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Cannabis Research - addictiveness, reinforcement, tolerance


Authors
Takahashi RN, Singer G
Title
Cross self-administration of delta 9-tetrahydrocannabinol and D-amphetamine in rats.
Source
Brazilian Journal of Medical & Biological Research
Date
1981 Dec
Issue
14(6)
Pages
395-400
Abstract
1. Schedule-induced intravenous self-injection of delta 9-tetrahydrocannabinol (delta 9-THC) and d-amphetamine was investigated in the same animals. 2. Rats self-injected significantly more amphetamine than delta 9-THC. However, the results suggested that delta 9-THC did not play a predisposing role to the increased amphetamine intake. When delta 9-THC was reinstated after amphetamine response rates were drastically reduced. 3. It is concluded that the reinforcing effects of delta 9-THC may be unrelated to its stimulant effects. The small number of responses for delta 9-THC is in agreement with reports of the poor reinforcing capability of cannabis compounds in rats.

Authors
Smith CG, Almirez RG, Berenberg J, Asch RH
Title
Tolerance develops to the disruptive effects of delta 9-tetrahydrocannabinol on primate menstrual cycle.
Source
Science
Date
1983 Mar 25
Issue
219(4591)
Pages
1453-5
Abstract
Long-term exposure of sexually mature female rhesus monkeys (Macaca mulata) to thrice weekly injections of delta 9-tetrahydrocannabinol resulted in a disruption of menstrual cycles that lasted for several months. This period was marked by an absence of ovulation and decreased basal concentrations of gonadotropin and sex steroids in the plasma. After this period, normal cycles and hormone concentrations were reestablished. These studies demonstrate that in rhesus monkeys subjected to long-term treatment with delta 9-tetrahydrocannabinol tolerance develops to the disruptive effects of the drug on the menstrual cycle.

Authors
Colasanti BK, Lindamood C 3d, Craig CR
Title
Effects of marihuana cannabinoids on seizure activity in cobalt-epileptic rats.
Source
Pharmacology, Biochemistry & Behavior
Date
1982 Apr
Issue
16(4)
Pages
573-8
Abstract
Rats rendered chronically epileptic by bilateral implantation of cobalt into frontal cortices were simultaneously prepared with permanent electrodes for longitudinal recording of the electroencephalogram (EEG) and electromyogram (EMG). Delta-8-tetrahydrocannabinol (delta-8-THC; 10 mg/kg), delta-9-tetrahydrocannabinol (delta-9-THC; 10 mg/kg), cannabidiol (CBD; 60 mg/kg), or polyvinylpyrrolidone (PVP) vehicle (2 ml/kg) was administered IP twice daily from day 7 through 10 after cobalt implantation, at which time generalized seizure activity in non-treated cobalt-epileptic rats was maximal. Relative to PVP-treated controls, CBD did not alter the frequency of appearance of seizures during the course of repeated administration. In contrast, both delta-8-THC and delta-9-THC markedly reduced the incidence of seizures on the first and second days of administration. Interictal spiking during this period, on the other hand, was actually enhanced. On the third and fourth days, tolerance to the effect on seizures was evident, with a return of seizure frequency of THC-treated rats to values not significantly different from those of controls. Unlike the effect on seizures, no tolerance developed to the marked suppression of rapid eye movement (REM) sleep induces by delta-8-THC and delta-9-THC. REM sleep remained reduced in the treated animals during the first 2 days after termination of THC administration. In contrast, REM sleep time was unaffected by repeated administration of CBD. These results suggest that delta-8-THC and delta-9-THC exert their initial anticonvulsant effect by limiting the spread of epileptogenic activity originating from the cobalt focus.

Authors
Uran B, Tulunay FC, Ayhan IH, Ulku E, Kaymakcalan S
Title
Correlation between the dose and development of acute tolerance to the hypothermic effect of THC.
Source
Pharmacology
Date
1980
Issue
21(6)
Pages
391-5
Abstract
The administration of 0.3-40 mg/kg delta 9-tetrahydrocannabinol (THC) produced a dose-dependent hypothermia in rats. The maximal hypothermic effect was obtained with the dose of 2.5 mg/kg of THC. When the same doses of THC were repeated on days 2 and 3, tolerance to the hypothermic effect of THC was apparent. Doses of THC higher than 2.5 mg/kg induced a significant and dose-dependent tolerance after the first administration whereas with the lower doses, tolerance was only apparent after the second injection. The possible mechanism of these effects of THC is discussed.

Authors
Weller RA, Halikas JA
Title
Change in effects from marijuana: a five- to six-year follow-up.
Source
Journal of Clinical Psychiatry
Date
1982 Sep
Issue
43(9)
Pages
362-5
Abstract
A five- to six-year follow-up study of 97 regular marijuana users in a large Midwestern city showed that the effect of marijuana intoxication remained fairly stable over time. However, continued use of the drug was associated with a decrease in pleasurable effects. Undesirable effects persisted but apparently did not discourage continued use. Decreases found in some undesirable effects (tachycardia, lightheadedness, and dry mouth) raised the possibility that some degree of tolerance had developed.

Id Code
76041247
Authors
Giono-Barber P, Bertuletti G, Giono-Barber H
Title
[Effect of cannabis on learning in the cynocephalic monkey (Papio Papio)].
Language
French
Source
Comptes Rendus des Seances de la Societe de Biologie et de Ses Filiales
Date
1975
Issue
169(1)
Pages
264-70
Abstract
Chronic treatment of monkeys with Cannabis reduce the speed of acquisition of learned behavior, yet, learning is nevertheless possible. After acquisition, Cannabis administration disturb the responses in the learning test. In this two experimental procedures, tolerance occurs to the effects of Cannabis.

Id Code
76176692
Authors
Snyder EW, Lewis EG, Dustman RE, Beck EC
Title
Sustained ingestion of delta 9-tetrahydrocannabinol and the operant behavior of stump-tailed macaques.
Source
Pharmacology, Biochemistry & Behavior
Date
1975 Nov-Dec
Issue
3(6)
Pages
1129-32
Abstract
Three stump-tailed macaques were trained to press a lever for liquid reinforcement on a tandem schedule which required the animal to delay responding for at least 30 sec after each reinforcer. If the animal responded during that interval, a clock was reset thus re-establishing the delay requirement. If he delayed responding appropriately, the monkey was shifted to a fixed-interval schedule of 135 sec duration. The FI component was terminated with a drop of flavored liquid at which point the delay requirement began anew. Following a stable baseline performance, two monkeys received 2 mg/kg of THC orally every third day for 90 days with the placebo administered on intervening days. The third animal received the placebo throughout testing. Each monkey's performance was described in terms of response rate and response patterning between reinforcers. Despite the sustained ingestion of THC neither animal showed appreciable change in test behavior attributable to tolerance to the drug. Although the drug continued to have a powerful effect throughout testing on the days it was administered, there was no evidence of any consistent or cumulative drug effect on placebo-day performance.

Id Code
76079139
Authors
Cutler MG, Mackintosh JH, Chance MR
Title
Behavioural changes in laboratory mice during cannabis feeding and withdrawal.
Source
Psychopharmacologia
Date
1975 Oct 31
Issue
44(2)
Pages
173-7
Abstract
The effects of feeding cannabis at a level of 0.4% in the diet has been studied by an ethological analysis of encounters between male mice. Administration of cannabis to dominant males resulted in a reduction of non-social activity and an increase in flight and in social and sexual investigation when compared with untreated controls, but the behaviour of subordinate males was not significantly altered by cannabis. One week after withdrawal of cannabis, the behaviour of diminant males showed a rebound effect with increase in aggression. Nevertheless, by a preference feeding test it was demonstrated that the treated mice were not dependent on the cannabis-containing diet but consumed the control diet in preference.

Id Code
76012544
Authors
Anderson PF, Jackson DM, Chesher GB, Malor R
Title
Tolerance to the effect of delta9-tetrahydrocannabinol in mice on intestinal motility, temperature and locomotor activity.
Source
Psychopharmacologia
Date
1975 Jul 23
Issue
43(1)
Pages
31-6
Abstract
The onset and duration of tolerance to three effects of delta9-tetrahydrocannabinol (delta9-THC) given orally to mice were compared. The effects of delta9-THC studied were: hypothermia, the depression of intestinal motility and the effect on spontaneous locomotor activity. When mice were dosed and tested at 24 hrs intervals it was apparent that tolerance was complete to its hypothermic and locomotor depressant effects after the first doses and to depression of intestinal motility after the fourth dose. Duration of tolerance also differed so that the normal hypothermic response had returned after 12 dose-free days, but not after 5 drug-free days; the effect on locomotor activity had returned within 4 days; and apparent partial tolerance to the depressant effect of an acute challenging dose of delta9-THC on intestinal motility still existed after 19 dose-free days. It is apparent that the time of onset and the duration of tolerance to delta9-THC in mice showed a different pattern in the three parameters studied. It seems unlikely therefore that any one mechanism, such as metabolic tolerance, explains all the results observed and that several mechanisms should be explored to explain the phenomenon of tolerance to delta9-THC.

Id Code
79102616
Authors
Wrenn JM, Friedman MA
Title
Effects of chronic administration of delta8- and delta9-tetrahydro-cannabinol on hepatic tyrosine aminotransferase activity in mice.
Source
Archives Internationales de Pharmacodynamie et de Therapie
Date
1978 Sep
Issue
235(1)
Pages
4-8
Abstract
The effects of delta8-THC and delta9-THC administered twice weekly for 8 and 12 weeks at doses of 3, 10, and 30 mg/kg on murine hepatic tyrosine aminotransferase activity are described. These data suggest that treatment with relatively low doses of cannabinoids over long periods of time appear to produce some type of biochemical "tolerance," resulting in a diminished response, in contrast to previously reported data utilizing high doses of delta8-THC and delta9-THC over short experimental time periods.

Id Code
79137293
Authors
Martin P, Consroe P
Title
Tolerance to delta9-tetrahydrocannabinol in adapted and nonadapted rabbits.
Source
Pharmacology, Biochemistry & Behavior
Date
1978 Dec
Issue
9(6)
Pages
753-8
Abstract
Two groups of New Zealand white rabbits, one which had been adapted to the testing chamber and one which had not been adapted to the testing chamber, were given delta9-tetrahydrocannabinol (delta9-THC; 0.5 mg/kg, IV) daily for 12 days. During vehicle control and on the first and last day of delta9-THC administration, electroencephalograms (EEG's) were recorded from the motor cortex and hippocampus, while standing, sprawling and behavioral activity were recorded concurrently. The results showed that tolerance to the behavioral and EEG effects of delta9-THC occurs in rabbits and that acute and chronic effects produced by delta9-THC are influenced by environmental factors.

Id Code
78255843
Authors
Kosersky DS
Title
Antihypertensive effects of delta9-tetrahydrocannabinol.
Source
Archives Internationales de Pharmacodynamie et de Therapie
Date
1978 May
Issue
233(1)
Pages
76-81
Abstract
Repeated oral administration of delta9-tetrahydrocannabinol (delta9-THC, 25 mg/kg) reduced systolic blood pressure in conscious spontaneously hypertensive rats. Tolerance to the antihypertensive actions of delta9-THC failed to develop during the 10-day treatment period. The failure of delta9-THC to alter blood pressure in normotensive rats suggests that the hypotensive action of delta9-THC is dependent, in part, on baseline blood pressure.

Id Code
77173203
Authors
ten Ham M
Title
Tolerance to the effects of delta9-THC on shuttle-box performance and body temperature.
Source
Pharmacology, Biochemistry & Behavior
Date
1977 Feb
Issue
6(2)
Pages
183-5
Abstract
Two groups of rats were trained in a shuttle-box and received delta9-tetrahydrocannabinol (delta9-THC), either before or after being tested. The drug-before group showed tolerance--within 3-6 sessions--to the response-inhibiting effect of THC. The drug-after animals appeared also to be tolerant when they received delta9-THC before being tested. It is concluded that the tolerance to this effect probably is not learned, but has a physiological base. This is corroborated by the finding that during the same study all the animals developed tolerance to the hypothermic effect of delta9-THC.

Id Code
77156324
Authors
Sofia RD, Knobloch LC, Harakal JJ, Erikson DJ
Title
Comparative diuretic activity of delta9-tetrahydrocannabinol, cannabidiol, cannabinol and hydrochlorothiazide in the rat.
Source
Archives Internationales de Pharmacodynamie et de Therapie
Date
1977 Jan
Issue
225(1)
Pages
77-87
Abstract
Orally administered delta9-tetrahydrocannabinol (THC) produced a dose-dependent increase in urine output in hydrated rats similar in mg/kg potency and magnitude of effect to hydrochlorothiazide (HCT). Whereas HCT promoted marked excretion of Na+, K+ and Cl- and an increase in the urinary Na+/K+ at all diuretic doses (1.25-20.0 mg/kg), THC had only a slight effect on Na+ and K+ excretion but not Cl- even after the highest dose tested (20.0 mg/kg). Hypophysectomy and adrenalectomy abolished the diuretic effect of THC, thus suggesting both central and peripheral sites of action for the diuretic effect of THC. Tolerance to the effect on urine output by THC developed after 15 days of repeated dosing, while urine output and electrolyte excretion remained significantly elevated after 25 days of HCT administration.

Id Code
77132894
Authors
Wikler A
Title
Aspects of tolerance to and dependence on cannabis.
Source
Annals of the New York Academy of Sciences
Date
1976
Issue
282
Pages
126-47
Abstract
Tolerance at all levels of complexity in the brain involves "learning" in the sense of the acquisition of compensatory adaptations to the consequences of the presence of a drug-produced disturbance in function. Depending on the function, species, and dose of cannabis, "tissue tolerance," behaviorally augmented (to provide the presence of the disturbed function) or not, develops at different rates or not all (e.g., to impairment of the logical sequence of thoughts, to which no tolerance has yet been demonstrated). "Dispositional tolerance" (increased rate of metabolism of delta 9-THC due to enzyme induction) may play a role in the development of tolerance or "reverse tolerance" to cannabis in man. There is evidence that for the label "high," placebo effects may account for the "reverse tolerance" seen in experienced users on smoking (but not on ingestion of delta 9-THC or placebo) along with evidence of residual tolerance to other not-so-labeled effects of the drug. Dependence on cannabis, in the sense of abstinence phenomena on abrupt withdrawal of delta 9-THC, has been demonstrated in monkeys made tolerant to delta 9-THC given four times daily for about 1 month. In man, physiologic marijuana abstinence signs have not been demonstrated, but behavioral (and some physiologic) abstinence phenomena have been reported in heavy users of hashish or ganja. The between-dose hyperirritability and dysphoria reported to occur in experimental studies on chronic marijuana intoxication may actually be early and short-lived abstinence changes. In the West, where marijuana with relatively low delta 9-THC content is widely smoked, dependence in the sense of drug-seeking behavior appears to be less a function of any pharmacologic reinforcing properties the drug may have than of secondary (conditioned) reinforcement derived from the social milieu in which the marijuana is smoked. In cultures where marijuana of higher delta 9-THC content, hashish, or ganja is used, pharmacologic reinforcement (through suppression of abstinence changes) may play a greater role in maintaining drug-seeking behavior.

Id Code
90083545
Authors
Marks DF, MacAvoy MG
Title
Divided attention performance in cannabis users and non-users following alcohol and cannabis separately and in combination.
Source
Psychopharmacology
Date
1989
Issue
99(3)
Pages
397-401
Abstract
The effect of delta 9-tetrahydrocannabinol (delta 9-THC) and alcohol, singly and in combination, on divided attention performance was investigated in cannabis users and non-users who were matched for alcohol use. Both cannabis and alcohol produced decrements in central and peripheral signal detections. Drug and alcohol effects were greater for signal presentations in the periphery. Cannabis users were less impaired in peripheral signal detection than non-users while intoxicated by cannabis and/or alcohol. These findings suggest the development of tolerance and cross-tolerance in regular cannabis users and/or the ability to compensate for intoxication effects.

Id Code
94159662
Authors
Rodriguez de Fonseca F, Gorriti MA, Fernandez-Ruiz JJ, Palomo T, Ramos JA
Title
Downregulation of rat brain cannabinoid binding sites after chronic delta 9-tetrahydrocannabinol treatment.
Source
Pharmacology, Biochemistry & Behavior
Date
1994 Jan
Issue
47(1)
Pages
33-40
Abstract
Specific cannabinoid receptors have been recently described in extrapyramidal and limbic areas and presumably might mediate the effects of marijuana exposure on behavioral processes related to those areas. In this work, we examined whether cannabinoid receptors exhibit downregulation as a consequence of the chronic exposure to delta 9-tetrahydrocannabinol (THC), which might explain certain tolerance phenomena observed in relation to motor and limbic effects of marijuana. To this end, we first characterized the binding of cannabinoid receptors, by using [3H]CP-55,940 binding assays, in the striatum, limbic forebrain, and ventral mesencephalon of male rats, and, second, we measured the density and affinity of those receptors in these brain areas after 7 days of a daily treatment with THC. Development of a tolerance phenomenon was behaviorally tested by using an open-field technique. Results were as follows. The three areas studies presented specific and saturable binding for the cannabinoid ligand, as revealed by their corresponding association and dissociation curves, displacement by THC, saturation curves, and Scatchard plots. A chronic treatment with THC produced the expected tolerance phenomenon: The decrease caused by an acute dose in spontaneous locomotor (49.4%) and exploratory (59.7%) activities and, mainly, the increase in the time spent by the rat in inactivity (181.7%) were diminished after 7 days of daily treatment (39.4, 40.4, and 31.7%, respectively). This tolerance was accompanied by significant decreases in the density of cannabinoid receptors in the striatum and limbic forebrain, the areas where nerve terminals for nigrostriatal and mesolimbic dopaminergic systems, respectively, which play an important role in those processes, are located.(ABSTRACT TRUNCATED AT 250 WORDS)

Id Code
93364745
Authors
Oviedo A, Glowa J, Herkenham M
Title
Chronic cannabinoid administration alters cannabinoid receptor binding in rat brain: a quantitative autoradiographic study.
Source
Brain Research
Date
1993 Jul 9
Issue
616(1-2)
Pages
293-302
Abstract
The active ingredient of marijuana is (-)-delta 9-tetrahydrocannabinol (delta 9-THC). delta 9-THC and other natural and synthetic cannabinoids such as CP-55,940 inhibit spontaneous activity and produce catalepsy in animals in a receptor-mediated fashion. Tolerance develops to the motor effects of delta 9-THC after repeated administration. To test the hypothesis that tolerance is mediated by changes in cannabinoid receptor binding characteristics, we used quantitative in vitro autoradiography of [3H]CP-55,940 binding to striatal brain sections from rats treated either chronically or acutely with delta 9-THC, CP-55,940, or the inactive natural cannabinoid cannabidiol. In the chronic conditions, rats were given daily i.p. injections of delta 9-THC (10 mg/kg), cannabidiol (10 mg/kg), or CP-55,940 (1, 3, or 10 mg/kg) for 2 weeks and sacrificed 30 min after the last injection. In the acute condition, animals received a single dose (10 mg/kg) prior to sacrifice. Rats developed tolerance to the inhibitory effects of delta 9-THC and CP-55,940, assayed in an open field on days 1, 7, and 14. Cannabidiol had no effect on behavior. Densitometry of [3H]CP-55,940 binding to brain sections showed that delta 9-THC- and CP-55,940-treated animals had homogeneous decreases in binding in all structures measured at the selected striatal levels. Cannabidiol had no effect on binding. Analysis of binding parameters showed that alterations in the acute condition were attributed to changes in affinity (KD), whereas the major changes in the chronic condition were attributed to a lowering of capacity (Bmax). The effects in the 1, 3, and 10 mg/kg CP-55,940 conditions were dose-dependent and paralleled the behavioral data showing that the animals given the highest dose developed the greatest degree of tolerance. The data suggest that tolerance to cannabinoids results at least in part from agonist-induced receptor down-regulation.

Id Code
93117281
Authors
Szeto HH, Wu DL, Cheng Y, Cheng PY, Decena JA
Title
Maternal marijuana smoking alters respiratory timing in the fetal lamb.
Source
Pharmacology, Biochemistry & Behavior
Date
1992 Dec
Issue
43(4)
Pages
1227-31
Abstract
The effect of single and repeated maternal marijuana smoke exposure on fetal breathing movements (FBMs) was investigated in 13 fetal lambs in the third trimester. These animals were surgically instrumented for long-term intrauterine recording of diaphragmatic electromyogram (EMG). Maternal inhalation of marijuana smoke [1.84% tetrahydrocannabinol (THC)] increased FBMs and resulted in a more continuous and regular breathing pattern. There was a significant increase in the number of breaths/h (p < 0.01) and the incidence of FBMs (p < 0.001) in the second hour. Breathing activity returned to presmoke level by the third hour. Duration of the longest breathing epoch was significantly increased from 16.8 +/- 3.3 min to 31.9 +/- 5.2 min (p < 0.005). Instantaneous breathing rate was much more stable in the second hour after marijuana exposure (p < 0.01). Inhalation of placebo smoke did not result in any significant change in either overall breathing activity or continuity and stability of the breathing rate. The effects of marijuana smoke on fetal breathing were not observed after repeated smoke exposure. These results suggest that tolerance develops rapidly to the respiratory stimulating effect of marijuana smoke in the fetus.

Id Code
92295437
Authors
Abood ME, Martin BR
Title
Neurobiology of marijuana abuse. [Review]
Source
Trends in Pharmacological Sciences
Date
1992 May
Issue
13(5)
Pages
201-6
Abstract
Marijuana has a long history of abuse yet, as described here by Mary Abood and Billy Martin, there is little evidence that animals will self-administer the primary psychoactive constituent, tetrahydrocannabinol, or that marijuana stimulates brain reward pathways. While marked tolerance develops to marijuana, it has been difficult to demonstrate physical dependence, and until recently the mechanisms by which cannabinoids produced their behavioral effects were poorly defined. The development of new synthetic analogs played a critical role in the characterization and cloning of the cannabinoid receptor. Insight into cannabinoid receptors may lead to a better understanding of marijuana abuse in humans and provide new therapeutic strategies for several disorders.
References
38

Authors
- Sim LJ, Hampson RE, Deadwyler SA, Childers SR
Title
- Effects of chronic treatment with delta9-tetrahydrocannabinol on cannabinoid-stimulated [35S]GTPgammaS autoradiography in rat brain.
Language
- Eng
Date
- 1996 Dec 15
Issue
- 0270-6474
Source
- J Neurosci
Pages
- 8057-66
Country
- UNITED STATES
Abstract
- Chronic Delta9-tetrahydrocannabinol (Delta9-THC) administration produces tolerance to cannabinoid effects, but alterations in signal transduction that mediate these changes are not yet known. The present study uses in vitro autoradiography of agonist-stimulated [35S]GTPgammaS binding to localize cannabinoid receptor-activated G- proteins after chronic Delta9-THC treatment. Cannabinoid (WIN 55212-2)- stimulated [35S]GTPgammaS binding was performed in brain sections from rats treated chronically with 10 mg/kg Delta9-THC for 21 d. Control animals received saline or an acute injection of Delta9-THC. Acute Delta9-THC treatment had no effect on basal or WIN 55212-2-stimulated [35S]GTPgammaS binding. After chronic Delta9-THC treatment, net WIN 55212-2-stimulated [35S]GTPgammaS binding was reduced significantly (up to 70%) in most brain regions, including the hippocampus, caudate- putamen, perirhinal and entorhinal cortex, globus pallidus, substantia nigra, and cerebellum. In contrast, chronic Delta9-THC treatment had no effect on GABAB-stimulated [35S]GTPgammaS binding. In membranes and brain sections, Delta9-THC was a partial agonist, stimulating [35S]GTPgammaS by only 20% of the level stimulated by WIN 55212-2 and inhibiting WIN 55212-2-stimulated [35S]GTPgammaS at high concentrations. Because the EC50 of WIN 55212-2-stimulated [35S]GTPgammaS binding and the KD of cannabinoid receptor binding were unchanged by chronic Delta9-THC treatment, the partial agonist actions of Delta9-THC did not produce the decrease in cannabinoid-stimulated [35S]GTPgammaS binding. These results suggest that profound desensitization of cannabinoid-activated signal transduction mechanisms occurs after chronic Delta9-THC treatment.
Research Institute
- Department of Physiology and Pharmacology, Center for the Neurobiological Investigation of Drug Abuse, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina 27157, USA.
Source
- J Neurosci 1996 Dec 15;16(24):8057-66