate, quiet experimental room under red-light conditions (5 days). Testing was therefore undertaken under conditions of familiarity, and in the absence of external disturbance. The animals were subdivided into 5 equal groups and assigned to the 4 dose conditions and vehicle control. Ten minutes following its injection, the animal was transferred to the observation box containing a plastic petri dish with a freshly-prepared sample (40-50 g) of the sweetened mash. Throughout the subsequent 60-min observation period, an observer kept a continuous record of the animal's behaviour within 8-rain bins separated by 2-min breaks, ie. the actual duration of observation was 48 min in total. Each episode of behaviour was recorded by entering the start and end into a microcomputer (BBC Master). Software logged the duration and sequence of each key-press. Six keys were assigned to six non-overlapping response categories, which were chosen on the basis of earlier studies and pilot work with cocaine. The six behavioural categories were: (i) feeding, i.e. biting, chewing and ingesting the sweetened mash; (ii) locomotor activity, horizontal movement about the test box employing all four limbs; (iii) rearing-to-side, front limbs raised and resting on the side of the observation box; (iv) rearing-to-centre, front limbs raised, and not supported on the side of the box; (v) grooming, i.e. licking, scratching or biting at any part of the body surface; (vi) stationary, resting or immobility, i.e. not engaged in any of the preceding activities. The software provided an analysis of the total duration (min) within each response category, the frequency of individual bouts or episodes for each category, and the mean duration of individual bouts. Food intake was calculated by successive weighings (to the nearest 0.1 g). any spillage was collected, weighed and the amount subtracted from the intake measure. The local rate of eating (g/min) was calculated for each test by dividing the amount of food consumed by the total duration of feeding.

Design and statistical analysis The data were analysed by analysis of variance for independent groups. Comparisons between the results for individual drug-treatment groups and the vehicle control group were made using Dunnett's t-test.

2.5 Food

Intake

Eating

rate

(g/min)

(g) 2,0

15 '~" ~

1.5

10 1.0

5 0.5

0

,

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0

5.6 Cocaine

,

,

10

17.8

(mg/kg)

, 30

0.0

,

,

,

0

5.6

10

Cocaine

, 17.8

, 30

(rng/kg)

Fig. 1. (left panel) Cocaine (5.6-30 mg/kg) produced a dose-dependent reduction in palatable food consumption in nondeprived rats. 60 min test. (right panel) Cocaine did not significantly affect the mean local eating rate (g/min) over the test period, n = 7 per group. Levels of significance for individual dose comparisons against the vehicle control group: * P < 0.01 (Dunnett's t-test).

47 RESULTS

Food intake and eating microstructure Under baseline conditions, the non-deprived rats consumed over 15 g of the sweetened palatable food in the 60 min test. Cocaine (5.6-30 mg/kg), i.p.) produced a pronounced dose-dependent reduction in food consumption (Fig. 1, left panel). Significant reductions occurred at doses of 10 mg/kg and greater. These reductions were not due to any significant change in the local rate of eating, as indicated in Fig. 1 (right panel). As Table I indicates, the explanation for the reduction in food intake is that cocaine produced dose-dependent reductions in the total duration of feeding. The total duration can be further subdivided in the frequency of eating bouts and their mean duration. Cocaine (10-30 mg/kg) significantly suppressed the number of eating bouts, but the mean bout duration was significantly affected only at the highest dose (Table I). Hence, cocaine acted relatively selectively to reduce the frequency of eating episodes, and this in turn led to a reduction in the time devoted to eating. When animals did eat, cocaine did not affect the local rate of eating. Fig. 2A illustrates the time course of feeding, and it is clear that during the first time period, cocaine at 10,

17.8 and 30 mg/kg produced complete suppression of feeding, in contrast to the high level of feeding activity under the vehicle condition. The duration of this suppressant effect was dose-related: after 10 mg/kg cocaine, feeding was largely suppressed during the first two time periods, but had returned to near-control levels by the third time period. Hence, its duration of action appeared to be between 20 and 30 min after initiation of the observation period. After 30 mg/kg cocaine, however, feeding gradually returned to the baseline level only in the sixth time period, or upto 60 min after initiation of the test. The data indicate that the probable reason for the cocaine-induced decrease in feeding frequency was a dose-related increase in the latency to initiate feeding behaviour. At the effective anorectic doses, cocaine completely suppressed feeding during the first time period despite the high control level of intake.

Locomotor activity Cocaine significantly increased the total duration of locomotor activity at 10, 17.8 and 30.0 mg/kg (Table I). The duration of individual bouts of locomotion showed little change, but there were large increases in the frequency of bouts, from nearly 90 under the vehicle condition to nearly 400 after 30 mg/kg cocaine. The

TABLE I

Microstructural analysis of behacioural responses following the administration of cocaine hydrochloride (5.6- 30 mg / kg, i.p.) to non-depriced rats in a test of palatable food consumption Results are shown in terms of m e a n 5: S.E.M. (n = 7). F ratios and levels of significance are shown for one-way A N O V A s for dose-effect results.

Behavioral response categories Feeding Total duration (min) Bout d u r a t i o n ( m i n ) Bout frequency Locomotor activity Total duration (min) Bout duration (min) Bout frequency Rearing (side) Total duration (min) Bout d u r a t i o n ( m i n ) Bout frequency Rearing (centre) Total duration (min) Bout duration (min) Bout frequency Grooming Total duration (min) Bout duration (min) Bout frequency

Cocaine (mg / kg) 0 5. 6

10

17.8

F

P

30. 0

8.175:0.56 0.375:0.08 26.435:4.58

7.535:1.10 0.295:0.07 28.295:2.71

5.81+ 0.87 0.405:0.06 15.145:1.87 *

2.33+ 0 . 2 7 * * 0.26+ 0.03 9.865: 1 . 4 6 " *

1.48 + 0.87 ** 0.12 5 : 0 . 0 5 * 8.29 + 3.9 **

14.81 3.75 8.75

<0.001 <0.025 <0.001

3.565:0.28 0.04 + 0.00 87.86+7.41

5.005:0.75 0.04 + 0.00 132.0 5:22.40

8.52+ 0.80 * 0.06 + 0.01 158.86+16.28

8 . 4 3 5 : 1 . 0 5 ** 0.05 + 0.01 175.0 5:12.89

13.13 5 : 0 . 7 3 ** 0.04 5 : 0 . 0 0 392.0 5:46.69 **

23.67 4.00 22.04

<0.001 < 0.025 <0.01

2.835:0.44 0.07+0.01 53.295:3.88

3.40+ 0.39 0.065:0.01 56.57_+ 5.84

2.92+ 0.38 0.05+ 0.00 64.57+ 9.03

5.37+ 0.91 0.035:0.00 ** 153.57_+ 17.5

13.49 5 : 1 . 7 9 ** 0.03 ± 0.01 * * 450.28 _+91.4 * *

22.78 7.36 16.40

< 0.001 <0.001 < 0.001

3.525:0.42 0.06_+0.01 46.43 5:3.89

4.525:0.32 0.06_+ 0.01 80.71 + 8.42

4.91_+ 0.75 0.05_+ 0.01 64.57 5 : 9 . 0 3

2.815:0.51 0 . 0 3 5 : 0 . 0 0 ** 84.3 5 : 9 . 3 2

3.20 5 : 0 . 9 6 0.03 5: 0 . 0 1 " * 96.0 5:11.3

1.96 7.71 2.01

N.S. <0.001 N.S.

12.82-+1.09 0.27-+0.02 47.435:4.60

5.675:1.05 ** 0.11_+ 0.01 ** 53.295:9.53

5.225:1.47 ** 0.10+ 0.01 * 49.57+10.84

1.605:0.33 ** 0.05_+ 0.01 * * 34.57+ 8.09

0.16 -+ 0.09 ** 0.025_+ 0.01 ** 3.71 5: 1 . 6 0 " *

26.45 80.24 6.91

<0.001 < 0.001 <0.001

levels of significance for individual dose comparisons against control conditions: * P < 0.05; * * P < 0.01 (Dunnett's t-test).

48 time course for the drug effect (Fig. 2B) indicates that cocaine (30 mg/kg) enhanced locomotion throughout the observation period, whereas at 10 and 17.8 mg/kg it was effective for the first time period only.

Rearing-to-side Cocaine increased the total duration for rearing to the side, significantly at 30 mg/kg (Table I). There were decreases in the bout duration at 10 and 30 mg/kg, with corresponding increases in the frequency of rearing bouts at these two higher doses. After 30 mg/kg cocaine, the number of rearing bouts was raised from a baseline level of just over 50 to 450 bouts. The

o----

A

4

FEEDING

Rearing-to-centre In contrast, cocaine did not increase the time spent rearing away from the sides of the observation box (Table I). Moreover there was no significant effect on the bout frequency measure.

Grooming Grooming proved to be the most sensitive behavioural index of cocaine's effects. The total duration of grooming was reduced by more than 50% by 5.6 mg/kg cocaine, a dose which had no significant effect

vehicle

--

5.6mg/kg

,& ,I,

10mg/kg 17.8mg/kg

i

"E

time course shows that the 30 mg/kg dose was effective throughout the test (Fig. 2C).

3~Omg/kg

LOCOMOTION E

O I< as .J ,¢ IO I-

k-

0

I

I

I

I

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1

2

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Time

17.8mg/kg 30mg/kg

2 1 0

-1 0

I

!

!

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!

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1

2

3

4

5

6

Time

4-

vehicle REARING(SIDE]

i=~

5.6mg/kg

--

3' ,I

E

vehicle 5.6mg/kg 10mg/kg

~

3

periods

4-C

g'~ ; A

4"

Z

°!

B

5-

10mg/kg 17.8mg/kg

.~ E

3,

30mg/kg

z

2.

periods

~

vehicle

7.

5.6mg/kg

A

10mg/kg

& o

17.8 mg/kg ~

v

z

2'

2

2 < a .J 0~"

o ..J

0p. -I

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Time

periods

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-1

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6

Time

periods

Fig. 2. A. Time course of feeding following administration of vehicle and cocaine (5.6-30 mg/kg). Scores are shown as mean total duration of feeding (min) for each time period throughout 60 min test. Whereas vehicle-treated animals and those treated with 5.6 mg/kg cocaine showed normal satiety functions (high initial level of feeding that declines subsequently), animals treated with 10-30 mg/kg cocaine showed complete initial suppression of feeding. The duration of the suppression was clearly proportional to the dose of cocaine, n = 7 per group. B. Time course for locomotion; 30 mg/kg cocaine elevated locomotion uniformly over the complete test session. C. Again, 30 mg/kg cocaine elevated rearing to the side of the observation tank throughout the complete test session. D. Cocaine dose-dependently suppressed grooming throughout the test; it was completely suppressed at 17.8 and 30 mg/kg. This behaviour was the most sensitive to cocaine's suppressant effects (c.f. Table I).

49 on any other behavioural measure (Table I). Furthermore, grooming was dose-dependently suppressed so that, at 30 mg /k g cocaine, it was completely suppressed for virtually all the observation period (c.f. time course data in Fig. 2D). The suppressant effect on grooming was largely due to a dose-dependent reduction in the mean bout duration; the frequency of grooming episodes remained unaffected at doses of cocaine less than 30 mg/kg.

Immobility Cocaine (5.6-30.0 mg/kg) had no significant effect on the duration of the immobility response during the observation period. DISCUSSION These data indicate that cocaine (5.6-30 mg/kg) produced a dose-dependent reduction in palatable food consumption in nondeprived male rats. The minimum dose to produce a significant reduction was found to be 10 mg/kg (Fig. 1). These results are generally consistent with earlier findings. The microstructural analysis provides further information, however, because it was clear that the reduction in food consumption was not due to a dose-related change in the rate of eating but to a reduction in the time devoted to feeding. Furthermore, at the anorectic doses of 10-30 mg/kg, the significant reductions in the frequency of feeding bouts were a major contributor to the reduction in feeding duration. With the exception of the 30 mg /k g dose, the mean duration of bouts of feeding was virtually unaffected by cocaine. When animals did eat, therefore the duration of feeding bouts and the rate of eating were not generally affected by cocaine. Time-course data (Fig. 2A) indicate that, at 10 and 17.8 mg/kg, cocaine suppressed feeding for 20-30 min, but then levels of feeding rose to exceed baseline levels. It is worth noting that vehicle-treated animals showed the highest level of feeding at the start of the test, and the level of feeding subsequently diminished as the animals presumably became sated. At anorectic doses, cocaine-treated animals showed an opposite pattern: an initial suppression followed by a recovery of what appears to have been near normal feeding. Two conclusions follow from these observations: the first is that cocaine may suppress food intake because it delays the onset of feeding; the second is that cocaine may exert relatively little effect on feeding per se, once it has been initiated. It is interesting, therefore, that a common feature of D-amphetamine's anorectic effect is that it invariably extends the latency to initiate feeding 4"5'8'9'15'24.In a recent study using human volun-

teers, whose food intake was continuously monitored in a residential laboratory, D-amphetamine reduced daily caloric intake by extending the time, post-drug-administration, to the first eating occasion ~°. Thereafter meal sizes were not affected. There may be a close similarity, therefore, between the microstructural features of the effects of D-amphetamine and those of cocaine on feeding behaviour. A critical effect for both drugs appears to be the increased latency to initiate feeding. This suggests that both drugs may act during the appetitive phase that precedes consumption to reduce food incentive, but that food ingestion that occurs during the consummatory phase is not necessarily affected. This suggestion is consistent with other data that Damphetamine acts in part to suppress appetitive behaviour 22 and that dopaminergic activity may be particularly involved in preparatory behaviours elicited by incentive stimuli 3. In any event, the microstructural data for cocaine (this study) differ quite considerably from those for the selective D 2 receptor agonist N-043721 and the selective D~ receptor agonist SK & F 383936 reported previously. N-0437 did not reduce the duration of feeding, but caused a decrease in food intake by selectively reducing the rate of eating. Cocaine, however, did not significantly alter the rate of eating. SK&F 38393 reduced the frequency of feeding bouts, but it did not alter the temporal structure of feeding: animals still showed the highest level of feeding initially which then declined through the test period (the overall level was reduced compared to control values). Cocaine, in contrast, suppressed feeding initially, followed by a relatively rapid recovery of feeding. There is no sense, therefore, in which cocaine's effects can be straightforwardly matched with the effects of either dopamine D 1 or dopamine D 2 receptor stimulation. There is considerable evidence that cocaine not only inhibits dopamine uptake 2° but also increases extracellular dopamine concentrations in the striatum and nucleus accumbens 16'~7'18. Postsynaptic dopamine receptors are therefore likely to be stimulated. Yet, in drug discrimination studies using rhesus monkeys, neither SK & F 38393 nor the dopamine D 2 receptor agonist quinpirole engendered cocaine-appropriate respondi n f 4. Using rats, SK & F 38393 and other dopamine D 1 agonists as well as a series of dopamine D 2 receptor agonists (including N-0437) only partially substituted for cocaine 27. In both studies it was concluded that stimulation of either D~ or D 2 receptors is not sufficient for the expression of cocaine's discriminative stimulus effects. Likewise the manner in which cocaine affected feeding behaviour in the present study could not be attributed to the selective stimulation of either

50

D~ or D 2 receptors. Nevertheless, cocaine-induced anorexia does appear to be dopaminergically-mediated. In an unpublished study (Cooper and van der Hoek), we found that the significant reduction of palatable food intake produced by cocaine (15 mg/kg, i.p.) in nondeprived rats was dose-dependently reversed by haloperidoi (0.03 and 0.1 mg/kg). This result confirms an earlier finding that 10 mg/kg cocaine's anorectic effect in food-deprived rats was antagonised by spiperone (spiroperidol) (0.1 mg/kg) t3. More recently, Rapoza and Woolverton have examined the role of dopamine receptors in the effect of cocaine on sweetened milk intake 19. Cocaine (4-32 mg/kg, i.p.) produced dose-dependent decreases in milk consumption, and both SCH 23390, a D~ receptor antagonist, and raclopride, a D 2 receptor antagonist, attenuated cocaine's effect for at least one of its effective doses. Stimulation of both D~ and O 2 receptors, therefore, may be involved in cocaine's effects on milk intake. In summary, stimulation of either D 1 or D 2 receptors is not sufficient to account for cocaine-induced anorexia; nevertheless, dopamine receptor stimulation (both D~ and D 2) may be necessary for cocaine's effects. The present study also provided new data for cocaine's effects on other behavioural response categories. At 30 mg/kg cocaine, the frequency of bouts of locomotion and of rearing-to-side were markedly increased, leading to large increases in the total durations of locomotion and rearing (Table I). These effects were present throughout the observation period of 60 min. The duration of locomotion was also significantly increased at 10 and 17.8 mg/kg, but these effects were more transient (Fig. 2B) and corresponded to the transient suppression of feeding (Fig. 2A). One of the most striking effects of cocaine, however, was its marked suppression of grooming. All doses tested (5.6-30 mg/kg) significantly suppressed grooming, and this continued largely unabated throughout the 60 rain observation period. Hence grooming was more sensitive than feeding to cocaine's suppressant effect, and was affected for a longer period of time. Since we did not observe the animal's behaviour beyond 60 min, we have no estimate of how long grooming would have remained suppressed. It is clear, however, that animals were recovering feeding (Fig. 2A) well before grooming recovered from suppression (Fig. 2D). These data imply that grooming behaviour may provide a particularly sensitive index of cocaine's behavioural suppressant effects. Since D 1 receptor agonists can induce excessive grooming 26, whereas the D 2 receptor agonist N-0437 significantly suppressed grooming 21, it is possible that stimulation of D 2 receptors is sufficient to account for cocaine's effects on grooming.

Acknowledgements. G.A. van der Hoek was in receipt of a Glaxo Group Research studentship. We wish to thank Mrs. Dorothy Trinder for her preparation of the manuscript.

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51 19 Rapoza, D. and Woolverton, W.L., Attenuation of the effects of cocaine on milk consumption in rats by dopamine antagonists, Pharmacol. Biochem. Behav., 40 (1991) 133-137. 20 Ritz, M.C., Lamb, R.J., Goldberg, S.R. and Kuhar, M.J., Cocaine receptors on dopamine transporters are related to self-administration of cocaine, Science, 237 (1987) 1219-1223. 21 Rusk, I.N. and Cooper, S.J., Microstructural analysis of the anorectic effect of N-0437, a highly selective dopamine D 2 agonist, Brain Res., 494 (1989) 350-358. 22 Salisbury, J.J. and Wolgin, D.L., Role of anorexia and behavioral activation in amphetamine-induced suppression of feeding: implications for unde1'standing tolerance, Behav. Neurosci., 99 (1985) 1153-1161. 23 Scheel-Kruger, J., Behavioural and biochemical comparison of

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