Chronic marijuana (MJ) smoking and urinary cortisol (UC) excretion in the monkey.
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Animals↗
Biomedical subjects
S F Ali
Publications and source records attributed to S F Ali.
Determination of amino acids in different regions of the rat brain. Application to the acute effects of tetrahydrocannabinol (THC) and trimethyltin (TMT).
A modified HPLC method is described for the determination of amino acids [aspartic acid, glutamic acid, glutamine, glycine, taurine, and gamma-aminobutyric acid (GABA)] in brain tissue utilizing precolumn derivatization with o-phthalaldehyde (OPA)-tert-butyl-thiol and electrochemical detection. A simple extraction procedure was employed and DL-homoserine used as internal standard. A neurotoxin previously shown to affect brain amino acids (trimethyltin, TMT) and a psychoactive compound hypothesized to act on these neurochemicals (delta-9-tetrahydrocannabinol, THC) were administered to adult male rats and amino acids were measured. Results revealed a gradient of distribution of most amino acids, with lowest levels posteriorly in the brain stem and increasing to the highest values in anterior cortical regions. TMT increased glutamine significantly in all brain regions examined, but increased glycine and decreased taurine only in the frontal cortex and hippocampus. No significant changes in any amino acid were found in hippocampus after THC treatment. The results establish the validity and usefulness of this HPLC method for detecting neurotoxicity-related changes in brain amino acid metabolism.
Amino Acids↗
Adrenocortical, beta-endorphin and behavioral responses to graded stressors in differentially reared rats.
Isolation rearing has long been suspected to alter hormonal and behavioral responses to stress. Two experiments were conducted to test the hypothesis that isolates are more timid or fearful than socially reared rats when exposed to novel test environments. In both, isolate response to 3 graded stressors was compared to that of socially-reared rats. In the first experiment, animals were handled, shocked or not treated prior to testing to produce three levels of conditioned fear. They were then tested on four paradigms previously shown sensitive to conditioned fear: open field activity, emergence latency, auditory startle, and latency to accept food from the experimenter. In the second experiment, rats were given a 0-, 5- or 20-min forced swim, then sacrificed for analysis of plasma corticosterone and pituitary and hypothalamic beta-endorphin. It was found that isolates showed little evidence of enhanced behavioral timidity, although rearing effects were seen on all 4 behavioral measures. Plasma corticosterone levels increased in a graded fashion over the course of the forced swim, but there was no effect of rearing conditions. While there were no effects of rearing or stress on hypothalamic beta-endorphin, pituitary beta-endorphin content was lower in females than in males, and isolate males had lower pituitary endorphin than social males. In summary, these experiments provide no evidence that isolation rearing produces a primary, global increase in fearfulness, but identify several behavioral and hormonal differences associated with differential housing in rats.
Animals↗
Neurochemical and neurohistological alterations in the rat and monkey produced by orally administered methylenedioxymethamphetamine (MDMA).
MDMA is an amphetamine analog prescribed by some health professionals in the field of psychotherapy and used as a recreational drug by the general public. In recent reports, investigators have suggested that MDMA produces acute neurotoxicity when administered by subcutaneous injection. In order to determine if MDMA produces lasting neurochemical alterations after oral administration, groups of six rats (adult male Sprague-Dawley) were dosed by gavage with either 40 or 80 mg/kg of MDMA or saline vehicle once every 12 hr for 4 days. These rats were terminated 2 weeks after the first dose along with an additional group of rats (80 mg/kg) terminated 4 weeks after the first dose. Brain regions including the hippocampus (H), caudate nucleus (CN), hypothalamus (HY), frontal cortex (FC), and brain stem (BS) were analyzed by HPLC with electrochemical detection for concentrations of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), and norepinephrine (NE). In the CN, 40 mg/kg MDMA produced no change in DA, DOPAC, or HVA, but a 50-60% decrease in 5-HT and 5-HIAA concentrations was observed at 2 weeks. Similar effects were observed at 80 mg/kg at both 2 weeks and 4 weeks. A temporary decrease was also seen in DA (21%) and in HVA (34%) 2 weeks but not 4 weeks after the 80 mg/kg dose regimen. In the H, MDMA (40 or 80 mg/kg) produced no change in NE, but a 50-60% decrease was seen in 5-HT and 5-HIAA concentrations at 2 weeks. Concentrations of 5-HT and 5-HIAA were significantly decreased in the HY and FC by all MDMA treatments, but DA and DOPAC concentrations were not altered as compared to vehicle controls. BS was least affected by treatment with no change in DA, DOPAC, or 5-HIAA concentrations and only a slight decrease in 5-HT (19-33%) concentrations at 2 weeks but not at 4 weeks. To determine the sensitivity of the nonhuman primate to MDMA, a total of nine rhesus monkeys were dosed with vehicle or 5 or 10 mg/kg MDMA (n = 3) by gastric intubation twice per day for 4 days. One month after MDMA dosing, a dose-related reduction from vehicle control values for 5-HT and 5-HIAA was observed. These results indicate that the monkey may be more sensitive than the rat to the persistent serotonergic neurotoxicity of MDMA.(ABSTRACT TRUNCATED AT 400 WORDS)
3,4-Methylenedioxyamphetamine↗
Gestational exposure to phencyclidine (PCP) in rats decreases PCP binding sites in term fetal brain.
Pregnant Sprague-Dawley rats were treated with 5 mg/kg body weight of phencyclidine (PCP) injected at 1 ml/kg subcutaneously on three consecutive days at four different stages of gestation. Within 10-30 min after treatment, dams showed some lack of motor coordination and became lethargic. On gestational day 21, all rats were killed by decapitation and brains were dissected and stored from mother and fetus for neurochemical analysis. PCP, dopamine and muscarinic cholinergic receptor binding was measured in membranes prepared from maternal and fetal whole brain. Neurotransmitter concentrations were also measured in the fetal brain homogenates. There was a significant decrease in PCP binding sites in fetal but not maternal brains after maternal PCP injection at gestational days 12-14, 15-17 and 18-20, but not at 9-11 days. Dopamine and muscarinic cholinergic receptor binding was not significantly altered in fetal or maternal brain when compared with vehicle control animals. The whole brain dopamine, 3,4-dihydroxyphenylacetic acid, serotonin, and 5-hydroxyindoleacetic acid concentrations did not show significant change in any group studied. These data indicate that gestational exposure to PCP decreases high affinity binding of PCP in term fetal brain at doses which do not alter maternal PCP receptor binding.
Animals↗
Role of dentate gyrus cells in retention of a radial arm maze task and sensitivity of rats to cholinergic drugs.
Male adult Fischer-344 rats that received bilateral injections of colchicine into two rostrocaudal sites showed relatively long-lasting alterations in the performance of a previously acquired radial arm maze task and specific destruction of dentate granule cells. Results of subsequent experiments with cholinergic drugs indicated that physostigmine or nicotine had no effect on the number of errors made in the maze, although other signs of cholinergic or pharmacological activity were present. RS-86, an analog of the muscarinic agonist arecoline, decreased errors in colchicine-treated rats, but these effects were associated with signs of parasympathetic overstimulation and behavioral sedation. Pretreatment with scopolamine, a muscarinic cholinergic receptor antagonist, increased errors in control rats but had no effect in colchicine-treated rats. Results of subsequent experiments found that colchicine-treated rats were less sensitive to the motor stimulant effect of scopolamine. These effects appeared to be associated with increased levels of choline acetyltransferase in the hippocampus and a down regulation of muscarinic postsynaptic receptors. One interpretation of these data is that intradentate colchicine may destroy granule cells, which leads to a compensatory reinnervation of cholinergic nerve terminals having cell bodies in the septum.
Acetylcholine↗
Acute effects of delta-9-tetrahydrocannabinol in rhesus monkeys as measured by performance in a battery of complex operant tests.
Acute effects of delta-9-tetrahydrocannabinol (THC) were assessed using a battery of food-reinforced complex operant tasks that included responding under delayed matching to sample (DMTS, n = 6), conditioned position response (CPR, n = 8) progressive ratio (PR, n = 8), temporal response differentiation (TRD, n = 3) and incremental repeated acquisition (IRA, n = 9) tasks. THC (0.003-0.3 mg/kg i.v.) given 15-min presession produced dose-dependent decreases in the number of reinforcers obtained in each task. TRD accuracy was decreased significantly at doses as low as 0.03 mg/kg, making TRD accuracy the most sensitive parameter measured. For PR, the break-point (number of responses emitted for the last reinforcer earned) was decreased significantly only at 0.3 mg/kg. Significant disruptions of performance in schedules other than PR were evident at doses of 0.1 mg/kg and above: response rates decreased or latencies to respond increased. Accuracy of responding was not altered in the IRA, DMTS or CPR tests at doses less than those that decreased response rates. The relative sensitivities of these tests for detecting THC behavioral effects were thus TRD greater than IRA = DMTS = CPR greater than PR. These results indicate that THC, at doses that produce plasma levels similar to those noted in humans after marijuana smoke exposure, produce acute behavioral effects on temporal differentiation in monkeys analogous to some effects reported in humans.
Animals↗
Neuropathological evaluation by combined immunohistochemistry and degeneration-specific methods: application to methylenedioxymethamphetamine.
To best interpret the significance of neurological alterations produced by chemicals, the changes in morphological as well as neurochemical parameters must be measured and compared to each other. We have devised an approach to readily label microscopic sections for multiple antigens (neurotransmitters, enzymes, peptides, etc.) as well as for the demonstration of degenerating structures by silver impregnation. Here, we applied silver-staining together with immunolabelling of 5-HT and tyrosine hydroxylase (the rate-limiting enzyme for dopamine synthesis) to study neurohistological alterations produced by methylenedioxymethamphetamine (MDMA), a hallucinogenic stimulant previously used as an adjunct to psychotherapy and now a popular recreational drug ("Ecstasy"). Single oral doses of 40 or 80 mg/kg MDMA doubled the density of silver-impregnated (degenerating) fiber terminals in the caudate nucleus compared to controls, when rats were sacrificed 18 hours after treatment. Four months after two 40 mg/kg oral doses per day for four days, rats had a reduced neurochemical content of 5-HT in the hippocampus, and fewer immunostainable 5-HT axons per unit area in the hippocampal stratum lacunosum but no change in brain-stem neurochemical 5-HT content or in the numeric density of 5-HT-positive cell bodies in the dorsal raphe nucleus. The neurohistology suggests interpreting the changes in neurochemical content of serotonin produced by MDMA as due to degeneration followed by subsequent loss of 5-HT axons, rather than a decrease in the rate of neuronal 5-HT synthesis or a toxicity directed toward 5-HT cell bodies. The combination of neurohistological and neurochemical evaluation will continue to prove useful in comprehensive evaluation of the neurological effects of chemical exposure.
3,4-Methylenedioxyamphetamine↗
Neurochemical evaluation of rats prenatally exposed to the adrenergic agonists clonidine and lofexidine.
Clonidine (CLON), an alpha-2 adrenergic agonist, is widely used to reduce hypertension; it is also recommended for blocking acute opiate withdrawal. Lofexidine (LOF), a CLON analog, is an investigational compound being readied for the marketplace. Since exposure to both drugs is likely to occur in the last two trimesters of human pregnancy, it is important to determine whether such exposure can have effects upon brain or behavior of offspring. Pregnant CD rat dams were given daily subcutaneous injections of saline, CLON, or LOF on days 8 through 20 of gestation. Maternal weight during gestation, neonatal weight and neurochemical measures were monitored. Maternal body weight was reduced in a dose dependent manner. At PND 1 brain ornithine decarboxylase (ODC) activity was reduced in LOF- but not CLON-exposed pups of both sexes. At this age no alteration was seen in whole brain catecholamine levels or in whole brain alpha-2-adrenergic binding.
Adrenergic alpha-Agonists↗
Behavioral evaluation of rats prenatally exposed to the adrenergic agonists clonidine and lofexidine.
Clonidine (CLON), is a widely used antihypertensive agent with a potential for expanded therapeutic application in combating drug withdrawal symptoms in opiate and alcohol addiction. Recently, CLON and an analogue lofexidine (LOF) have been shown to block the opiate withdrawal syndrome in a variety of species, including man. One new application of these agents may be as an alternative to methadone maintenance for pregnant opiate addicts. Any consideration along these lines will require screening for reproductive outcome and behavioral teratogenic effects. Dams were given s.c. injections of CLON (0.16 or 0.64 mg/kg) of LOF (0.64 or 2.56 mg/kg) once daily from gestational day (GD) 8-20. Neonatal body weights, at postnatal days (PNDs) 2, 15 and 30 were reduced in a dose-dependent manner, with LOF-induced reduction twice that of CLON. No significant differences were obtained on negative geotaxis, an auditory startle test, or a series of swimming immobilization tests across the periadolescent period. A series of activity measures carried out on PND 12, 14, 16 and 18 showed minor differences in the high dose LOF male animals, but not in any of the other drug-treated groups.
Animals↗
Morphometric studies of the rat hippocampus following chronic delta-9-tetrahydrocannabinol (THC).
Persistent behavioral effects resembling those of hippocampal brain lesions have been reported following chronic administration of marijuana or its major psychoactive constituent, delta-9-tetrahydrocannabinol (THC) to rats. We used morphometric techniques to investigate the effects of chronic THC on the anatomical integrity of the hippocampus. Rats dosed orally for 90 days with 10 to 60 mg/kg THC or vehicle were evaluated by light and electron microscopy up to 7 months after their last dose of drug. Electron micrographs revealed a striking ultrastructural appearance and statistically significant decreases in mean volume of neurons and their nuclei sampled from the hippocampal CA3 region of rats treated with the highest doses of THC. A 44% reduction in the number of synapses per unit volume was demonstrated in these same rats. Golgi impregnation studies of additional groups of rats treated with 10 or 20 mg/kg/day THC and sacrificed 2 months after their last treatment with THC revealed a reduction in the dendritic length of CA3 pyramidal neurons, despite normal appearing ultrastructure and no changes in synaptic density. The hippocampal changes reported here may constitute a morphological basis for behavioral effects after chronic exposure to marijuana.
Administration, Oral↗
Effects of chronic delta-9-THC treatment on cardiac beta-adrenoceptors in rats.
This study was designed to determine if chronic treatment with delta-9-tetrahydrocannabinol (THC) alters cardiac beta-adrenoceptors in the rat. Following daily oral administration of 10 or 20 mg/kg THC or an equivalent volume of control solvent for 90 days, rats were sacrificed, and sarcolemmal membranes were prepared from ventricular myocardium. Beta-adrenoceptor density and binding affinity estimated with (-)[3H]dihydroalprenolol; a beta-adrenergic antagonist, were not significantly affected by treatment with THC when compared to vehicle controls. These results suggest that the tolerance to cardiovascular effects of THC which develops during chronic exposure in the rat is not associated with alterations in cardiac beta-adrenoceptors as monitored by radiolabeled antagonist binding.
Animals↗
Effect of trimethyltin on ornithine decarboxylase in various regions of the mouse brain.
Male C57B1/6N mice, 8-10 weeks old were given a single oral dose of 0, 1.0 or 3.0 mg/kg body weight of trimethyltin hydroxide (TMT). Levels of ornithine decarboxylase (ODC) activity were measured in several brain areas, 1, 2 and 7 days later. The lower dose of TMT produced a decrease of ODC in the caudate nucleus and hippocampus at all time points studied. Hypothalamus, cerebellum and brain stem levels of this enzyme were unaltered. At the higher dose of TMT, ODC activity in hippocampus, cerebellum and brain stem were increased relative to controls at 1 and 2 days after treatment, while other regions were not significantly affected. These elevated ODC levels returned to control values within 7 days. Thus, trimethyltin treatment causes changes in ODC activity in a region and dose-specific manner.
Animals↗
Developmental toxicology of trimethyltin in the rat.
Pregnant rats were treated on either gestational day (GD) 7, 12, or 17 with single doses of trimethyltin chloride (TMT) ip at either 0, 5, 7, or 9 mg/kg. A significant effect of dose was manifest as decreased maternal weight at term, which persisted during lactation until postnatal day (PND) 15 in some groups. For all treatments combined, term weights of dams exposed on GDs 7 and 12 were greater than those treated on GD 17. Litter sizes were decreased for groups treated on GD 17 with 9 mg/kg TMT. Pups treated in utero and exhibiting treatment-induced decreases in weight at or near birth remained smaller than untreated animals into adulthood (PND 280). By PND 20, weights of pups treated on GD 7 greater than GD 12 greater than GD 17. Neuropathology of pups sacrificed on PND 1 was minimal in all animals with lesions only identified in animals treated on GDs 12 or 17 which consisted of subtle degenerative changes in the CA3 and CA4 regions of Ammon's horn of the hippocampus. Muscarinic cholinergic receptor binding in whole brains from pups on PND 1 did not show any significant changes compared to controls for any dose or day of exposure. These data indicate that prenatal TMT exposure results in postnatal toxicity in treated pups but only in the presence of maternal toxicity.
Animals↗
Prenatal reserpine exposure in rats decreases caudate nucleus dopamine receptor binding in female offspring.
The effects of prenatal exposure to reserpine on [3H]spiroperidol binding in caudate nucleus at postnatal day (PND) 21 were investigated. Pregnant rats were dosed with 0, 0.375 or 0.750 mg/kg/day reserpine s.c. on days 12-15 of gestation. At PND 21, pups were killed and their brains were dissected and stored at -70 degrees C for analysis. Dopamine receptor binding was measured in membrane prepared from caudate nucleus of both sexes over a [3H]spiroperidol concentration range of 0.02 to 2.0 nM. Scatchard analysis revealed that the number of dopamine receptors (Bmax) in the membrane of female caudate nucleus was significantly decreased in a dose-dependent manner, while the dissociation constant (KD) was relatively unchanged. In male rats, neither Bmax nor KD was significantly reduced in either dose group. These results show that prenatal exposure to reserpine decreased the dopamine receptor number in caudate nucleus in a sex-dependent manner. This alteration may underly several sex-related behavioral changes that were previously found in offspring from identically treated dams.
Animals↗
Cholinergic and dopaminergic alterations in the mouse central nervous system following acute trimethyltin exposure.
Male mice were given a single oral dose of 0, 1 or 3 mg/kg TMT-hydroxide and sacrificed 48 hrs, 1 and 2 weeks later. Brain areas were removed, dissected and frozen for later analysis of neurotransmitter receptor binding by filtration techniques and determination of concentrations of monoamines and their metabolites by HPLC/EC. Muscarinic cholinergic receptor binding was measured over a [3H]-quinuclidinyl benzilate (QNB) concentration range of 0.02 to 2.0 nM. Two days after TMT treatment, affinity of [3H]-QNB binding in frontal cortex increased. Gradual return to control binding affinity was seen over the next 2 weeks. The number of receptors decreased only at high dose after 1 week. In hippocampus, a similar increase was seen only at the 3 mg/kg dose after 1 and 2 weeks. Homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations were significantly decreased in the caudate nucleus 2 weeks after TMT treatment; concentrations of serotonin (5-HT), dopamine (DA), and 3,4-dihydroxyphenylacetic acid (DOPAC) were unaltered, nor was there a change in dopamine receptors as measured by [3H]-spiroperidol binding in the caudate nucleus or frontal cortex. To determine if TMT altered monoamine turnover or metabolite efflux, mice were dosed with 0 or 3 mg/kg TMT; 2 weeks later, pargyline (75 mg/kg, intraperitoneally) was administered and the mice sacrificed 0, 30 and 60 min. later. Monoamines and their metabolites were measured in caudate nucleus. The HVA elimination rate was unchanged. The data suggests that the lower concentrations of dopamine metabolites observed 2 weeks after TMT treatment were due to a decrease in dopamine turnover. The decrease in muscarinic receptor affinity in frontal cortex and hippocampus and the decrease in the rate of dopamine turnover in the caudate nucleus indicate that these 2 systems are affected by TMT and may participate in the expression of its toxicity.
Animals↗
Early neurobehavioral and neurochemical alterations in rats prenatally exposed to imipramine.
Pregnant CD rats were treated subcutaneously with 0, 5 or 10 mg/kg/day of imipramine (IMI) on days 8-20 of gestation. Behavioral and neurochemical endpoints were measured at different postnatal days (PND). Three behavioral tests were conducted: negative geotaxis on PNDs 7-9; auditory startle habituation (ASH) on PNDs 14, 16 and 18; locomotor activity before and after intraperitoneal (i.p.) injection of saline or 0.5 mg/kg d-amphetamine on PND 21. Catecholamine levels, B-adrenergic and muscarinic cholinergic binding were measured on PND 1 and in PND 21 rats 3 hours after challenge. Maternal weight gained during the dosing period was decreased in a dose-related manner, but there were no dose-related differences in offspring body weights. On PND 7, low-dose males turned significantly sooner in negative geotaxic testing, and more high-dose males successfully turned (94%) than did controls (61%). A significant reduction in ASH amplitude was found only in males from the low-dose group on PND 18. IMI-exposed males tended to be more active prior to and following amphetamine challenge. On PND 1, male offspring from the low-dose group showed a 65% reduction in B-adrenergic receptor binding and a trend toward increased brain epinephrine (EPI) levels. On PND 21, no consistent dose-related receptor binding changes were observed. Cortical levels of EPI, however, tended to be higher in treated males and high-dose females challenged with d-amphetamine. These same rats also showed a marked elevation in locomotor activity following challenge with d-amphetamine. Thus, prenatal IMI exposure appeared to alter functional development of the central adrenergic systems in a complex manner, but one consistent with changes noted in both neurochemical and behavioral endpoints.
Analysis of Variance↗
Modulation of anterior pituitary dopamine receptors by estradiol 17-beta: dose-response relationship.
Exposure of ovariectomized rats to estradiol-17-beta for 48-96 hr resulted in a dose-dependent reduction in the number but not the Kd of D-2 dopamine receptors of the anterior pituitary. No influence of estrogen was observed on dopamine or muscarinic acetylcholine receptors of caudate or hypothalamus. The dose-response relationship observed suggested that the influence of estrogen is directly on the pituitary, not secondary to the alteration of dopaminergic systems in the hypothalamus.
Animals↗