Tetrahydrocannabinol Exposure Research Articles

Gender-dependent behavioral and biochemical effects of adolescent delta-9-tetrahydrocannabinol in adult maternally deprived rats

Preclinical data support the long-term adverse effects on cognition, emotionality, and psychotic-like behaviors of adolescent exposure to natural and synthetic cannabinoids. To investigate whether the long-lasting adverse effects induced by cannabinoids in adolescence are influenced by early-life stress, female and male rats were subjected to 24-h maternal deprivation at postnatal day (PND) 9 and treated with tetrahydrocannabinol (THC) during adolescence (PND 35–45) according to our previously reported protocol. At adulthood, rats were tested in the novel object recognition, social interaction, and forced swim tests, to evaluate possible alterations in recognition memory, social behavior, and coping strategy. Moreover, cannabinoid CB1 receptor density and functionality, as well as NMDA and dopamine D1 and D2 receptor densities were measured through autoradiographic binding studies. In female maternally deprived rats, THC failed to impair recognition memory, counteracted aggressiveness induced by maternal deprivation, whereas no interaction was observed in the passive coping behavior. In males, the association of the two events increased passive coping response without affecting other behaviors. This behavioral picture was accompanied by gender-dependent and region-specific alterations in NMDA, D1 and D2 receptors. In conclusion, this study demonstrates that adolescent THC exposure might have different behavioral outcomes in animals previously exposed to early-life stress compared with non-stressed controls. The interaction between the two events is not univocal, and different combinations may arise depending on the sex of the animals and the behavior considered. Alterations in NMDA, D1 and D2 receptors might be involved in the behavioral responses induced by maternal deprivation and in their modulation by THC.This article is part of a Special Issue entitled: Stress, Emotional Behavior and the Endocannabinoid System.

Prenatal tetrahydrocannabinol (THC) alters cognitive function and amphetamine response from weaning to adulthood in the rat

Research suggests that not only is marijuana use prevalent among women of reproductive age, but a significant number of women continue to use marijuana and its derivatives throughout pregnancy. Many studies have shown, in both humans and animals, that marijuana exposure during adolescence and adulthood is detrimental to normal cognition and memory. In this study, we examined the effects of daily intravenous injections of 0.15mg/kg Δ9-tetrahydrocannabinol (THC), given to pregnant dams throughout gestation, on cognitive function in the offspring. Offspring were exposed to three tests: a passive avoidance test at postnatal day (PND) 22, an active place avoidance test at PND 45, and an attention task at PND 60, which assessed learning and long-term memory, spatial working memory and prediction, and attention, respectively. Other offspring were also given a 1mg/kg amphetamine challenge at PND 60. Passive avoidance testing showed that prenatal THC had no effect on acquisition but interfered with consolidation during retention testing. The active place avoidance task showed no treatment-related effects on acquisition but a significant treatment effect was observed in reversal performance in males. The attention task showed that a smaller percentage of THC-exposed rats completed the test, although the failure rate of both groups was quite high. Finally, THC exposed animals, both male and female, showed a dampened locomotor response to amphetamine, but females were more active than males overall. These results suggest that prenatal THC exposure has effects on certain aspects of cognitive function in rats from weaning to adulthood. These effects suggest that prenatal marijuana exposure could also alter cognitive function in humans and therefore have an impact on school performance and dampen responses to psychostimulants as well.

Association between cannabis and psychiatric hospitalization

To investigate the relationship between cannabis use and mental health. A cross-sectional analysis in a sample of 17 698 individuals with a mean age of 22 years (SD: 4.2). Participants provided information on the amount and initial age of cannabis use and history of psychiatric hospitalizations through a web-based questionnaire. To quantify Δ(9) -tetrahydrocannabinol exposure, we operationalized cannabis use as the amount of money spent on cannabis per week over the last month. The odds ratio of having a history of psychiatric hospitalizations was the primary outcome measure. We found a dose-response relationship between the amount of cannabis use and the odds for psychiatric hospitalization. Adjusted odds ratios for hospitalization increased with the amount of cannabis consumed from 1.6 (95% CI: 1.1-2.3) in incidental users to 6.2 (95% CI: 4.3-8.9) in heavy users (>€25/week). Our data suggested that concomitant drug use was an intermediate factor. Exposure to cannabis before the age of 12 years was found to carry a 4.8 (95% CI: 2.9-7.8) times increased odds for past psychiatric hospitalizations. We conclude that early and heavy uses of cannabis are each and independently associated with poor mental health in its users.

Regional enhancement of cannabinoid CB1 receptor desensitization in female adolescent rats following repeated Δ9‐tetrahydrocannabinol exposure

Disruption of the substantial re-organization of the brain during adolescence may be induced by persistent abuse of marijuana. The aim of this study was to determine whether adolescent and adult rats exhibit differential adaptation of brain cannabinoid (CB(1)) receptors after repeated exposure to Delta(9)-tetrahydrocannabinol (THC). Rats of both ages and sexes were dosed with 10 mg kg(-1) THC or vehicle twice daily for 9.5 days. Subsequently, CB(1) receptor function and density were assessed. In all brain regions, THC treatment produced desensitization and down-regulation of CB(1) receptors. While the magnitude of down-regulation did not differ across groups, greater desensitization was evident in the brains of THC-treated female adolescent rats for most regions. Adolescent females showed greater desensitization than adult females in the prefrontal cortex, hippocampus, periaqueductal gray (PAG) and ventral midbrain. In contrast, adolescent males exhibited less desensitization in the prefrontal cortex, hippocampus and PAG, an effect opposite to that seen in females. With the exception of the PAG, sex differences were seen only in adolescents, with greater desensitization in the prefrontal cortex, striatum, hippocampus, PAG, and ventral midbrain of females. These results suggest that the brains of adolescent females may be particularly vulnerable to disruption of CB(1) receptor signalling by marijuana abuse. Alternatively, increased desensitization may reflect protective adaptation. Given the extensive re-organization of the brain during adolescence, this disruption has potential long-term consequences for maturation of the endocannabinoid system.

Structural MRI Findings in Long-Term Cannabis Users: What Do We Know?

In animal studies, tetrahydrocannabinol (THC) has been found to affect brain morphology, particularly within areas rich in cannabinoid receptors (e.g., hippocampus, cerebral cortex). While cannabis remains the most widely used illicit drug worldwide, there has been limited work investigating its effects on human brain tissue. In this paper, we conducted a systematic review of existing structural magnetic resonance imaging studies to examine whether cannabis use is associated with significant changes in brain anatomy. We identified only 13 structural neuroimaging studies, which were diverse in terms of sample characteristics (e.g., age of participants, duration and frequency of use) and methodology (e.g., image analysis). No study found global structural changes in cannabis users, although six studies reported regional alterations. While changes in the hippocampus and parahippocampus were frequently identified, the findings were inconsistent across studies. The available literature also provides some evidence that regional structural changes are associated with cannabis use patterns (particularly cumulative dosage and frequency of use), as well as measures of psychopathology (e.g., measures of depressive and psychotic symptoms). Together, these structural imaging findings suggest that THC exposure does affect brain morphology, especially in medial–temporal regions. Given the small literature available and the limitations of studies to date, further research is clearly required, particularly given the prevalence of cannabis use worldwide.

Sexually dimorphic alterations in locomotion and reversal learning after adolescent tetrahydrocannabinol exposure in the rat

Research suggests that use and abuse of marijuana can be especially harmful if it occurs during adolescence, a period of vast developmental changes throughout the brain. We examined the effects of 2 mg/kg ∆ 9-tetrahydrocannabinol (THC) administered daily via intra-peritoneal injections during juvenile/early adolescence (postnatal day 22–40) or late adolescence (postnatal day 41–60) on locomotor activity, development of tolerance, and acquisition/retention of spatial avoidance in adulthood. THC caused locomotor depression in both male and female animals dosed during early adolescence but only in female animals dosed during late adolescence. Evidence of reverse tolerance to THC was seen in early adolescent animals only. In the active place avoidance test (APA), male and female animals administered THC during early adolescence made more errors on the reversal trial requiring flexibility in learning, but in animals dosed during late adolescence there were no significant sex or treatment differences. The results of the locomotor activity study indicate that females may be more sensitive to the effects of THC than males, while results of both locomotor activity and APA studies suggest that early adolescents appear to be more vulnerable to these effects than late adolescents/young adults.

CS10-02 Maternal deprivation in rat: Model of vulnerability to opiate addiciton

Aims:The concept of individual vulnerability applied to mental pathology involves genetic background and/or environmental context. We studied the impact of environmental factors such as maternal deprivation on the appearance of a vulnerability to addiction. Maternal deprivation represents an early stress, a lack of nursing occurring during a period of intense neuronal development and then could lead to long term brain functioning abnormalities. It has been recently shown that > 900 genes are stably regulated by maternal care in rat.Methods:Pups were separated from their mother and littermate the day after birth 3h/day for 14 days. Place preference and oral auto-administration tests were performed at the adulthood. Opioidergic and dopaminergic systems were studied.Results:We showed that maternal deprivation leads in adult male rats to a hypersensitivity to the rewarding and reinforcing effects of morphine correlated with a basal hypoactivity of the striatal enkephalinergic system. Maternal deprivation did not change oral self-administration behavior of cocaine and alcohol. Adolescent chronic tetrahydrocannabinol exposure suppressed morphine dependence in adult deprived rats.Conclusion:Maternal deprivation represents a highly valuable model to study environmentally triggered inter-individual vulnerability to opiate addiction. The suppression of morphine dependence in adult deprived rats after adolescent chronic tetrahydrocannabinol exposure raise the question of the beneficial effects of cannabis in opiate dependence vulnerability context.

Prenatal Cannabis Exposure Increases Heroin Seeking with Allostatic Changes in Limbic Enkephalin Systems in Adulthood

Prenatal cannabis exposure is a growing concern with little known about the long-term consequences on behavior and neural systems relevant for reward and emotional processing. We used an animal model to study the effects of prenatal exposure to Delta(9)-tetrahydrocannabinol (THC) on heroin self-administration behavior and opioid neural systems in adult males (postnatal day 62). Rats were exposed to THC (.15 mg/kg) or vehicle from gestational day 5 to postnatal day 2. Both pretreatment groups showed similar heroin intake, but THC-exposed rats exhibited shorter latency to the first active lever press, responded more for low heroin doses, and had higher heroin-seeking during mild stress and drug extinction. THC exposure reduced preproenkephalin (PENK) mRNA expression in the nucleus accumbens during early development, but was elevated in adulthood; no adult striatal changes on preprodynorphin mRNA or PENK in caudate-putamen. PENK mRNA was also increased in the central and medial amygdala in adult THC-exposed animals. THC animals had reduced heroin-induced locomotor activity and nucleus accumbens mu opioid receptor coupling. This study demonstrates enduring effects of prenatal THC exposure into adulthood that is evident on heroin-seeking behavior during extinction and allostatic changes in mesocorticolimbic PENK systems relevant to drug motivation/reward and stress response.

Previous Exposure to THC Alters the Reinforcing Efficacy and Anxiety-Related Effects of Cocaine in Rats

The hypothesis that prior cannabis exposure increases the likelihood of becoming addicted to other drugs can be evaluated by giving rats a history of tetrahydrocannabinol (THC) exposure, then allowing them to self-administer other drugs. In Experiment 1, THC pre-exposure did not alter the acquisition of cocaine self-administration or the amount of cocaine taken under a fixed-ratio 1 (FR1) schedule, with one response required for each injection. Under a progressive-ratio schedule, with the response requirement increasing exponentially with each injection, cocaine-seeking was significantly reduced in THC-exposed rats, suggesting that the regimen of THC exposure used in the present study caused cocaine to be devalued as a reinforcer. In contrast, in an earlier study that used the same regimen, a history of THC exposure did not alter the value of heroin as a reinforcer under the progressive-ratio schedule, but it increased heroin self-administration under the FR1 schedule. Experiment 2 examined how this regimen of THC pre-exposure alters the locomotor effects of cocaine and heroin. THC pre-exposure produced cross-tolerance to the motor-depressant effects of heroin; this may explain the shortened post-injection pauses exhibited by THC-exposed rats under FR1 heroin self-administration. When given cocaine, THC-exposed rats exhibited normal increases in locomotion, but they avoided the center of the open field, suggesting that this THC pre-exposure regimen enhances the anxiogenic effects of cocaine. This enhanced anxiogenic effect-which was verified in Experiment 3 using another model of anxiety, the light-dark test-may explain the reduced reinforcing value of cocaine observed in THC-exposed rats in Experiment 1.

Tetrahydrocannabinol suppresses immune function and enhances HIV replication in the huPBL-SCID mouse

Epidemiologic studies identify marijuana as a potential cofactor in the development and progression of HIV infection. To evaluate this interaction we employed a hybrid model in which human peripheral blood leukocytes (PBL) were implanted into severe combined immunodeficient mice (huPBL-SCID) and infected with an HIV reporter construct in the presence or absence of tetrahydrocannabinol (THC) exposure. Administration of THC alone, in the absence of HIV, decreased CD4 counts and the CD4:CD8 ratio. Co-administration of THC and HIV did not reduce CD4 counts further, but significantly increased the percentage of HIV-infected PBL when compared to saline-treated animals (17 ± 4.6% vs. 7 ± 1.4%). Quantitative PCR confirmed a 50-fold increase in systemic viral load in THC-treated animals. The CCR5 and CXCR4 chemokine receptors function as coreceptors essential for HIV infection. Administration of THC for 5 days increased the percentage of PBL expressing CCR5 and, to a lesser extent, CXCR4. This effect was lost after 10 days of THC administration, but the number of HIV-infected cells had significantly increased by that time suggesting a role for early upregulation of these coreceptors in the pathogenic effect of THC. Finally, the impact of treatment on the number of human interferon-gamma (IFN-γ) producing cells was determined by ELISPOT. Both THC and HIV infection independently decreased the number of IFN-γ producing cells and co-administration produced additive effects. These results suggest that exposure to THC in vivo can suppress immune function, increase HIV coreceptor expression, and act as a cofactor to significantly enhance HIV replication.

Perinatal Exposure to Δ9-Tetrahydrocannabinol Alters Heroin-Induced Place Conditioning and Fos-Immunoreactivity

In the present study, the effects of perinatal exposure to Delta(9)-tetrahydrocannabinol (THC) on heroin-induced place conditioning and Fos-immunoreactivity (Fos-IR) were examined. Male albino Wistar rats (N=104) were pretreated with vehicle (n=52) or 5 mg/kg THC (n=52) from postnatal days 4 through 14. At approximately 8 weeks of age, 72 rats were divided into six equal groups (n=12 per group) and injected subcutaneously (s.c.) with vehicle, 0.5, or 2.0 mg/kg heroin and tested in an unbiased two-compartment place conditioning task. In vehicle-pretreated rats, 2.0 mg/kg but not 0.5 mg/kg heroin produced a significant place preference. Perinatal THC exposure significantly enhanced the rewarding properties of both doses of heroin. In the second experiment, 32 rats were divided into four equal groups (n=8 per group) and injected with vehicle or 0.5 mg/kg heroin s.c. and perfused 2-h later. Fos-IR was examined in several brain regions directly or indirectly involved in reward. Acute administration of heroin in vehicle pretreated rats increased Fos-IR in the central, medial, and dorsomedial caudate putamen (CPu), nucleus accumbens (NAC, core and shell regions), lateral septum, islands of Calleja-major (ICjM), bed nucleus of the stria terminalis (BNST), central nucleus of the amygdala (CEA), dorsolateral and dorsomedial periaqueductal gray (PAG), ventral tegmental area (VTA), Edinger-Westphal nucleus (EW). Perinatal THC exposure significantly increased heroin-induced Fos-IR in the dorsomedial CPu. Conversely, perinatal THC exposure reduced heroin-induced Fos-IR in the NAC (shell), BNST, CEA, dorsolateral and lateral PAG, VTA, and EW. The present study demonstrates an increase in the rewarding properties of heroin following exposure to THC at an early age and provides new evidence regarding possible neural correlates underlying this behavioral alteration. Neuropsychopharmacology (2006) 31, 58-69. doi:10.1038/sj.npp.1300770; published online 25 May 2005.

Reduced Glial Fibrillary Acidic Protein and Glutamine Synthetase Expression in Astrocytes and Bergmann Glial Cells in the Rat Cerebellum Caused by Δ9-Tetrahydrocannabinol Administration during Development

In this study we analyzed the responses of cerebellar astroglial cells to pre- and perinatal Δ⁹-tetrahydrocannabinol (THC) exposure in three postnatal ages and both sexes. To determine whether THC during development directly modifies astroglial growth, this study investigated the effects of THC on astroglial morphological changes and on the expression of specific astroglial markers (glial fibrillary acidic protein: GFAP and glutamine synthetase: GS). Our results demonstrated that the administration of THC during development has deleterious effects on astroglial maturation in the cerebellum. These results also indicate that THC might interfere with astroglial differentiation in a way dependent on sex. The effect of cannabinoids on the development of cerebellar astroglial cells (astrocytes and Bergmann glial cells) is to reduce protein synthesis, since both GFAP and GS decreased in astroglial cells, not only during THC exposure but also in adult ages. Our data suggest that pre- and perinatal THC exposure directly interferes with astroglial maturation by disrupting normal cytoskeletal formation, as indicated by the irregular disposition of GFAP and the lower GFAP expression observed at all the ages studied. THC exposure during development may also modulate glutamatergic nervous activity since GS expression is reduced in THC-exposed brains. GS expression increased progressively after THC withdrawal, but GS expression had still not reached control values two months after THC withdrawal. This indicates that glutamate uptake is lower in glial cells exposed to THC, since GS expression is lower than in older controls. Consequently, glutamatergic neurotransmission may be affected by cannabinoid exposure during gestation. Therefore, cannabinoids exert developmental toxicity, at least on astroglial cells, which could contribute to fetal brain growth retardation.

Delta 9-tetrahydrocannabinol disrupts mitochondrial function and cell energetics.

We have observed rapid and extensive depletion of cellular energy stores by Delta(9)-tetrahydrocannabinol (THC) in the pulmonary transformed cell line A549. ATP levels declined dose dependently with an IC(50) of 7.5 microg/ml of THC after 24-h exposure. Cell death was observed only at concentrations >10 microg/ml. Studies using JC-1, a fluorescent probe for mitochondrial membrane potential, revealed diminished mitochondrial function at THC concentrations as low as 0.5 microg/ml. At concentrations of 2.5 or 10 microg/ml of THC, a decrease in mitochondrial membrane potential was observed as early as 1 h after THC exposure. Mitochondrial function remained diminished for at least 30 h after THC exposure. Flow cytometry studies on cells exposed to particulate smoke extracts indicate that JC-1 red fluorescence was fivefold lower in cells exposed to marijuana smoke extract relative to cells exposed to tobacco smoke extract. Comparison with a variety of mitochondrial inhibitors demonstrates that THC produced effects similar to that of carbonyl cyanide p-trifluoromethoxyphenylhydrazone, suggesting uncoupling of electron transport. Loss of red JC-1 fluorescence by THC was suppressed by cyclosporin A, suggesting mediation by the mitochondrial permeability transition pore. This disruption of mitochondrial function was sustained for at least 24 h after removal of THC by extensive washing. These results suggest that exposure of the bronchopulmonary epithelium to THC may have important health and physiological consequences.

Delta(9)-tetrahydrocannabinol-induced apoptosis in the thymus and spleen as a mechanism of immunosuppression in vitro and in vivo.

Delta(9)-tetrahydrocannabinol (THC), the main psychoactive component of marijuana has been shown to suppress the immune response. However, the exact mechanism of THC-induced immunosuppression remains unclear. In the current study, we tested the hypothesis that exposure to THC leads to the induction of apoptosis in lymphocyte populations. Splenocytes of C57BL/6 mice cultured in the presence of 10 microM or greater concentrations of THC showed significantly reduced proliferative response to mitogens, including anti-CD3 monoclonal antibodies (mAbs), concanavalin A (Con A), and lipopolysaccharide (LPS) in vitro. Thymocytes and naive and activated splenocytes exposed to 10 microM or 20 microM THC showed significantly increased levels of apoptosis. Treatment with CB2 antagonist inhibited THC-induced apoptosis in thymocytes and activated splenocytes. Administration of 10 mg/kg body weight of THC into C57BL/6 mice led to thymic and splenic atrophy as early as 6 h after treatment. This effect could be partially inhibited by treatment with a caspase inhibitor in vivo. THC exposure led to reductions in the numbers of all subpopulations of splenocytes and thymocytes examined. Functional studies revealed that splenocytes from THC-treated mice had significantly reduced proliferative response to anti-CD3 mAbs, Con A, and LPS in vitro. Finally, thymocytes and splenocytes exposed to THC in vivo exhibited apoptosis upon in vitro culture. Together, these results suggest that in vivo exposure to THC can lead to significant suppression of the immune response by induction of apoptosis.

Perinatal delta(9)-tetrahydrocannabinol exposure alters the responsiveness of hypothalamic dopaminergic neurons to dopamine-acting drugs in adult rats.

We have recently reported that perinatal cannabinoid exposure altered the normal development of dopaminergic neurons in the medial basal hypothalamus at early postnatal and peripubertal ages. Most of these effects tended to disappear in adulthood, although we suspect the existence of a persistent, but possibly silent, alteration in the adult activity of these neurons. To further explore this possibility, we evaluated the responsiveness of these neurons to pharmacological challenges with a variety of dopaminergic drugs administered to adult male and female rats that had been exposed to delta(9)-tetrahydrocannabinol (delta(9)-THC) or vehicle during the perinatal period. In the first experiment, we evaluated the sensitivity of hypothalamic dopaminergic neurons to amphetamine (AMPH), which causes enhancement of dopaminergic activity by a variety of mechanisms. The most interesting observation was that both adult males and females, when perinatally exposed to delta(9)-THC, showed a more marked AMPH-induced decrease in the production of L-3,4-dihydroxyphenylacetic acid (DOPAC), the main intraneuronal metabolite of dopamine (DA), although this did not affect the prolactin (PRL) release. In the second experiment, we evaluated the in vivo synthesis of DA by analyzing the magnitude of L-3,4-dihydroxyphenylalanine (L-DOPA) accumulation caused by the blockade of L-DOPA decarboxylase with NSD 1015. As expected, NSD 1015 increased L-DOPA accumulation and decreased DOPAC production, with a parallel increase in PRL release, all of similar magnitude in both delta(9)-THC- and oil-exposed adult animals. In the last experiment, we tested the magnitude of the increase in PRL release produced by the administration of either SKF 38393, a specific D1 agonist, or sulpiride, a specific D2 antagonist. Both compounds increased plasma PRL levels in adult animals of both sexes, the effects in females being significantly more marked. The perinatal exposure to delta(9)-THC also modified the degree of increase in plasma PRL levels induced by both compounds, with opposite responses as a function of sex. Thus, delta(9)-THC-exposed females responded more intensely to SKF 38393 and, particularly, to sulpiride than oil-exposed females, whereas delta(9)-THC-exposed males responded to SKF 38393 lesser than oil-exposed males, although both responded equally to sulpiride. In summary, our results are consistent with the possible existence of subtle changes in the activity of hypothalamic dopaminergic neurons in adulthood caused by the exposure to delta(9)-THC during perinatal development. These silent changes could be revealed after the administration of drugs such as: (i) AMPH, whose effect producing a decreased DOPAC accumulation was more marked in delta(9)-THC-exposed males and females; and (ii) SKF 38393 and sulpiride, whose stimulatory effects on PRL secretion were of different magnitude in delta(9)-THC-exposed animals, with an evident sexual dimorphism in the response. The neurochemical basis for these differences remains to be determined.

Effect of delta-9-tetrahydrocannabinol on the in vitro uptake of alpha-amino isobutyric acid by term human placental slices.

Tetrahydrocannabinol (THC), the active component in marijuana smoke, crosses the placenta and is a potential fetotoxic agent. In both human and animal studies, the most consistent fetal effect of THC is intrauterine growth retardation. Since fetal somatic growth is dependent on placental transfer of nutrients, including essential amino acids, we studied the effect of THC upon the in vitro uptake of amino acid by term human placental slices. Uptake of alpha-amino isobutyric acid was inhibited in a dose-dependent fashion, correlating with the log of the dose (1-100 microM THC; r = 0.945; p less than 0.01). Compared to control tissue, significant impairment of alpha-amino isobutyric acid uptake began at 20 microM THC. Similar results were found for valine. The time course (30-120 min) for alpha-amino isobutyric acid uptake showed linearity for both control and THC-(50 microM) treated tissue, but there was a marked reduction in the THC slope. Uptake of alpha-amino isobutyric acid was significantly reduced at all times. The sustained effect of THC was slightly, but significantly, reversed by removal of THC from the medium after 90 min of 50 microM THC exposure. Only partial reversal may have been due to the 15- to 20-fold accumulation of THC in the placental tissue. Uptake kinetics showed noncompetitive inhibition with decreased Vmax: control Vmax = 51.66 +/- 6.26 versus 50 microM THC = 26.96 +/- 6.22 (mmol/liter intracellular water per h) (p less than 0.01); and no change in diffusion constant (Km): control Km = 0.78 +/- 0.08 versus 50 microM THC = 0.80 +/- 0.09 (mM).(ABSTRACT TRUNCATED AT 250 WORDS)