'This investigation was supported in part by grant MH 17001 from the National Institute of Mental Health. Some of these data were reported at the 1970 Annual Meeting of the Federation of American Societies for Experimental Biology and at the 1970 Eastern Psychological Association Annual Meeting.

 

1-2-trans-Tetrahydrocannabinol (0°-THC) is the most abundant tetrahydrocannabinol in Cannabis sativa (Gaoni and Mechoulam, 1964; Mechoulam and Gaoni, 1967; Mechoulam, 1970). The effects of marihuana and hashish, which arc widely used illicit preparations of C. sativa, are mimicked by 01-THC in man (Isbell et al., 1987; Hollister et al., 1968; Waskow et at., 1970). /-W-trans-Tetrahydrocannabinol (AsTHC) is found in small quantities in C. sativa (Hively et al., 1966; Mechoulam, 1970), and it also mimics the effects of marihuana and hashish in man (Adams, 1942).

 

Cannabinol was the first pure component isolated from C. sativa (Wood et ca., 1896, 1898, 1899). This component is generally believed to be pharmacologically inactive (Adams, 1942; Loewe, 1944; Farnsworth, 1968; Mechoulam, 1970; Mechoulam et at., 1970).

 

Since 2-THE had not been isolated in a pure form, and its structure had been known only in a general way before 1964 (Goani and Mechoulam), there a few studies of the behavioral effects of this drug. The present experiments describe some of the behavioral pharmacology of 2-THE and 2-THE in pigeons and rats, as well as the effects of very large doses of cannabinol in pigeons.

 

METHODS. SUBJECTS. The pigeons were 12 White Carneaux males whose individual weights ranged from 500 to 675 g when they had free access to food and water. The birds were deprived of food until they reached 80% of their free-feeding weights, and they were maintained at this level throughout the experiments. Water was always available.

 

The rats were four Boltzmann males who were four to six weeks old and experimentally naive when training was initiated. They were maintained on a 23-hour water deprivation regime throughout the experiments. Food was always available in the home cage, and water was available for 15 minutes, after the one-hour experimental session, in the home cage.

 

APPARATUS. The pigeon experimental chambers, after Ferster and Skinner (1957), were two sound-attenuating chambers. A translucent plastic response key, 2 cm in diameter, was mounted on a wall inside each chamber. The minimum force to operate the key was about 15 g. Opening saf the key contacts defined the pecking. response. The key could be transilluminated by either red or blue lamps. Each chamber was illuminated by a 15-w bulb, and white noise was present in the chamber at all times to mask extraneous sounds.

The rat experiments were in a small animal test cage (model 1417, Lehigh Valley Electronics, Fogelsville, Pa.), housed in a sound-attenuating chamber. The test cage contained two model 1352 response levers (Lehigh Valley Electronics), but only the right-hand lever was connected to the programming and recording circuits. Lamps were mounted above the response lever. The left-hand lamp had a red lens and the right-hand lamp had a blue lens. An electrically operated dipper mechanism was used to deliver approximately 0.01 ml of water after a lever press. The chamber was illuminated by a 6-w bulb, and white noise was present in the chamber at all times.

 

Conventional relay programing and recording apparatus were employed to control the delivery of food (pigeons) or water (rats) and to record the key pecks of the pigeons or lever presses of the rats. All programing equipment was housed in a room separate from the test compartments.

 

SCHEDULES. The multiple fixed-ratio 30-response, fixed-interval 5-minute (mult FR 30 FI 5) schedule of food presentation for pigeons has been described in detail elsewhere (Ferster and Skinner, 1957), as has its application to behavioral pharmacology (Dews and Skinner, 1956; Dews and Morse, 1961; Morse, 1962; McMillan, 1968a). Briefly, the mult FR 30 FI 5 schedule may be described as follows. In the presence of a blue key light the 30th key peck (FR 30) resulted in 5-second access to grain. In the presence of a red key light the first peck after 5 minutes (FI 5) resulted in 5-second access to grain. The key colors and the associated components alternated after each presentation of the food. If no response occurred within 40 seconds after 5 minutes in the presence of the red light (40-second limited hold) the schedule changed to the FR component. A 40-second limited hold also applied to the FR component. A session terminated at the first schedule component switch after 60 minutes.

 

The multiple fixed-ratio 6-response, fixed-interval 1-minute (mult FR 6 FI 1) schedule of water presentation used for the rats was similar. In the presence of a blue light (right-hand lamp) the 6th lever press (FR 6) resulted in water presentation. In the presence of a red light (left-hand lamp) the first press after 1 minute (FI 1) resulted in water presentation. These components and their associated stimulus lights alternated after each water presentation. A 40-second limited hold applied to both schedule components. A session terminated at the first schedule component alternation after 60 minutes.

 

The temporally, spaced responding schedule of food presentation specified that a key peck which followed the previous key peck (or the beginning of the session or the termination of a food presentation) by at least 20 seconds, but not by more than 24 seconds, produced food. That is, a response terminating an interresponse time (IRT) of between 20 and 24 seconds produced food. Responses terminating IRT's shorter than 20 seconds or longer than 24 seconds did not produce food, but began a new IRT. This schedule procedure will be specified as IRT > 20 seconds < 24 seconds, after Morse (1966). A session terminated at the first key peck after 60 minutes, or 20 seconds after 60 minutes if no responses were occurring. This schedule was chosen because of numerous reports of impaired time estimation caused by C. sativa preparations or synthetic tetrahydrocannabinols (for example, Williams at at., 1946; Ferster and Skinner, 1957, p. 629; Weil et at., 1968; Isbell et at., 1967), and one report (Boyd et at., 1963) of synthetic tetrahydroeannabinols (not Y-TIIC or a°-THC) appearing to increase the ability of rats to estimate elapsed time.

 

DRUG PROCEDURE. The synthetic tetrahydrocannabinols and cannabinol were stored in the dark at about 4°C. When ready for use, the YTHC, i'-THC or cannabinol was suspended in an aqueous solution of Triton X-100. Suspensions were kept at about 4°C in the dark, but were allowed to stand at room temperatures (in the light) for at least 10 minutes before the injection. Dilutions were made so that the volume injected was always 1 ml/kg.

 

To correspond with the amount of Triton X-100 in the most concentrated suspension, a 1% (by volume) solution of the detergent was used as a vehicle control injection in the pigeons, and a 6.5% solution was used as a vehicle control injection in the rats. To correspond with the amount of Triton X-100 in the most concentrated ‘V-THC suspension, a 3.5% solution was used as a vehicle control in the pigeons.

 

Four of the pigeons were used to examine the effects of the tetrahydrocannabinols under the mult FR FI schedule. These birds had worked under this schedule for a year prior to these experiments. A second group of four birds was used to test the tetrahydrocannabinols under the temporally spaced responding schedule. These birds had worked under variations of this schedule for several years prior to these experiments. The birds had received no drugs for two months prior to the trials with ‘1°-THC.

 

A third group of four pigeons who had never received drugs was used to examine the effects of cannabinol under the mult FR FI schedule. These birds were under this schedule for one month, receiving no drugs, prior to the trials with cannabinol.

 

The group of four rats were under the mult FR 6 FI 1 schedule for three weeks, receiving no drugs, prior to the trials with A°-THC.

 

Because preliminary trials had shown a slow onset of action by marihuana constituents (also reported by Scheckel et at., 1968; Loewe, 1944), injections in the breast muscle of the pigeons were made two hours before a session. Injections in the peritoneum of the rats also were two hours before a session.

 

Doses for the pigeons were given in a mixed order separated by at least three days without injections. Doses for the rats were given in a mixed order separated by at least six days without injections. Noninjection control sessions for all animals studied were at least three days after an injection and were generally one day before an injection. The dose-effect relation was determined for A°-THC in every animal before A'-TEIC administration was begun.

 

MEASUREMENT OF DRUG EFFECTS. FR Fl schedules. Average rates of responding (key pecking or lever pressing) during FR and FI conponents throughout a session were computed in responses per second from digital counters and elapsed-time meters.

F! 5 (pigeons). From the total number of responses recorded in each tenth (30 seconds) of the FI duration over the entire session, the percentage of the interval taken for the first quarter of the responses to occur was determined. This estimated quarter-life value provides an indication of the temporal patterning of FI responding which is relatively independent of FI rates of responding (Herrnstein and Morse, 1957; Gollub, 1964).

FI i (rats). In order to evaluate the effects of the drugs on response patterning, the total number of lever presses for the first and last 30 seconds of the FI duration over the entire session were re corded separately. The total number of responses during the first 30 seconds of the FI was expressed as the percentage of the number of responses during the last 30 seconds (McKearney, 1968).

 

IRT > 20 seconds < 24 seconds schedule. The rate of key pecking for an entire session was computed in responses per second. Interresponse time distributions (Anger, 1956) were also obtained. All IRT's less than 36 seconds were recorded in 9 class intervals with an interval width of 4 seconds, and all IRT's longer than 36 seconds registered in the 10th class interval. As a measure of temporal discrimination under this schedule, conditional probabilities were calculated according to the method of Anger (1963). Anger's conditional probability is the probability that a response will occur within a class interval, given that a response has not prevented the occurrence of that class interval.

 

RESULTS. Control performance of pigeons under mult FR 30 FI 5. When the birds were not injected, this reinforcement schedule engendered performance like that previously described (Ferster and Skinner, 1957). In the early part of the FI component, in each interval, very little responding occurred. Later in the FI component the rate of pecking increased, becoming highest just before the reinforced response occurred. This pattern df responding was reflected by the fact that the mean quarter-life value of FI responding, i.e., the percentage of the interval duration taken for the first quarter of the responses to occur, was 52% in noninjection sessions, mating that it took about 21/2 minutes of the 5-minute interval for 25% of the responses in an interval to occur. Under the FR component of the schedule, the pigeons developed relatively high, steady rates of key pecking.

 

Drug effects on performance of pigeons under milt FR 30 Fl 5. Figure 1 shows the effect of a range of doses of W-THC on the average rate of pecking during each component of the mult FR. Ft schedule. The control injection, 0.3 and 1 mg/kg of A"-THC, had no effect on response rate under either component of the schedule two hours after injection. The 1.8 mg/kg dose decreased the average response rate, and 3 mg/kg brought it to zero, under both schedule components. No dose tested increased the response rate under either schedule component.

In the individual birds, an effective dose of W-THC usually completely eliminated responding. Thus, 0.3 and 1 mg/kg of Y-TIIC did not markedly affect the rate of responding of any of the birds under the mult FR FI schedule. The 1.8 mg/kg dose had no effect on the rate of responding under either schedule component in one pigeon, and suppressed responding almost completely in two of the birds. Marked suppression of responding occurred only during the latter half of the session in the remaining bird. The 3 mg/kg dose of 2-THC almost completely eliminated responding in the four pigeons in the sessions beginning two hours after the injection.

 

Rates of key pecking in the sessions one and two days after injection of these doses of .0.°- TEIC were within, or close to, the range of rates in the noninjection sessions (three days after injection, see METHODS) in all four pigeons under the mult FR FI schedule.

The effect of 0;-THC on the average rate of key pecking during each component of the schedule is shown in figure 2. The control injection and 3 mg/kg of W-THC had no effect on the rates of key pecking two hours after injection. Response rates were reduced about equally under each schedule component by 5.6 mg/kg, and 10 mg/kg further reduced response rates under each schedule component. At the doses tested, 0°-THC brought about no increases in response rate under either schedule component.

 

In none of the four pigeons did the vehicle control injection or 3 mg/kg of A°-THC markedly affect the rate of key pecking under either schedule component. The next higher dose tested, 5.6 mg/kg, markedly decreased responding in the session two hours after the injection in two of the birds: one of these birds abruptly ceased responding when the session was two-thirds over, and the other bird ceased responding after the first third of the session was over. The 10 mg/kg dose of .Y-THC completely eliminated responding in two of the birds; it greatly decreased responding throughout the session in the third bird, and in the remaining bird the responding during the ratio component of the schedule was decreased slightly, whereas the interval responding was unaffected.

 

Two pigeons had decreased rates of responding under the FR schedule component throughout the session one day after the injection of 10 mg/kg of 0°-THC, and a third pigeon had a decreased rate during the FI component throughout the session one day after this injection. In these three instances of decreased rate one day after .'-THC injection, the rate was higher than the rate on the previous day two hours after 0°-THC was injected. All other rates of key pecking one and two days after injection of A'-THC or its placebo control were within, or close to, the range of rates in the noninjection sessions in all four pigeons.

 

The group mean rate of responding under the FR component was markedly decreased (1.81 responses/sec) in the sessions one day after injection of 10 mg/kg 'A-THC, whereas the mean FI rate was not decreased.

 

Doses of L!,'- and A'-THC which did not completely suppress responding had no effect on the mean quarter-life value (see METHODS) in any sessions—two hours, one day or two days after injection. The ratio of responses during the first half of the intervals to responses during the second half of the intervals by the pigeons likewise was unaffected by the tetrahydrocannabinols. This indicates that the tetrahydrocannabinols had little tendency to disrupt the temporal pattern of responding under the interval component.

 

Cannabinol was administered in doses of 0 (vehicle alone), 56, 100 and 180 mg/kg to pigeons in another group under the mult FR FI schedule. None of these injections affected the rate of responding or the quarter-life. In addition to the usual experimental sessions two hours after an injection, sessions were initiated at seven hours after injection of the 180 mg/kg dose, and there was still no effect of cannabinol observed. Also, the cannabinol did not affect responding in the sessions on the day after the injection.

 

Control performance of pigeons under IRT schedule. This schedule produced a steady rate of responding in all of the pigeons, but little additional control over the distribution of responses with respect to time in three of the four pigeons: most of the responses occurred within eight seconds of a previous response. The performance of the fourth bird was different, in that a mode of responding occurred in the 16 to 20 second IRT class interval, in addition to the short IRT's.

Drug effects on performance of pigeons under IRT schedule. Figure 3 shows the L°-THC dose-dependent decrease in the mean rate of key pecking of the four birds under the IRT schedule. Injections of Triton X-100 alone and of 0.3 mg/kg W-THC did not affect the rates of key pecking in any of these birds. A dose of 1 mg/kg markedly reduced the rate of responding in two of the birds, whereas 1.8 and 3 mg/kg of 2- THC reduced the response rate of all birds markedly.

 

With the highest dose, the rate of responding was still considerably reduced one day after injection in three of these birds (mean, 0.100 responses/sec); however, by two days after the injection, the rate of responding was normal for all birds. In the sessions one and two days after lower doses, the mean rate of responding was not reduced. Only decreases in the rate of responding were seen.

 

Figure 4 shows the A8-THC dose-dependent decrease in the mean rate of pecking of the four birds under the IRT schedule. Injection of the Triton X-100 alone had no effect in any of the birds. A dose of 3 mg/kg reduced the rate of key pecking in one bird, 5.6 mg/kg reduced the response rate in three birds and 10 mg/kg of 0°- THC brought responding to zero or near zero in three of the four birds. After 5.6 and 10 mg/kg the rate of responding was still reduced in the session 24 hours after injection in some birds (mean rate 24 hours after 5.6 mg/kg, 0.152; mean rate 24 hours after 10 mg/kg, 0.139 responses/sec). Only decreases in the rates of key pecking were seen.

 

The temporal pattern of responding under this schedule is reflected by a distribution of the pauses between responses (that is, a distribution of the IRT's) according to their duration (Weiss and Laties, 1967). Anger (1963) has quantified the pattern of responding by calculating conditional probabilities from the IRT distributions. Conditional probability gives the probability that a response will occur within any class interval, given that a response has not prevented the occurrence of that class interval. A peak in the conditional probability plot near the sixth class interval, during which a response will produce food, indicates that the temporal pattern of responding has come under control of the schedule, since the probability of responding becomes highest when the response will produce food. A nearly flat conditional probability plot (responding is equally likely during all class intervals) indicates that responding is random with respect to time.

Figure 5 shows the conditional probability plots for .Y-THC. During noninjection control sessions bird 337 showed a high conditional probability in and around the sixth class interval (20-24 seconds), which would indicate that the schedule was exerting strong control over the temporal pattern of responding. Birds 7338 and 329 showed some evidence of temporal control by the schedule in that the conditional probability of a response was lower during the first class interval than it was in subsequent class intervals; however, almost all the IRT's were less than 16 seconds in duration. Bird 7262 showed almost equal conditional probabilities of responding in all the early class intervals with few IRT's longer than 16 seconds. £5-THC flattened the conditional probability plots and increased the frequency of long IRT's for all three of the birds that had shown evidence of temporal control by the schedule, suggesting that W-THC interfered with temporal aspects of schedule control in these birds. In the other bird 0°-TIIC decreased the conditional probability of a response during early class intervals and increased the conditional probability during later class intervals. ,Y-THC increased the frequency of long IRT's for all birds, and hence increased the frequency of food delivery for the birds that rarely obtained food. However, there was no evidence that 0°-THC produced a peak in the conditional probability around the sixth class interval, which might have been interpreted as "improved temporal discrimination "

 

6,'-THC produced changes in the conditional probability (not shown) which were almost identical to those seen with 0,'-THC.

 

Control performance of rats under mult FR 6 Fl 1. This schedule of water presentation engendered performance by the rats like that previously described by Ferster and Skinner (1957). Under the FI component, the rats paused at the start of each interval and then responded with increasing frequency until water was presented. This pattern of responding was reflected in the mean rate of responding during the first 30 seconds of the FI, expressed as the percentage of the rate during the last 30 seconds, which averaged 10.7% in noninjection sessions. Under the FR component, after a short pause, a high, steady rate of lever pressing was maintained until water presentation.

Drug effects on performance of rats under mutt FR 6 Fl I. Figure 6 shows the effect of a range of doses of on the mean rate of lever pressing for the four rats during each component of the schedule. The control injection had no effect on the response rate of any of the four rats under either component. Under the FR component, 3 mg/kg of ,e-THC markedly reduced the mean response rate. In the individual rats, this dose of the drug greatly reduced the rate of lever pressing, but did not reduce the rate to near zero, in three of the four rats, two hours after the injection. But 5.6 nag/kg of 0,°- THC greatly reduced the lever-pressing rate in only one rat (the mean rate was not reduced) under the FR component. At 10 and at 18 mg/ kg, the rate of responding was near zero for all the rats under the FR component, in the sessions beginning two hours after injection.

 

Doses of 3 and 5.6 mg/kg of Y-THC did not reduce the response rate under the FI component of the schedule in any rat. The 10 mg/kg dose of A°-THC greatly reduced responding in one of the rats two hours after injection and reduced responding to zero in the other three rats. In the session beginning two hours after injection of 18 mg/kg, responding was zero or near zero in all rats. No dose tested increased the rate of lever pressing to outside of the non-injection control range under either schedule component (three standard errors above and below the FI control mean were from 0.16-0.31, and the FI rate after 3 mg/kg of Y-THC was 0.30).

 

The mean rate of lever pressing was 0.40 responses/sec under the FR component in the sessions 24 hours after injection of 18 mg/ kg of 0a-THC. This is below the range of the means for the noninjection sessions and the control injection sessions. However, the mean FI rate was 0.24, which is within the control range. In the sessions two days after injection of 18 mg/kg, there was no reduction in response rate under either schedule component. In the sessions one and two days after injection of 10 (or less) mg/kg of W-THC, there was no reduction in response rate.

 

Doses of W-THC had little or no effect on the mean ratio of responses during the first 30 seconds of the interval to responses during the second 30 seconds, indicating that A°-TFIC had little tendency to disrupt the temporal patterning of FI responding by rats.

 

About two weeks after the last W-TliC injection, these same rats were used in an attempt to determine the dose-effect relation for IV-THC, but doses of up to 100 mg/kg of the A° isomer had no effect on responding. Finally, a second dose of 18 mg/kg of .e-THC was administered, and this injection had no effect on responding in any of the four rats.

 

Discussion. These experiments showed that both 2-THG and W-THC cause dose-dependent decreases in the rates of key pecking by pigeons conditioned to obtain food, or under several reinforcement schedules and 0°-TEIC also decreases bar pressing by rats conditioned to obtain water under a multiple schedule. CV-THC was about 3 times more potent in the pigeon (by i.m. route) than in the rat (by i.p. route).

 

The effects of W- and 0'-THC can be compared with the effects of other drugs on schedule-controlled behavior. For example, the tetrahydrocannabinols differ from narcotic analgesics and morphine antagonists, in that the narcotics and the antagonists, at appropriate doses, increase the rate of responding under the fixed-interval component of a mult FR 30 FI 5 schedule (McMillan and Morse, 1967; McMillan et al., 1970c), whereas none of the doses tested of either tetrahydrocannabinol produced significant increases in response rates in pigeons or rats.

 

Boyd et a/. (1963) tested a synthetic tetrahydrocannabinol derivative (not 6,°- or A.°-THC) for a reserpine-like action. They found that the tetrahydrocannabinol did not resemble reserpine in their behavioral tests. Under the schedules used in the present experiments, be- and A°THC again did not have reserpine-like effects, in that a dose of reserpine, administered to pigeons working under a mult FR 33 FI 5 schedule, had a much greater effect on fixed-interval responding than on fixed-ratio responding (Smith, 1964), whereas A°- and A'-THC did not have this differential effect on the schedule components.

 

The tetrahydrocannabinols may also be distinguished from the barbiturates, which at low doses increase the rates of both FI (McKearney, 1970) and FR responding (Waller and Morse, 1963), and at higher doses selectively decrease the rate of FI responding (Dews, 1955; Morse, 1962). These effects were not shown by the tetrahydrocannabinols in the present experiments.

 

None of the doses tested of either tetrahydrocannabinol produced the increases in response rates of rats or pigeons which are commonly seen under fixed-interval schedules with amphetamines (Dews, 1958; Smith, 1964; Clark and Steele, 1966; McKearney, 1968; McMillan, 1968a,b, 1969), imipramine (Dews, 1962; Smith, 1964), cocaine and pipradrol (Smith, 1964), chlordiazepoxide (Richelle et al., 1962) and meprobamate (Kelleher et at., 1961).

 

Boyd et al. (1963) found that the synthetic tetrahydrocannabinol derivatives in their experiments resembled chlorpromazine in their effects on the performance of rats responding for food under mult FR FI schedules. However, these experimenters concluded that it was possible to differentiate chlorpromazine from the THC derivatives by means of the performance generated by a mixed schedule (similar to the multiple schedules except that there was no cue light as to which component of the schedule was in effect). In the present experiments W- and A°THC did not resemble chlorpromazine since the latter has been shown (Clark, 1969; Laties and Weiss, 1966) to disrupt the temporal patterning of FI responding by rats and pigeons under a multiple schedule, even when the total output was little affected, whereas Li°- and As-THC did not affect temporal patterning of FI performance by rats and pigeons.

 

Thus, A°- and 0°-THC do not appear to resemble narcotics (morphine and methadone), narcotic antagonists (cyclazocine, pentazocine, nalorphine and naloxone), major tranquilizers (chlorpromazine and reserpine), minor tranquilizers and sedative hypnotics (barbiturates, chlordiazepoxide and meprobamate), or central nervous system stimulants and antidepressants (cocaine, pipradrol, amphetamines and imipramine) in their effects on responding under mult FR FI schedules.

 

A°- and 0°-THC decreased the rate of responding about equally under the FR and the FI components of the multiple schedules (figs. 1, 2 and 6) in both pigeons and rats. Vaillant (1967) has shown that physostigmine dose-effect curves are very similar for the FI and FR components of a multiple schedule with pigeons, and McMillan (1968a) has reported similar observations with metaraminol, phenylephrine and nor-epinephrine. Further, A°- and W-THC had little effect on the temporal patterning of responding under the FI component at doses that did not markedly decrease response rates. McMillan et al. (1970c) have observed a similar lack of effect on the quarter-life with naloxone. Thus, the effects of A°- and A°-THC on schedule-controlled behavior are not unique, although they differ from the effects of many centrally active drugs.

 

Both A°- and 0°-THC disrupted the temporal pattern of responding by pigeons under a schedule that reinforced the spacing of key pecks 20 to 24 seconds apart, but neither 21°- nor A°-THC disrupted the temporal pattern of responding under the FI component of the multiple FR F1 schedule. That tetrahydrocannabinols have differential effects on temporal patterns of responding under different schedules is not a'paradox, because the spaced responding schedule specifically reinforces long IRT's (20-24 seconds), whereas FI schedules usually reinforce much shorter IRT's (Catania and Reynolds, 1968). Thus, the schedule contingencies are very different, even though it is possible to measure the temporal pattern of responding under both schedules.

 

The decreases in responding lasted as long as 24 hours after 3 mg/kg of 0°-THC in the pigeons, 5.6 and 10 mg/kg of 40-THC in the pigeons, and 18 mg/kg of S.-Tile in the rats. Scheckel et al. (1968) have pointed out the long-term effects of tetrahydrocannabinols injected i.p. in monkeys, whereas Loewe (1944) has pointed out the long duration of action of tetrahydrocannabinols with i.v. as well as p.o. administration in dogs. The prolonged duration of action may be due to the slow removal of a relatively water-insoluble substance from the site of administration, which may provide a depot for the drug, or to a slow pattern of excretion (King and Forney, 1967; Agurell et al., 1970).

 

In the pigeons, At.-THC exhibited qualitatively the same effects as the A° isomer in the experimental procedures employed in this study. However, A'-THC administered in doses up to 100 mg/kg had no effect on responding in the rats. It may be that A"-THC has little or no activity in rats under these experimental conditions, but this is unlikely since it has been reported (Foltz et al., 1970; Truitt, 1970) that A°-THC exhibits behavioral effects in the rat similar to that exhibited by A°-THC.

 

The development of tolerance to /V-THC, and cross-tolerance to A°-THC, may explain why the W-THC, administered after the A°-THC, was not effective in depressing behavior in these rats. Silva et al. (1968) has shown that lever-pressing rats develop tolerance to daily injection of 10 mg/kg of A°-THC, whereas McMillan et al. (1970b) have shown that pigeons made tolerant to A°-THC by repeated administration were cross-tolerant to A°-THC (relative to pigeons that had never received A"-THC). Furthermore, in the experiments reported in this paper, a second injection of 18 mg/kg of A°-THC, which initially almost completely eliminated responding, was without effect after the intervening determinations of the A"- and A"-TIIC dose-effect curves.

 

Sinte A°-THC was administered after the A°- THC dose-effect relation was determined in the pigeons as well as the rats, the possible development of tolerance to A°-THC, and cross-tolerance to W-THC makes it difficult to compare the potencies of the two isomers. With this reservation, in the pigeons A"-THC appeared to be about one-fourth as potent as A°-THC, regardless of reinforcement schedule.

 

In figure 6, there is a reversal in the rat group dose-effect curve at 5.6 mg/kg of A°-THC under the FR component. Although the doses were otherwise administered in a mixed order, this dose was given last to all four rats in an attempt to generate a graded dose-effect curve, since 3 mg/kg had no effect on FI response rate and 10 mg/kg brought responding to almost zero. Thus, the development of tolerance to A°-THC in rats may explain this irregularity.

 

Since tolerance develops to A°-THC in rats (Silva et al., 1968) and in pigeons (McMillan et al., 1970a,b; Black et al., 1970), it is possible that the dose-effect relations presented in this paper were distorted or biased by the development of tolerance in individual subjects.

 

However, to minimize this problem, doses were administered at least three days apart in a mixed order (with one exception, noted above), and no appreciable differences were seen in drug dose-effect in the individual subjects which could be correlated with differences in order of dose administration.

 

Doses of up to 180 mg/kg of cannabinol, administered to pigeons that had never before received drugs, did not affect schedule-controlled responding, thus supporting the findings (Adams, 1942; Loewe, 1944; Farnsworth, 1968; Mechoulam, 1970; 1\flechoulam et al., 1970) that cannabinol is an inactive component of C. sativa.

 

CONCLUSIONS. A°- and A°-THC have similar effects on the schedule-controlled behavior of pigeons. Under all three schedules studied, with both food and water as reinforcers and in both species, A°-THC decreased the rate of responding. Pigeons were affected at lower doses of A°- THC than were rats, and A°-THC was more potent than W-THC in pigeons. Cannabinol, even at relatively high doses, does not affect schedule-controlled behavior in pigeons.

 

ACKNOWLEDGMENTS. The authors wish to thank Mr. J. S. Kennedy and Mr. R. D. Ford for assistance.

 

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