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PubMed1992

Modulation of acute morphine tolerance by corticotropin-releasing factor and dynorphin A in the mouse spinal cord.

Previously, we have demonstrated that intrathecally (i.t.) administered corticotropin-releasing factor (CRF) in mice produces stimulus-specific antinociception and modulation of morphine-induced antinociception by mechanisms involving spinal kappa opioid receptors. Recently, we also have found that CRF releases immunoreactive dynorphin A, a putative endogenous kappa opioid receptor agonist, from superfused mice spinal cords in vitro. Dynorphin A administered intracerebroventricularlly (i.c.v.) to mice has been shown to modulate the expression of morphine tolerance. In the present study, the possible modulatory effects of i.t. administered CRF as well as dynorphin A on morphine tolerance were studied in an acute tolerance model. Subcutaneous administration of 100 mg/kg of morphine sulfate (MS) to mice caused an acute tolerance to morphine-induced antinociception. The antinociceptive ED50 of MS was increased from 4.4 mg/kg (naive mice) to 17.9 mg/kg (4 hours after the injection of 100 mg/kg MS). To study the modulatory effects of spinally administered CRF and dynorphin A on the expression of morphine tolerance, CRF and dynorphin A were injected i.t. at 15 min and 5 min, respectively, before testing the tolerant mice by the tail-flick assay. The antinociceptive ED50 of MS in tolerant mice was decreased to 8.8 mg/kg and 7.1 mg/kg, respectively, after i.t. administration of CRF (0.1 nmol) and dynorphin A (0.2 nmol). In contrast, 0.5 nmol of alpha-helical CRF (9-41), a CRF antagonist and 0.4 nmol of norbinaltorphimine, a highly selective kappa opioid receptor antagonist, when administered i.t. at 15 min before the tail-flick test in tolerant mice, increased the antinociceptive ED50 of MS to 56.6 mg/kg and 88.8 mg/kg, respectively. These data confirmed the modulatory effect of dynorphin A on morphine tolerance and suggested that CRF, which releases dynorphin A in several central nervous system regions, also plays a modulatory role in the expression of morphine tolerance.

Animals↗

PubMed1975

Effects of portacaval anastomosis on glucose tolerance in the dog: evidence of an interaction between the gut and the liver in oral glucose dosposal.

Continuous infusions of glucose (90 min duration) were given into the duodenum (ID), or the portal vein (IP), or a peripheral vein (IV) in conscious dogs, intact dogs, or dogs with portacaval anastomoses. In intact animals ID glucose tolerance was better than IV glucose tolerance, but IP glucose tolerance was not significantly different from IV glucose tolerance. Thus, the superiority of tolerance to ID glucose was not accounted for by relatively high levels of glucose in portal blood. IV glucose tolerance was not significantly affected by protacaval anastomosis with ligation of the portal vein, but ID glucose tolerance was markedly impaired. Disproportionate impairment in tolerance to enterically administered glucose in dogs with portacaval shunts, and the similarity of IP and IV glucose tolerance in intact dogs, suggest that both liver and the gut are important in determination of oral glucose tolerance through mechanisms that have little or no effect on responses to parenterally administered glucose. The results also suggest that the hepatic contribution is not dependent upon portal venous perfusion of the liver, and that a humoral interaction between the gut and the liver is involved which is not simply dependent on endocrine responses of the pancreas.

Animals↗

PubMed1982

Hypothalamic peptide hormone, prolyl-leucyl-glycinamide and analog, inhibit tolerance to the analgesic and locomotor depressant but not to the locomotor stimulant effects of morphine in the mouse.

The effects of prolyl-leucyl-glycinamide (melanotropin release inhibiting factor, MIF) and cyclo(Leu-Gly) on development of tolerance to the analgesic, locomotor stimulant and depressant effects of morphine were investigated in the mouse. Mice were made tolerant to morphine by subcutaneous implantation of pellet (each pellet contained 75 mg of morphine free base) for three days. Both MIF and cyclo(Leu-Gly) inhibited the development of tolerance to the analgesic response to a challenge dose of morphine in peptide-treated as compared to vehicle-treated morphine-tolerant mice. Morphine in a small dose (10 mg/kg) depressed spontaneous motor activity, while, in a larger dose (80 mg/kg), increased the motor activity. Implantation of a morphine pellet resulted in the development of tolerance to both the locomotor depressant and stimulant effects of morphine. Administration of MIF or cyclo(Leu-Gly) during induction of tolerance in doses (2 mg/kg/day for 3 days) that inhibited the development of tolerance to morphine-induced analgesia and locomotor depressant activity, did not alter the development of tolerance to the locomotor stimulant effect. These studies indicate that the development of tolerance to the analgesic and locomotor depressant effect of morphine may involve similar mechanisms, whereas, tolerance to the locomotor stimulant effect of morphine may be mediated via a different mechanism.

Analgesia↗

PubMed1985

Cross tolerance between ketamine and morphine to some pharmacological and biochemical effects.

Whether morphine and ketamine induced cross-tolerance to some of their common pharmacological and biochemical effects, namely analgesia and enhancement of metabolites of dopamine (DA) in the striatum and limbic area of the rat was analysed. Ketamine was given at the dose of 100 mg/kg, twice a day for 8 days. After this treatment, a challenge dose of morphine (15 mg/kg, i.p.) still induced analgesia comparable to that induced by morphine alone, showing no cross-tolerance to this effect. In contrast, the challenge dose of morphine given to ketamine-tolerant rats no longer enhanced metabolism of DA, indicating the appearance of cross-tolerance to this effect. A high degree of tolerance to morphine was obtained after the subcutaneous implantation of rats with pellets of morphine; a challenge dose of ketamine to morphine-tolerant rats induced marked analgesia, with no cross-tolerance to this pharmacological effect, while cross-tolerance was present to the biochemical effect. The existence of a high degree of reciprocal cross-tolerance in both areas and on both metabolites of DA is consistent with the hypothesis of action at a common receptor; the lack of cross-tolerance to the analgesic effect indicates that analgesia is achieved by a different mechanism for the two drugs.

3,4-Dihydroxyphenylacetic Acid↗

PubMedDate not supplied

Analysis of the role of behavioural factors in the development of tolerance to the benzodiazepine midazolam.

Two experiments were conducted on the acute and chronic effects of the short-acting benzodiazepine midazolam on fixed ratio schedule-maintained operant responding in rats. Acute administration of midazolam produced suppression of responding in large doses but elevation of responding in small doses. Following intermittent (every third day) chronic treatment tolerance developed rapidly to the rate-suppressant effects of large doses of midazolam but did not develop to the rate-elevating effects of small doses, even after chronic treatment with large doses of the drug. Thus, when tolerance was measured in terms of shifts in dose-effect curves, it was manifested as a non-parallel shift in the curve after chronic treatment. Since tolerance developed to the effects of large but not small doses, the observed tolerance could not be attributed to changes in disposition of the drug. The development of tolerance did not depend on whether the drug was given before or after behavioural testing. These findings contrast with data reported in behavioural studies with other sedative-hypnotics (ethanol, barbiturates). Animals tolerant to midazolam showed no cross-tolerance to ethanol, a drug for which there is reliable evidence indicating that behavioural factors play a role in acquisition of tolerance. Tolerance to midazolam cannot therefore be explained in terms of learned strategies acquired as a result of drug-induced loss of rewarding stimuli. This conclusion contrasts with recent suggestions (File, 1985; File and Pellow, 1985) that tolerance to benzodiazepines may be mediated by instrumental conditioning processes.

Animals↗

PubMed1986

Differential alteration of lipoxygenase and cyclooxygenase metabolism by rat peritoneal macrophages induced by endotoxin tolerance.

Altered macrophage arachidonic acid metabolism may play a role in endotoxic shock and the phenomenon of endotoxin tolerance induced by repeated injections of endotoxin. Studies were initiated to characterize both lipoxygenase and cyclooxygenase metabolite formation by endotoxin tolerant and non-tolerant macrophages in response to 4 different stimuli, i.e. endotoxin, glucan, zymosan, and the calcium ionophore A23187. In contrast to previous reports of decreased prostaglandin synthesis by tolerant macrophages, A23187-stimulated immunoreactive (i) leukotriene (LT)C4/D4 and prostaglandin (PG)E2 production by tolerant cells was greater than that by non-tolerant controls (p less than 0.001). However, A23187-stimulated i-6-keto-PGF1 alpha levels were lower in tolerant macrophages compared to controls. Stimulation of prostaglandin and thromboxane (Tx)B2 synthesis by endotoxin or glucan was significantly less in tolerant macrophages compared to controls (p less than 0.05). iLTC4/D4 production was not significantly stimulated by endotoxin or glucan, but was stimulated by zymosan in the non-tolerant cells. Synthesis of iLTB4 by control macrophages was stimulated by endotoxin (p less than 0.01). These results demonstrate that arachidonic acid metabolism via the lipoxygenase and cyclooxygenase pathways in macrophages is differentially altered by endotoxin tolerance.

6-Ketoprostaglandin F1 alpha↗

PubMed1988

Does chronic ethanol intake confer full cross-tolerance to chlordiazepoxide?

Four behavioral tests, namely, hypothermia, horizontal dowel, runway and head-dipping, were used to assess tolerance to ethanol and cross-tolerance to chlordiazepoxide (CDP) in mice chronically treated with an ethanol diet for 15 days. Mice were tested on day 3 of ethanol withdrawal, with some being retested on day 8. In terms of hypothermia and the horizontal dowel test, ethanol tolerance conferred full cross-tolerance to CDP, but the conclusion based on results of the latter test may be equivocal. Partial cross-tolerance to CDP was observed in the runway test, while no cross-tolerance to CDP was detected in the head-dipping test. For these latter two tests ethanol tolerance was present in the mice. Thus, the degree of equivalence between tolerance to ethanol and cross-tolerance to CDP in ethanol-dependent mice varied with the behavioral tests to assess tolerance. Possible mechanisms are discussed.

Alcoholism↗

PubMed1991

Cellular and learned tolerances for ethanol hypothermia.

Four groups of rats received ethanol: 1) intermittently while experiencing hypothermia, 2) chronically while experiencing hypothermia, 3) intermittently while protected from hypothermia, and 4) chronically while being protected from hypothermia. On postchronic testing, Group 1 showed tolerance to 2.0 and 2.3 but not 2.7 g/kg ethanol, Group 2 was tolerant to all 3 doses, Group 3 was tolerant to none, and Group 4 was tolerant only to 2.7 g/kg. On withdrawal of chronic ethanol or vehicle, Groups 1 and 2 showed trends to lose tolerance which became significant after subsequent extinction training. The treatments were repeated in other rats up to the postchronic test for tolerance, after which they were killed at 15-120 min after ethanol to assay serum and brain concentrations. Serum and brain levels of ethanol were higher in Groups 2 and 4 despite less intense hypothermia (i.e., no metabolic tolerance). Analysis of covariance indicated less tolerance in Group 1 vs. Group 2 and Group 3 vs. Group 4 for the same brain levels of ethanol (i.e., cellular tolerance in Groups 2 and 4). Therefore, both learned and cellular tolerances were observed in these subjects and appeared to be separable phenomena according to the various treatments imposed.

Animals↗

PubMed1992

Ketamine retards chronic but not acute tolerance to ethanol.

Motor impairment (tilt-plane test) was used to investigate whether the noncompetitive N-methyl-D-aspartate (NMDA) antagonist ketamine prevents the development of chronic and acute tolerance to ethanol. Rats were treated with ethanol or saline in the presence and absence of ketamine (separate groups) for 10 days and tested for ethanol tolerance in the absence of ketamine on the fifth and tenth days. In other studies, the effect of ketamine on acute tolerance to ethanol was examined. Rats that received ethanol daily without ketamine showed significant tolerance to ethanol on days 5 and 10, but those receiving ethanol plus ketamine daily showed significantly less tolerance to ethanol. Thus, ketamine interfered with the development of chronic tolerance just as it had been found previously to prevent rapid tolerance. In contrast, ketamine failed to block acute tolerance to ethanol. These results would suggest that the phenomena of acute tolerance and chronic tolerance have differences not previously reported.

Animals↗

PubMed1993

Contingent tolerance to carbamazepine is not affected by calcium-channel or NMDA receptor blockers.

We previously demonstrated that tolerance to carbamazepine's anticonvulsant effects occurs only with contingent presentation of the drug relative to the seizure (i.e., drug administration before but not after the seizure). Moreover, this tolerance can be reversed by altering the contingencies of drug administration (e.g., giving the drug after the seizure has occurred) without discontinuation of drug treatment. These findings imply an associative component to tolerance development in this model. Thus, we evaluated the effects on contingent tolerance development of two agents that have been shown to affect rate of tolerance development and acquisition or retention in other learning paradigms. Rats were electrically kindled in the amygdala until they reliably experienced seizures with each stimulation. In three separate studies, MK-801 (0.3 and 0.15 mg/kg), an NMDA receptor antagonist, and nimodipine (20 mg/kg), an L-type calcium channel blocker, were coadministered with carbamazepine prior to each kindling stimulation to evaluate the rate of tolerance development compared to controls. No effect of either drug was seen on the rate of contingent tolerance development to carbamazepine, suggesting that neither NMDA receptors nor L-type calcium channels are critically involved in this type of tolerance. The contingent tolerance paradigm may, however, prove useful in elucidating novel biochemical mechanisms of associative learning that might ultimately be explored in clinical situations where tolerance is a problem.

Animals↗

PubMed1994

Dissipation of contingent tolerance to the anticonvulsant effect of diazepam: effect of the criterion response.

The effect of convulsive stimulations on the dissipation of tolerance to the anticonvulsant effect of diazepam was investigated using the kindled-convulsion model. Amygdala-kindled rats were rendered tolerant to diazepam's anticonvulsant effect by 25 "bidaily" (one/48 h) diazepam injections (2.5 mg/kg), each followed 1 h later by a convulsive stimulation. They were then divided into nine groups for the tolerance-dissipation phase of the experiment. Of the nine groups, three received bidaily control handling for one trial, three trials, or seven trials; three received bidaily saline injections, each 1 h before a convulsive stimulation, for one, three, or seven trials; and three received bidaily diazepam injections, each 1 h after a convulsive stimulation, for one, three, or seven trials. Finally, each rat received a tolerance-retention test (i.e., a diazepam injection followed 1 h later by a convulsive stimulation) 48 h after its last tolerance-dissipation trial. The tolerance dissipated gradually but completely over the 4-, 8-, and 16-day test intervals in the rats that received a convulsive stimulation before each injection during the tolerance-dissipation phase, whether they were injected with saline or diazepam; in contrast, tolerance did not dissipate in the rats that received saline injections but no stimulations. Remarkably, the discontinuance of the bidaily diazepam injections, even for 16 days, was not sufficient to dissipate the tolerance that had developed to diazepam's anticonvulsant effect; nor was the continuation of the bidaily diazepam injections sufficient to keep tolerance from dissipating.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

D-cycloserine enhances rapid tolerance to ethanol motor incoordination.

In a recent study, we showed that D-cycloserine, an agonist at the glycine site of the NMDA receptor, enhances the development of rapid tolerance to ethanol. In the present study, we report that the acquisition of rapid tolerance to the motor incoordination effect of ethanol (tilt-plane test) was increased only when D-cycloserine was injected before, but not after, the intoxicated practice under ethanol. The effect of D-cycloserine on tolerance when this agonist was administered in divided doses before and after test was similar to that obtained when D-cycloserine was injected before test. Higher doses of D-cycloserine did not produce a further enhancement of rapid tolerance. Moreover, when the dose of ethanol on day 1 was large enough to induce rapid tolerance per se, D-cycloserine did not further enhance the tolerance. The enhancement of tolerance by D-cycloserine was antagonized by previous administration of ketamine. The enhancement of ethanol tolerance by D-cycloserine and the antagonism of this effect by ketamine cannot be attributed to changes in pharmacokinetics of ethanol. Taken together, these results confirm the participation of the NMDA receptor system in the development of tolerance to ethanol, and reinforce earlier findings about the involvement of learning in tolerance.

Animals↗

PubMed1994

Effects of copper concentration on mineral nutrient uptake and copper accumulation in protein of copper-tolerant and nontolerant Lotus purshianus L.

One copper-tolerant and one copper-sensitive inbred line of Lotus purshianus L. derived from a copper mine waste site in Northern California and one inbred line of the same species derived from a pasture next to the mine waste were examined for the effects of excessive copper concentrations on mineral nutrient uptake and accumulation of copper in protein fractions. Plants were grown from seeds for a period of 24 days in a modified Hoagland nutrient solution culture supplemented with 3, 6, and 10 microM copper as copper sulfate. The basal nutrient solution without copper amendment was used as the control treatment. The uptake of Cu found in the roots was 100 times or more than that in the leaves. The root tissue copper concentrations reached a plateau under 6 microM copper treatment. The leaf tissue copper concentrations increased with the increase of copper concentration in the solution culture. No difference in pattern of copper uptake was detected between the copper-tolerant and nontolerant plants. The effects of excessive copper concentrations caused reduction of Ca uptake in the leaf tissue and P uptake in both the root and leaf tissues, and no difference was found between the copper-tolerant and nontolerant plants. Increased tissue copper concentration caused greater reduction of Fe, Mn, and Zn uptake in the nontolerant plants than in the tolerant plants; this difference may be important for the growth of the tolerant plants under conditions of excessive copper concentrations. Protein extracted from the roots and leaves of both the copper tolerant and nontolerant plants was subjected to Sephadex G-75 column separation. Two major peaks of protein fractions were detected. Under low (normal level) copper concentration treatment, the copper-tolerant and nontolerant plants had similar Cu/protein ratios. However, under high copper concentration challenged conditions the copper-tolerant plant had a considerably greater Cu/protein ratio (peak II protein) than the nontolerant plants. The amino acid composition of the copper-rich protein fraction (peak II) extracted from both the tolerant and nontolerant plants demonstrated a high asparate (about 25%) content. The contents of glutamate, cystine, and glycine were about 11, 2.5, and 10%, respectively, and the rest of the amino acids were in a range of 2 to 6%. This pattern of amino acid composition is different from the amino acid composition of the phytochelatin metallothionein-like proteins found in copper-tolerant plants which are very high in cysteine.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acids↗

PubMed1991

Misclassification of diabetic subjects may account for the increased vascular risk of impaired glucose tolerance: the Islington Diabetes Survey.

We have studied the associations of macrovascular disease and hypertension with impaired glucose tolerance in a recall sample of 223 subjects selected from a population aged greater than or equal to 40 years who had been screened for diabetes using two separate glucose tolerance tests. Blood pressure was higher in subjects with diabetes, but not in those with impaired glucose tolerance, than in normals. Coronary heart disease, based on ECG criteria and history, was more frequent both in subjects with impaired glucose tolerance (odds ratio 1.94, 95% CI 1.02-3.69) and those with diabetes (odds ratio 3.88, 95% CI 1.33-11.97) than in normals, but the excess in the impaired glucose tolerance group was reduced, and was no longer significant, when adjusted for other variables (odds ratio 1.29, 95% CI 0.62-2.66). Peripheral vascular disease was more frequent in subjects with diabetes, but not in those with impaired glucose tolerance. When the subjects with impaired glucose tolerance on a single test were reclassified according to the results of a separate glucose tolerance test, the prevalence of coronary heart disease increased significantly with increasing degrees of glucose intolerance. Subjects with impaired glucose tolerance on both tests had an adjusted odds ratio of coronary heart disease of 0.90 (95% CI 0.42-1.94) compared with normal subjects. The excess of macrovascular disease in subjects with impaired glucose tolerance may result, at least in part, from the admixture of 'false negative diabetics' in that class.

Adult↗

PubMed1989

Blockade of tolerance to morphine analgesia by cocaine.

Tolerance to morphine analgesia was induced in male Sprague-Dawley rats by s.c. implantation of a morphine base pellet (75 mg) on the first and second day and determining the magnitude of tolerance 72 h after the first implant by s.c. injection of a test dose of morphine (5 mg/kg). Implantation of a cocaine hydrochloride pellet (25 mg), concurrently with morphine pellets or of a cocaine hydrochloride (50 mg) pellet after the development of tolerance, blocked both the development and expression of morphine analgesic tolerance. In morphine-pelleted animals pretreatment for 3 days with desipramine or zimelidine or phenoxybenzamine but not haloperidol produced no significant morphine tolerance. Pretreatment with a combination of desipramine and zimelidine, however, was as effective as cocaine in blocking morphine tolerance. Alpha-Methyl-p-tyrosine methyl ester counteracted the effect of cocaine in blocking morphine tolerance and potentiated the tolerance development. Blockade of morphine tolerance by cocaine was reinforced and facilitated by pretreatment with fenfluramine or p-chlorophenylalanine ethyl ester and to a lesser extent by clonidine and haloperidol. Acute administration of fenfluramine or zimelidine or a combination of desipramine and zimelidine or alpha-methyl-p-tyrosine methyl ester or p-chlorophenylalanine ethyl ester did not significantly affect morphine analgesia. The study suggests an important role of the concomitant depletion of both central noradrenaline and serotonin in the blockade of morphine tolerance by cocaine and stresses the importance of the counter-balancing functional relationship between these two neurotransmitters in the central nervous system.

Analgesics↗

PubMedDate not supplied

The effects of neurohypophyseal hormones on tolerance to the hypothermic effect of ethanol.

Mice were made tolerant to the hypothermic effect of ethanol by repeated administration of ethanol (4 g/kg, 25% v/v, IP) on three consecutive days. The colonic temperature was measured in individually-housed animals immediately before and 45 min after ethanol treatment. Peptide treatments with various schedules were made SC 2 hr before the first ethanol challenge. The decrease in hypothermic response was accepted as a tolerance phenomenon, which developed in control animals by day 2. A single injection of oxytocin (OXT) or lysine vasopressin (LVP [0.1 or 1 IU peptide] animal) before the first ethanol injection did not change the initial sensitivity to ethanol. This absence of acute interactions is also reflected in the sleep onset and sleep duration after 5 g/kg ethanol (IP). In contrast, both OXT and LVP affected the development of tolerance. Repeated treatments with graded doses of OXT (0.5-2 IU) or LVP (0.25-1 IU) every day for 3 days blocked the development of tolerance. 0.002 IU LVP facilitated the development of hypothermic tolerance. The remaining doses of the peptides were ineffective. A high dose of LVP (1 IU) facilitated hypothermic tolerance if the peptide was injected when tolerance to ethanol had developed fully without previous peptide treatment. OXT, on the other hand, was ineffective in this particular experimental model. The data suggest that both neurohypophyseal hormones (LVP and OXT) block the early developmental phase of tolerance to ethanol. On the other hand, LVP facilitated the expression of tolerance if the peptide was given to mice with fully developed tolerance.

Animals↗

PubMed2004

The development of morphine antinociceptive tolerance in nitric oxide synthase-deficient mice.

UNLABELLED: Elevations in nitric oxide (NO) have been implicated in the development of morphine antinociceptive tolerance. This study was conducted to establish the role of specific isoforms of NO synthase (NOS) in morphine tolerance development using genetically modified mice. METHODS: Three groups of mice (endothelial NOS [eNOS]-deficient, neuronal NOS [nNOS]-deficient, and NOS-competent) were used in this experiment. On Day 1, the analgesic response (radiant heat tail-flick) to a challenge dose of morphine (4 mg/kg) was determined over 3 hr. Tolerance was induced on Days 1-5 by administering morphine subcutaneously (10 mg/kg) or L-arginine, a NO precursor, intraperitoneally (200 mg/kg), twice daily. Analgesic response to the challenge dose was determined again on Day 6. RESULTS: Following sustained morphine administration, nNOS-deficient mice exhibited less tolerance development when compared to the control group, although measurable tolerance still occurred. Mice deficient in eNOS evidenced a degree of tolerance similar to that of control. Prolonged L-arginine administration produced significant functional tolerance to morphine in NOS-competent and eNOS-deficient mice. The loss of morphine responsivity after L-arginine administration was similar to that after morphine pretreatment. L-Arginine did not affect the antinociceptive response to morphine in mice deficient in nNOS, suggesting that the small degree of morphine-induced tolerance in this group occurs through an alternate pathway. CONCLUSIONS: These data demonstrate the pivotal role of the neuronal isoform of NOS in development of morphine antinociceptive tolerance. Furthermore, tolerance development appears to be predominantly a NO-mediated process, but likely is augmented by a secondary (non-NO) pathway.

Analgesics↗

PubMed2004

Behavioral and molecular changes elicited by acute administration of SR141716 to Delta9-tetrahydrocannabinol-tolerant rats: an experimental model of cannabinoid abstinence.

Whether chronic cannabinoid consumption produces a dependent state comparable to that occurring with other drugs (e.g. the appearance of withdrawal signs when consumption is interrupted), and whether chronic cannabinoid consumption increases the risk of consuming other drugs of greater addictive power, are probably the two questions relating to cannabinoid addiction that provoke the most controversy. The present study was designed to further explore these two questions in laboratory animals. Firstly, we examined the effects of an acute challenge with SR141716 (an antagonist for the cannabinoid CB(1) receptor) in Delta(9)-tetrahydrocannabinol (Delta(9)-THC)-tolerant rats. This antagonist has been reported to precipitate a cannabinoid withdrawal syndrome. Thus, the administration of SR141716 to Delta(9)-THC-tolerant rats reduced inactivity in the open-field test and enhanced responses as tremor, turning and retropulsion-these responses that were only slightly enhanced in control rats. The administration of SR141716 increased the plasma prolactin and the corticosterone concentration in controls, but these increases were much lesser in Delta(9)-THC-tolerant rats. In addition, CRF-mRNA levels in the paraventricular hypothalamic nucleus, while reduced in SR141716-treated controls, were significantly increased in Delta(9)-THC-tolerant rats. The analysis of endocannabinoids also revealed that the administration of SR141716, which was mostly inactive in control rats, was able to reverse the changes in anandamide or 2-arachidonoylglycerol concentrations found in Delta(9)-THC-tolerant rats, in the striatum, limbic forebrain, diencephalon, cerebellum and brainstem, but not in the midbrain and hippocampus. As a second objective, we evaluated whether Delta(9)-THC-tolerant rats were more vulnerable to morphine in a self-administration paradigm. The Delta(9)-THC-tolerant and control rats self-administered morphine to a similar extent, in concordance with the similar values of dopaminergic activity in limbic and motor regions. In summary, our data indicate that Delta(9)-THC-tolerant rats were not more vulnerable to the reinforcing properties of morphine. However, they responded to the blockade of CB(1) receptors by exhibiting slightly but possibly relevant differences in behavioral, endocrine and molecular parameters compared to the response in non-tolerant rats. This is indicative of the existence of a withdrawal syndrome in cannabinoid-tolerant rats that is mild compared with abstinence in opioid-dependent rats.

Animals↗