Bengt G. Henriksson

Discriminative response control produced with hashish, tetrahydrocannabinols (δ8-THC and δ9-THC), and other drugs

In a series of experiments the discriminative properties of hashish and its derivatives and other, noncannabinoid drugs have been examined. To determine the specificity of the drug induced response control a variety of psychotropic drugs were tested for their possible generalization to the training drugs. It is concluded that tetrahydrocannabinols (δ8-THC and δ9-THC) are interchangeable with respect to cue function and that hashish, inhaled as smoke, produces cue effects similar to synthetic THC in rats. Neither cannabidiol nor cannabinol evidenced transfer to hashish or its derivatives. Lack of generalization to THC was also apparent for CNS depressants, anticholinergics, tacrine, sernylan, psilocybine, morphine, CNS stimulants, yohimbine, and phenitrone. Some of these drugs as well as levallorphan tartrate were tested for antagonistic effects but found ineffective in preventing the THC discrimination.Except for atropine (150.0 mg/kg), the transfer testings for the non-cannabinoid drugs yielded results that were anticipated from previous literature. For example, chlordiazepoxide showed transfer to diazepam. Results from transfer testings in rats required to differentiate one drug state from another drug induced state, gave additional support to the previous conclusions.

Characteristics of tetrahydrocannabinol (THC)-produced discrimination in rats

Rats were trained in a T-shaped maze to discriminate the effects produced by i.p. injections of tetrahydrocannabinol (THC) and the no-drug state (state-dependency, StD). Several doses of both Δ8-THC (range: 0.75–5.0 mg/kg) and Δ9-THC (range: 0.75–10.0 mg/kg) were used in order to compare the number of sessions required by the animals until reaching criterion performance. An additional group of rats had to discriminate pentobarbital sodium (20.0 mg/kg) from the no-drug state.Results: THC discrimination was proportional to dose i.e., animals that had to differentiate high doses of THC from no drug acquired the T-maize task faster than animals trained with the lower doses of THC. Acquisition data further suggest that Δ8-THC is somewhat less potent than the Δ9-isomer. Δ9-THC (10.0 mg/kg) produces strong StD, as defined by Overton (1971), since both this group and the barbiturate group reached the criterion within the first 10 training sessions. Time and dose testings suggest that stimulus properties of drugs vary in a quantitative way and that the calculated ED50 values are mainly determined by the training dose used. It was found that the higher the training dose used the higher was the corresponding ED50 value. Hashish smoke can maintain drug responding among THC-trained rats. A lowered content of brain catecholamines and/or serotonin, induced by AMPT (150 mg/kg) and PCPA (310–350 mg/kg), did not lessen Δ9-THC (2.5 mg/kg) discrimination.

The effect of two tetrahydrocannabinols, ( 9 -THC and 8 -THC) on conditioned avoidance learning in rats and its transfer to normal state conditions.

Rats trained in conditioned avoidance responding (CAR) after injections of either 7.5 mg/kg Δ9-THC (tetrahydrocannabinol) or 15 mg/kg Δ8-THC, showed no transfer when tested in the non-drugged state. Furthermore, these doses of the isomeric tetrahydrocannabinols exerted a disruptive effect on previously established CAR in rats, trained under normal conditions.Only the Δ9-THC-group showed an impairment of acquisition which was statistically significant compared to the control group.

Δ9-Tetrahydrocannabinol and pentobarbital as discriminative cues in the Mongolian gerbil (Meriones unguiculatus)

Abstract Male Mongolian gerbils were trained to escape electric shocks in a T-shaped maze contingent upon the presence or absence of certain drug effects (state-dependency; StD). The drug discriminative cues used were those of either Δ 9 -tetrahydrocannabinol (THC) or pentobarbital (P-barb.) vis-a-vis the respective vehicles. Several doses of THC (0.5–16.0 mg/kg) were used and compared with P-barb. (20.0 mg/kg), a dose at which the most rapid drug discrimination occurs in the rat. When drug discrimination was established dose-time- and transfer characteristics for the training drugs were studied. Possible potentiation and antagonism was also examined in the pentobarbital trained gerbils. It was found that none of the THC doses were discriminated as rapidly as that of P-barb. Decreasing the amounts of training drug administered or increasing the injection-test intervals resulted in a decline of the number of drug associated choices. There was a maximum of 40% drug choices between THC and P-barb at the transfer tests. Mixtures of the two compounds increased the number of drug choices in an additive or even more than additive manner. Amphetamine (4.0 mg/kg) did not interact with the P-barb. induced choice responding. The analeptic drug, bemegride was found effective in antagonizing the P-barb. cued choice behavior.

Drug discrimination in rats: the effects of phencyclidine and ditran.

Choice responding in a T-shaped maze has been made contingent upon whether or not rats experienced certain drug effects. The drug discriminative cues used in the present state-dependent (StD) model were those of phencyclidine (PCP) and ditran. The specificity of these cues and their possible drug inhibition and antagonism was studied.It was found that the lower the training dose used the slower the appearance of the drug discriminative formation. Transfer testings with ketamine and cyclohexamine showed that they were interchangeable with PCP. The order of their relative potency was: cyclohexamine > PCP > ketamine. Atropine transferred to ditran. Administration of compounds not structurally related to the training drugs did not show transfer.Pretreatment with parachlorphenylalanine (p-CPA) or tetrabenazine (TBZ) plus imipramine did not indicate inhibition or antagonism in PCP trained rats.Tacrine (THA) and especially physostigmine effectively antagonized the ditran-induced cues. Yohimbine and neostigmine did not.

Influence of tetrahydrocannabinols (Δ8-THC and Δ9-THC) on body weight, food, and water intake in rats

Abstract Female Wistar rats, six to a group, were injected daily for a 23-day period with Δ 8 -THC (5.0 mg/kg), Δ 9 -THC (2.5 mg/kg) or vehicle. Body weight, food and water intake were recorded every second day. It was found that Δ 8 -THC caused a decrease of body weight, to a level maintained throughout the injection period, with only slight signs of recovery. Both drugs caused a marked decrease of water intake. Food intake was not significantly affected by the drugs. Factors in relation to the effects of THC on body weight, food and water intake are discussed.

Δ9-Tetrahydrocannabinol used as discriminative stimulus for rats in position learning in a T-shaped water maze

Rats were trained to swim differentially to either of the two arms of a T-shaped water maze on the basis of Δ9-tetrahydrocannabinol or solvent only. The two states, drugged (D) and nondrugged (ND), were changed from day to day. After 11–13 sessions, the animals performed the task at virtually the 100% level, i.e., the imposed state (D or ND) determined the choice of arm in the T-maze. After 2 weeks of rest, the animals were retested in both the D and ND states, and the results indicate that this differentially controlled performance is very well retained.

Δ9-tetrahydrocannabinol produced discrimination in pigeons ☆

In an operant situation pigeons learned to peck one response key 90 min after an injection of 0.25 mg/kg Δ9-tetrahydrocannabinol (Δ9-THC) and another key when trained nondrugged. When tested with doses of Δ9-THC lower than the training dose the birds discriminated 0.20 mg/kg of the drug from the nondrugged state but not 0.15 mg/kg or lower doses. The animals were able to discriminate the drug state from the nondrugged 180 min but not 360 min after the injection. At ashorter interval (45 min) both drug and nondrug responding appeared. Cannabinol and cannabidiol (4.0 – 8.0 mg/kg) did not elict any drug responses, nor did pentobarbital, ditran or amphetamine. Tests with LSD resulted in both drug and nondrug responding. When administering noncannabinoid drugs in combination with Δ9-THC 0.15 mg/kg the birds responded at the key associated with the drug state, suggesting interactional effects.

Effects of diazepam on conditioned avoidance learning in rats and its transfer to normal state conditions.

Rats trained in conditioned avoidance responding (CAR) after injections of diazepam, 10 mg/kg, showed little or no transfer when tested in the non-drugged state. In this moderate dose diazepam did not significantly facilitate the acquisition of CAR nor did it decrease already established avoidance behavior.

Acute effects of two tetrahydrocannabinols (Δ9-THC and Δ8-THC) on water intake in water deprived rats: Implications for behavioral studies on marijuana compounds

Water intake was studied in water deprived albino rats at various time intervals after injections of two tetrahydrocannabinols (Δ9-THC and Δ8-THC) and solvents. The dose levels used were: 1.25, 2.5, and 5.0 mg/kg of Δ9-THC and 2.5, 5.0, and 10.0 mg/kg of Δ8-THC. The results show a clear, dose dependent inhibitory effect on water intake as compared to the controls.Reduced intake of food was seen at 1 day post injection. This effect was, however, significant only for the groups treated with 5.0 and 10.0 mg/kg of Δ8-THC. A decreased body weight was also recorded after the drug treatment, especially with Δ8-THC. With respect to cannabis-induced vocalization the data suggest an increased possibility of its appearance with increasing dosages of THC.