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Physiology and Behavior, Vol. 9, pp. 795--800. Brain Research Publications Inc., 1972. Printed in U.S.A.

Effects of A - Tetrahydrocannabinol and Food Deprivation Level on Responding Maintained

by the Opportunity to Attack

D. R. CHEREK, 2 T. THOMPSON AND G. T. HEISTAD

Psychiatry Research Unit, Box 392 Mayo, University o f Minnesota Minneapolis, Minnesota 55455

(Received 24 February 1972)

CHEREK, D. R., T. THOMPSON AND G. T. HEISTAD. Effects of A 1 -tetrahydrocannabinol and food deprivation level on responding maintained by the opportunity to attack. PHYSIOL. BEHAV. 9(5) 795-800, 1972.- Pigeons responded in a two key situation for food presentation and access to a restrained target bird that could be attacked. Doses of A ~ -tetrahydrocannabinol (0.125 and 0.25 mg/kg) which resulted in minimal changes in the rate of food reinforced responding, produced a marked suppression of attack responses and responding for target presentation, relative to their vehicle control rates. Manipulations of the level of food deprivation failed to mimic the effects of A'-tetrahydrocannabinol. As the percent of frce-feeding weights of the birds was increased (5-10%) the rate of attack responses and responding for target presentation was unchanged or slightly increased, while the rate of food reinforced responding was decreased, in terms of percent change from the vehicle control rate. The selective suppressing effect of A'.tetrahydrocannabinol on attack rate and responding for target presentation does not appear to be due to a general depressant action of the drug or a change in the level of food deprivation.

Aggression A ~ -tetrahydrocannabinol Food deprivation Pigeon

IN EVALUATING the selective effect of a drug in reducing aggressive behavior, it is necessary to demonstrate that the effect does not merely represent a generalized depressant action (i.e., ataxia, impaired motor function, etc.). One method of dealing with this problem is to measure the effects of the drug on more than one behavior at the same or approximately the same times [21]. Previously, three studies have reported that crude marihuana extracts decreased isolation-induced aggression in mice. In two of these studies [2, 19], the specificity of this effect could not be ascertained, since the effects of the drug on other behaviors were not determined. Santos, Sampaio, Fernandes and Carlini reported a decrease in aggression at doses of marihuana that produced no effects on motor activity [20]. These authors concluded that marihuana had a very selective effect of decreasing aggression.

In the present experiment, schedule-induced aggression in pigeons was used to evaluate the effect of ~l- te t ra- hydrocannabinol. The monoterpenoid numbering system for tetrahydrocannabinols was employed. Delta-one- t e t r a h y d r o c a n n a b i n o l is equivalent to delta-nine- tetrahydrocannabinol using the pyran numbering system.

This technique had two advantages over the isolation- induced procedure in evaluating the effects of drugs on aggression. First, the method uses an objective automated recording of the aggressive behavior, thus avoiding the problems of reliability associated with the use of direct observational recording. Secondly, it is possible to compare the effects of delta-one-THC on two concurrently occurring behaviors, food reinforced responding and aggressive attack. The determination of selectivity of drug action on two behaviors occurring over the same time interval, within the same environmental context, affords a more valid estimate of the specificity of drug action.

EXPERIMENT 1 : EFFECTS OF DELTA-ONE-TETRAHY- DROCANNABINOL ON RESPONDING MAINTAINED BY

THE OPPORTUNITY TO ATTACK

METHOD

Animals

Six experimentally naive male White Carneaux pigeons

~This research was supported by U.S.P.H.S. grant MH-08565. 2 Reprints may be obtained from D. R. Cherek, Research Department, Kalamazoo State Hospital, Kalamazoo, Michigan 49001. Basic data

tables may be obtained from D. R. Cherek upon request.

795

796 CHEREK, THOMPSON AND HEISTAD

(Palmetto, Sumter, So. Carolina) 6 - 1 2 months old were used. Three pigeons served as experimental birds, and three as target birds. The experimental birds were food deprived and maintained at 80% of their free feeding weights. Target birds were not food deprived. Each target bird was paired with a specific bird for the entire experiment. All pigeons were housed in individual cages with water continuously available.

Apparatus

The experimental apparatus was a standard pigeon test chamber (LeHigh Valley Electronics), containing two response keys and a solenoid operated food delivery mechanism. The response keys were illuminated by white lamps; the chamber contained an overhead light.

The apparatus for recording aggressive attack was very similar to that described by Azrin, Hutchinson and Hake [1]. The target birds were restrained in a box by metal bands fastened over each wing. The restraining box was mounted on a metal frame containing an adjustable spring and microswitch. A force of at least 100 g exerted against the front of this box by the experimental bird, during periods of attack, resulted in a switch closure. Each switch closure was recorded as an attack response. The restraining box was located on the side of the chamber. Plexiglas shields on either side of the restraining box prevented the experimental pigeon from getting behind the target, since only displacements of the front of the box were recorded. Although the target birds made vigorous defensive movements prior to attack episodes, such movements, by themselves, failed to activate the microswitch.

Procedure

Schedules. Responding on the right (food) key resulted in the presentation of food (Purina poultry pellets) for 3 sec. Access to food was presented on a response-initiated fixed-interval (FI) 2 min schedule [17]. On such a schedule, the first response (at the beginning of the session or following food presentation within the session) initiated a 2 min interval, and the first response after the interval elapsed resulted in food presentation. This schedule has been found to induce aggression in pigeons [4], and the highest rates of responding for the opportunity to attack and of attack responses were observed at an FI value of 2 or 3 min [6].

Responding on the left (target) key on a fixed-ratio (FR) 2 schedule (i.e., two responses) resulted in access to a live target bird that could be attacked. A transparent Plexiglas shield, positioned in front of the target bird, prevented the experimental bird from gaining access to the target bird. In the original description of the apparatus [ 1 ], a shield was not used, thus allowing the experimental bird continual access to the target bird throughout the session. Responding on the target key produced a 3 sec tone, and activated a motor driven shaft that pulled the shield to one side, exposing the target bird. The shield remained in the open position for 15 sec, and then was closed by a second activation of the motor. During the time that the target bird was accessible, the light on the target key was extinguished, and the responses on that key were of no consequence.

To ensure that responding for access to the target bird was not maintained by superstitious food reinforcement (i.e., an accidental correlation of food presentation with

responding on the target key): (a) a 15 sec change over delay (COD) was interposed between the occurrence of each response on the target key and the presentation of food following a response on the food key [3] ; and, (b) a 15 sec protective contingency between the termination of target availability (the returning of the shield in front of the target bird) and the presentation of food following a response on the food key. This prevented the accidental temporal association of responding on the target key or movement of the shield with access to food.

Drug. Synthetic delta-one-THC in 95% ethanol (200/mg/cc) was suspended in a mixture of Arlacel-20 and Tween-65 in saline [18]. Suspensions were stored in the dark at 4°C. Doses of 0.125, 0.25, 0.5, and 1.0 mg/kg of delta-one-THC were administered in a random order, with each dose being given twice. Pigeons were injected I. M. with vehicle or delta-one-THC suspension in a constant volume of 1 ml/kg of body weight two hr prior to the beginning of the session. Six days elapsed between each drug session to minimize the development of tolerance [16].

Training. Birds were hand shaped to key peck for food on a FR 1 schedule. An FI 5 sec schedule was then instituted, and over sessions, the value of the FI was increased to 2 min. Pigeons were run on the FI 2 min food reinforcement schedule until the rate of responding stabilized (approximately 2 weeks). During this initial training, the target key was covered and the restraining box was absent. Following stabilization of food reinforced responding, the target was placed in the restraining box, and the target key was uncovered and illuminated. For three consecutive sessions, a single response (FR 1) on the target key resulted in access to the target bird. After the third session, two responses (FR 2) on the target key were required to gain access to the target bird. Pigeons were run on the FI 2 rain (food) FR 2 (access to the target bird) schedules for ten 45 rain daily sessions.

Following this training phase, birds were given the opportunity to respond for access to the target bird on every third session. During other intervening sessions, the pigeons were run on the FI 2 min food schedule alone, with the target bird and restraining box absent. Pigeons were not given access to the target bird on each session: (a) to minimize injury to the target; and, (b) to avoid the decrease in aggression sometimes observed when birds are exposed to a live target bird over successive sessions [5]. Vehicle or delta-one-THC injections were also given every third session, when the target bird was present (see Table 1). Drug sessions were run every 6 days, with one vehicle control session run before and after each drug session.

RESULTS

A'-Tetrahydrocannabinol produced a dose-dependent decrease in responding on the FI 2 min food reinforcement schedule. The slight decrease in response rate observed at 0.125 and 0.25 mg/kg of delta-one-THC, was primarily the result of increased postreinforcement pausing (i.e., the time between food presentation and the initiation of the next fixed interval). Higher doses of delta-one-THC (0.5 and 1.0 mg/kg) resulted in further increases in pausing, or a complete cessation of responding after birds had responded through some intervals early in the session. There was very little effect on the temporal patterning of responding,

~1 -THC, FOOD DEPRIVATION AND AGGRESSION 797

TABLE 1

EXPERIMENTAL DESIGN FOR EXPERIMENTS 1 AND 2

Exp. 1 Exp. 2 Session Schedule(s) Target Drug % body weight

1 FI 2 min (food) absent no 80


3 FI 2 min (food); FR 2 (target) present vehicle 80 (control)



6 FI 2 min (food) FR 2 (target) present THC 85, 90, or 100

(experimental)

7 sequence repeated

except at the highest dose (1.0 mg/kg). Similar results have been reported for pigeons responding on fixed ratio and fixed intervals reinforcement schedules following the administration of delta-one-THC [ 14 ].

The effects of delta-one-THC on the overall mean response rate on the FI 2 min (food) and FR 2 (target presentation) schedules are shown in Fig. 1. At 1.0 mg/kg, both rates of responding decreased to between 0 - 2 0 % of the control (vehicle) rate in pigeons P 51 and P 52; with pigeon P 50 the rate of food reinforced responding decreased to 30% of control, and the response rate for target presentation decreased to less than 10% of the control rate. All other doses of delta-one-THC resulted in suppression of responding for target presentation more than the rate of responding for food presentation, relative to their vehicle control rates. This effect is most evident at 0.125 mg/kg of delta-one-THC, where there was little or no effect (95-110% of control rate) on food responding, while the rate of responding for target presentation was decreased to 50-60% of the vehicle control rate. Similarly, at 0.25 and 0.5 mg/kg of delta-one-THC the decrease in food responding (75-90% and 40 -55% of control rate) was substantially less than the observed decrease in the rate of responding for target presentation ( 2 5 - 5 0 and 0 -2 0% of the control rate).

The effects of delta-one-THC on the mean number of target and food presentations per session are shown in Table 2. Low doses of delta-one-THC (0.125 and 0.25 mg/kg) resulted in marked decreases in the number of target presentations, while having little or no effect on the n u m b e r of food presentations. Higher doses of delta-one-THC (0.5 and 1.0 mg/kg) decreased the number of target and food presentations, with the number of target presentations being decreased more than the number of food presentations at both dosage levels. reinforced responding, produced a marked decrement in the rate of attack responses (15-60% of the control rate). Both the rate of responding for target presentation and the rate

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FIG. 1. The effects of delta-one-THC on the mean response rate on the FI 2 min (food) and FR 2 (target presentation) schedules. The verticle lines labeled F (food responding) and T (responding for target presentation), represent the range of response rates observed during vehicle control sessions expressed as a percentage of the mean control value. The mean response rates (vehicle controls) for food responding were: 30.31 (P 50),41.92 (P 51), and 34.98 (P 52); responding for target presentation were: 0.74 (P 50), 0.60 (P 51), and 0.66 (P 52) responses per minute. The verticle lines at each

dosage point represent the range of two observations.

of attack responses are similarly affected by delta-one-THC, with the rate of attacks being suppressed more at a given dose of delta-one-THC (relative to control rate) than the rate of responding for food presentation.

EXPERIMENT 2: EFFECTS OF FOOD DEPRIVATION LEVEL ON RESPONDING MAINTAINED BY THE

OPPORTUNITY TO ATTACK

Falk has proposed that schedule-induced aggression, schedule-induced escape, and polydipsia be included in a new class of behaviors termed "adjunctive" [11]. This classification is based upon common properties and similar functional relationships to a number of variables reported for these behaviors.

The level of food deprivation has been shown to be an important determinant of schedule-induced or adjunctive behaviors. Schedule-induced polydipsia and airlicking are decreased following decreases in the level of food deprivation [7, 10]. In the present experiment, the percent of free feeding weight was varied to determine its effects on the rate of responding for target presentation and the rate of attack, and to contrast these results with the effects of delta-one-THC on schedule-induced aggression observed in the previous experiment. Since decreases in the level of

798

TABLE 2

EFFECTS OF AI-TETRAHYDROCANNABINOL ON MEAN NUMBER OF TARGET AND FOOD PRESENTATIONS

Mean number of target presentations

P 50 P 51 P 52

Vehicle* 16.5 13.6 15.0

A'-THC mg/kg'~ 0.125 10.0 8.5 0.25 7.5 5.5 0.5 2.5 2.5 1.0 1.0 0.0

Mean number of food presentations

P 50 P 51 P 52

Vehicle* 13.2 t6.3 17.1

A'-THC mg/kgl 0.125 14.0 16.5 0.25 13.0 15.5 0.5 9.5 10.0 1.0 5.5 0.0

*Value represents the mean of eight vehicle control sessions. tValue represents the mean of two drug sessions at each dosage level.

food deprivation result in decreases in rate of adjuncitve behaviors, the effects of delta-one-THC on schedule- induced aggression may represent a change in the effective level of food deprivation. A possible effect of delta-one- THC on food deprivation level is supported by reports of decreased food intake in dogs and rats following the administration of delta-one-THC [ 14, 15].

METHOD

The same subjects and apparatus described in Experiment 1 were used.

Procedure

Pigeons were run on an FI 2 min (food) FR 2 (access to target bird) schedules or the food schedule alone, with the target bird present on every third session as discussed in Experiment 1. During the control condition (with the target bird present), birds were run at 80% of their free feeding weights. During experimental sessions (with the target present), pigeons were prefed to 85, 90, and 100% of their freefeeding weights two hr prior to the beginning of the session. Body weights were manipulated in a random order. When pre-fed to 100% of free feeding weight, birds were not run for the next two days. Following prefeeding to 85 or 90% of free feeding weight, the body weight returned to the 80% level by the time that the next control

CHEREK, THOMPSON AND HEISTAD

session was conducted (see Table 1). One control session was run before and after each prefeeding experimental session.

RESULTS

The effects of increasing the percent of free feeding weight on responding on the FI 2 min food reinforcement schedule were similar to those produced by delta-one-THC. The amount of postreinforcement pausing increased as the percent of free feeding weight increased, resulting in a decrease in the rate of food reinforced responding. Responding during the fixed interval was suppressed only when the body weight was increased to 100% of the free feeding level.

8.0 The mean response rate for target presentation and the 4.5 rate of food reinforced responding as a function of percent 0.0 of free feeding weight are shown in Fig. 2. Both the rate of 0.0 food reinforced responding and the rate of responding for

target presentation decreased as the percent of free feeding weight increased. The rate of food and target key responses is approximately equal (relative to controls) for pigeon P 52 at 85, 90 and 100% of free feeding weights. For pigeon P 50 and P 51, at 85 and 90% of their free feeding weights, the rate of food key responding was decreased more, in terms of percent units below control, than the rate of target key responding. The rate of food reinforced responding was decreased to 60-90% and 70-80% of the control rate, while responding for target presentation was 95-135% and

17.5 80-105% of the control rate when pigeons (P 50 and P 51) 18.5 were run at 85 and 90% of their free feeding weights. 11.5 The rate of attack responding showed similar changes as a

3.5 function of the percent of free feeding weight. At 100% of free feeding weight, the percent decrease (relative to controls) in attack rate was equal to or slightly more than the decrease in food response rate. The rate of attack was higher (95-105% of control rate) than the rate of food reinforced responding (60-90% of control rate) for pigeons P 50 and P 51 at 85 and 90% of the free feeding weight.

DISCUSSION

The results of Experiment 1 indicate that delta-one-THC appears to have a relatively selective effect of decreasing responding for target presentation and attack responses when compared to its effects on food reinforced responding. This supports previous reports of the effects of marihuana extracts in suppressing isolation-induced aggression in mice [2, 19, 20].

The suppressing effect of delta-one-THC on schedule- induced aggression observed in Experiment 1 cannot be attributed to a nonselective depressant action. Doses of delta-one-THC (0.125 and 0.25 mg/kg) which had little or no effect on food reinforced responding resulted in substantial decreases in the rate of attack responses and responding for target presentation in terms of percent change from their vehicle control rates.

The manipulation of food deprivation level failed to mimic the effects of delta-one-THC on schedule-induced aggression. In Experiment 2, it was found that decreasing the level of food deprivation had no selective effect on food reinforced responding, responding for target presentation, or attack responses. As the level of food deprivation was decreased, the rates of all responses decreased. At 85 and 90% of free feeding weight the rate of attack and the rate

/ ` ' -THC, FOOD DEPRIVATION AND AGGRESSION 799

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FIG. 2. The mean response rate for target presentation and the rate of food reinforced responding as a function of the percent of free feeding weight. The verticle lines labeled F (food responding) and T (responding for target presentation), represent the range of response rates observed during base line control sessions expressed as a percentage of the mean control value. The mean control response rates for food responding were: 30.28 (1) 50), 45.54 (P 51), and 36.13 (P 52); responding for target presentation were: 0.91 (P 50), 0.88 (P 51), and 0.56 (P 52) responses per rain. The verticle lines at 85, 90 and 100 percent of free feeding weight represent the range of

two observations.

of responding for target presentation were essentially unchanged or slightly increased, while the rate of food reinforced responding was decreased relative to their vehicle control rates. If an important aspect of THC's action on schedule-induced aggression is the result of an effect on deprivation level, then the effects of manipulating food deprivation level should produce effects similar to those observed when delta-one-THC is administered [8]. The effect of varying the level of food deprivation clearly is not similar to the effects of delta-one-THC. Following delta- one-THC administration the rate of responding for target presentation and attack responses is markedly decreased relative to its effects on food reinforced responding. Thus, the selective suppressing effect of delta-one-THC on these two behaviors (attack and responding for target presentation) does not appear to be due to a change in the level of food deprivation.

The effects of varying food deprivation level on responding for target presentation are consistent with changes in schedule-induced polydipsia and airlicking brought about by similar alterations of food deprivation level [7, 10]. Other similarities between responding for target presentation and schedule-induced polydipsia and schedule-induced escape have been previously reported [6 ]. The effects of delta-one-THC on aggressive behavior reported in this experiment may represent a selective effect on aggression, or on schedule-induced behaviors (i.e., adjunctive) as a class of behaviors.

Numerous studies have shown that the schedules con- trolling the presentation of events are a critical determinant of the behavioral actions of drugs [9, 13]. Since an accessible target and food were presented on different reinforcement schedules (fixed ratio and fixed interval), the apparent differential effects of delta-one-THC may have been due to this factor.

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13. Kelleher, R. T. and W. H. Morse. Determinants of the specificity of behavioral effects of drugs. Ergebn. Physiol. 60: 1-56, 1968.

14. Manning, F. J., J. H. McDonough, Jr., T. F. Elsmore, C. Saller and F. J. Sodetz. Inhibition of normal growth by chronic administration of /`-9-tetrahydrocannabinol. Science 174: 424-426, 1971.

15. McMillan, D. E., W. L. Dewey and L. S. Harris. Characteristics of tetrahydrocannabinol tolerance. Ann. N. Y. Acad. Sci. 191: 83-99, 1971.

16. McMillan, D. E., L. S. Harris, J. M. Frankenheim and J. S. Kennedy. l-/,9-trans-tetrahydrocannabinol in pigeons: Tolerance to the behavioral effects. Science 119: 501-503, 1970.

17. Mechner, F., L. Guewekian and V. Mechner. A fixed-interval schedule in which the interval is initiated by a response. J. exp. AnalysisBehav. 6: 323-330, 1963.

800 CHEREK, THOMPSON AND H E I S T A D

18. Moreton, J. E. and W. M. Davis. A simple method for the preparation of injectablcs of tetrahydrocannabinols and cannabis extracts. J. Pharm. Pharmac. 24: 176, 1972.

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