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1.
Summary The effects of 9-tetrahydrocannabinol, ( 9THC) the major psychoactive compound of marijuana, and cannabidiol (CBD), a non-psychoactive component, on the acetylcholine (ACh) concentration and the turnover rate of ACh (TR ACh) have been studied in various regions of the rat brain. Neither 9THC doses from 0.2 to 10 mg/kg nor CBD (10 or 20 mg/kg) alter the ACh concentration in the brain areas examined 30 min, after the intravenous injection. However, 9-THC (doses from 0.2 to 10 mg/kg) causes a marked dose-related decrease in the TR ACh in hippocampus whereas CBD is without effect in this brain region even when 20 mg/kg is given. Furthermore, high doses of 9-THC (5 mg/kg) and CBD (20 mg/kg) that produce a significant decrease in the TR ACh of striatum fail to change the TR ACh in parietal cortex. The low doses of 9-THC required to reduce hippocampal TR ACh suggest that an action on these cholinergic mechanisms may play a role in the psychotomimetic activity of 9-THC. 相似文献
2.
Summary Intraseptal administration of morphine (70 nmol) or -endorphin (0.7 nmol) reduced the rate of acetylcholine (ACh) turnover (TR ACh) in rat hippocampus but not in striatum or cortex. These intraseptal injections failed to modify the ACh content and did not elicit analgesia. Naltrexone (15 mol/kg, i.p.) completely antagonized the decrease of hippocampal TR ACh elicited by the two opiate receptor agonists. Furthermore, intraseptal injections of naltrexone partially blocked the decrease in hippocampal TR ACh induced by intraperitoneal administration of morphine (70 mol/kg, i.p.). These data suggest that opiate agonists decrease hippocampal TR ACh by regulating septal cholinergic neurons, and that this effect is not associated with analgesia. 相似文献
3.
The actions of μ agonists, partial agonists and enkephalin analogues on the turnover rate of acetylcholine (TR Ach in several brain areas have been studied. The μ agonists and enkephalin analogues all suppressed TR Ach in the parietal cortex and hippocampus but not in the striatum or frontal cortex. The partial agonists (κ agonists, μ antagonists), however, were unique in that they did not alter hippocampal TR ACh, suggesting that the septal hippocampal cholinergic neurons do not possess κ receptors and/or are not regulated by neurons bearing κ receptors. These data along with those of Yaksh and Rudy ( Pain4: 299–359, 1978) indicate that κ receptor mediated analgesia may involve different neural substrates from those of μ agonists and supports the concept of multiple opiate receptors within the CNS. 相似文献
4.
Intrastriatal injections of Δ 9-THC and 1 l-hydroxy-Δ 9-THC induced dose-dependent catalepsy in the rat, the parent compound being more potent than the metabolite. Catalepsy was not induced following intrapallidal injection of either drug. The results suggest that the caudate-putamen could be a “specific site” in the mediation of catalepsy induced by Δ 9-THC.Intrastriatal amphetamine attenuated Δ 9-THC-induced catalepsy whereas intrapallidal amphetamine potentiated the effect indicating a complex interaction with dopaminergic systems in the basal ganglia.Δ 9-THC and the central cholinergic stimulant, RS-86 synergize on administration to either area indicating a possible cholinergic involvement in the phenomenon. 相似文献
5.
(?)-Δ 9- trans-tetrahydrocannabinol (Δ 9-THC) (39 μg-5 mg/kg, i.v.) decreased heart rate in a dose related manner in dogs under pentobarbital anesthesia. This cardiac effect of Δ 9-THC was neither due to an impairment of transmission across the sympathetic ganglia nor to a specific stimulation of parasympathetic ganglia. Selective blockade of either parasympathetic (atropine, bilateral vagotomy) or sympathetic (propranolol, spinal section at C 2C 4 neurogenic activity to the heart partially prevented the negative chronotropic effect of Δ 9-THC. However the bradycardic effect of Δ 9-THC was completely abolished in animals in which the autonomic pathways to the heart were pharmacologically or surgically inactivated.Administration of Δ 9-THC into the vascularly isolated, neurally intact cross-perfused head of dogs significantly slowed the heart rate in intact as well as debuffered recipients. This bradycardia was reduced in recipients in which the trunk was atropinized prior to cerebral administration of Δ 9-THC into the femoral vein of the recipient in the dog cross circulation preparation also caused a significant decrease in heart rate which was essentially abolished either by bilateral vagotomy or by atropinization of the recipients.These results are compatible with the hypothesis that the negative chronotropic effects of Δ 9-THC in dogs under pentobarbital anesthesia is of central origin and involves both a direct and reflexogenic alteration of central autonomic outflow regulating the heart rate. 相似文献
6.
The long-term effects of perinatal Δ 9-tetrahydrocannabinol (Δ 9-THC) exposure – from gestational day (GD) 15 to postnatal day (PND) 9 – on hippocampal glutamatergic neurotransmission were studied in slices from the 40-day-old offspring of Δ 9-THC exposed (Δ 9-THC-rats) and vehicle-exposed (control) dams. Basal and in K+-evoked endogenous hippocampal glutamate outflow were both significantly decreased in Δ 9-THC-rats. The effect of short Δ 9-THC exposure (0.1 μM) on K +-evoked glutamate release disclosed a loss of the stimulatory effect of Δ 9-THC on hippocampal glutamate release in Δ 9-THC-rats, but not in controls. In addition, l-[ 3H]-glutamate uptake was significantly lower in hippocampal slices from Δ 9-THC-rats, where a significant decrease in glutamate transporter 1 (GLT1) and glutamate/aspartate transporter (GLAST) protein was also detected. Collectively, these data demonstrate that perinatal exposure to cannabinoids induces long-term impairment in hippocampal glutamatergic neurotransmission that persist into adolescence. 相似文献
7.
Δ 9-Tetrahydrocannabinol (Δ 9-THC) 1 mg/kg, i.v. produced a slight but significant reduction in the heart rate of conscious mongrel dogs, and these effects were greatly potentiated by pentobarbital and/or urethane anesthesia. However, significant increase in the heart rate was noted following Δ 9-THC administration in the dogs anesthetized with a combination of morphine plus chloralose; further, neither morphine nor chloralose alone could reverse the bradycardic effects of Δ 9-THC. Tachycardia induced by Δ 9-THC in these dogs could be reversed by bilateral vagotomy or by pretreatment of the animals with methylatropine, or propranolol and/or practolol. The data indicated a complex interaction between Δ 9-THC and morphine-chloralose combination and the tachycardia induced by Δ 9-THC under this anesthesia may be due to release of epinephrine by a reflexogenic mechanism involving afferent vagi. Further, while the bradycardic effects of Δ 9-THC were essentially identical under pentobarbital or urethane anesthesia, the hypotensive effects were similar in urethane or chloralose anesthetized dogs. The study emphasizes that anesthetic interaction should be taken into consideration while investigating mechanisms of actions of pharmacological agents. 相似文献
8.
Δ 9-Tetrahydrocannabinol (Δ 9-THC) and a water soluble ester derivative (compound I) caused a concentration-related decrease in the uptake of 14C-dopamine into crude synaptosomal preparations derived from mouse striata. Both were less potent than amphetamine in this preparation. In the presence of 10 ?7m amphetamine the IC 50 of Δ 9-THC was unaffected. The IC 50 is the concentration of drug in the medium which will inhibit the uptake of 14C-dopamine into the synaptosomes by 50%. However in the presence of 3.0 × 10 ?6m Δ 9-THC, the dose response curve to amphetamine was shifted to the right and the IC 50 of amphetamine was increased. Δ 9-Tetrahydrocannabinol and compound I increased the release of 14C-dopamine from preparations pre-incubated with 14C-dopamine. The effect was small but significant. The effects of amphetamine and Δ 9THC combined were additive on this system. The mode of action of Δ 9-THC with regard to the dopaminergic system of the striatum is discussed. 相似文献
9.
(-)-Δ 9- trans-Tetrahydrocannabinol (Δ 9-THC), when given intravenously (2 mg kg ?1) to cats, produced marked decreases in blood pressure and heart rate which developed gradually and were of prolonged duration. Cervical spinal transection (C 1-C 2) abolished these effects whereas surgical removal of neurogenic tone to the myocardium selectively eliminated the bradycardia. Bilateral vagotomy alone did not modify the action of Δ 9-THC upon heart rate or blood pressure. Recordings of spontaneous sympathetic outflow in the inferior cardiac nerve indicated a rapid reduction in neural discharge rate after Δ 9-THC administration. These observations support the hypothesis that Δ 9-THC produces a cardiodecellerator and hypotensive effect by acting at some level within the sympathetic nervous system. Experiments conducted to investigate transmission in the superior cervical and stellate ganglia demonstrated that Δ 9-THC did not alter ganglionic function. Also, responses to intravenous isoprenaline and noradrenaline were unchanged which suggested that Δ 9-THC did not interact with α- or β- adrenoceptors. The possible action of Δ 9-THC on central sympathetic structures was investigated by perfusion of Δ 9-THC into the lateral cerebral ventricle. Δ 9-THC so administered produced a significant reduction in heart rate without a substantial lowering of blood pressure. Tritiated or 14C-Δ 9-THC perfused into the lateral ventricle demonstrated that the amount of radioactive compound passing into the peripheral circulation was insignificant and could not account for the decrease in heart rate. The current data are in agreement with the proposal that Δ 9-THC produces cardiovascular alterations by an action on the central nervous system which results in a decrease in sympathetic tone. 相似文献
10.
- The biphasic nature of the potent modulatory action of interleukin-2 (IL-2) on hippocampal acetylcholine (ACh) release was investigated by use of brain slice superfusion.
- Both the potentiating (10−13 M) and inhibitory (10−9 M) effects of IL-2 on hippocampal ACh release were stimulation-dependent and were blocked by a neutralizing IL-2 receptor antibody, suggesting the activation of typical IL-2 receptors in both cases.
- Tetrodotoxin (TTX; 10 μM) failed to block the potentiation of ACh release induced by a very low concentration of IL-2 (10−13M) suggesting a direct effect on cholinergic nerve terminals.
- In contrast, the inhibitory effect seen at a higher concentration (10−9 M) was TTX-sensitive, and hence indicative of an indirect action.
- To establish the nature of this intermediate mediator, blockers of nitric oxide synthesis, and of opioid and γ-aminobutyric acid (GABA) receptors were used. Only GABAA and GABAB receptor antagonists altered the inhibitory action of IL-2, suggesting the participation of GABA as mediator.
- Taken together, these results provide further evidence for the potent role of IL-2 in the modulation of cholinergic function in the rat hippocampus.
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11.
Recent evidence suggests that the psychoactive effect of delta-9-tetrahydrocannabinol (Δ 9-THC), the major psychoactive constituent of marihuana, may be mediated through an alteration of cholinergic neurotransmission. One possible mechanism by which Δ 9-THC could have its effect is by affecting acetylcholinesterase (AChE) and there is evidence that has suggested that this may be an important mechanism. The results reported in the present study have shown that there is no physiologically important interaction between AChE and Δ 9-THC or its metabolites that could explain its psychoactive effects or the profound clinical depression observed when human marihuana users are administered the cholinesterase inhibitor physostigmine. 相似文献
12.
Rationale The results of recent in vitro studies have underscored the important role that activation of CB 1 receptors has on GABAergic activity in brain areas associated with memory.Objectives The primary purpose of this study was to test the hypothesis that the memory disruptive effects of 9-tetrahydrocannabinol ( 9-THC) in vivo are mediated through GABAergic systems. Conversely, we also evaluated whether blocking CB 1 receptor signaling would alter memory deficits elicited by GABA agonists.Methods The GABA A antagonist bicuculline and GABA B antagonist CGP 36742 were evaluated for their ability to ameliorate 9-THC-induced deficits in a mouse working memory Morris water maze task. Mice were also assessed in a T-maze task, as well as non-cognitive behavioral assays. Additionally, the effects of GABA A and GABA B agonists were assessed in either CB 1 (–/–) mice or wild type mice treated with the CB 1 antagonist SR 141716.Results Memory deficits resulting from 10 mg/kg 9-THC in the Morris water maze were completely reversed by bicuculline, though unaffected by CGP 36742. Bicuculline also blocked the disruptive effects of 9-THC in the T-maze, but failed to alter non-mnemonic effects of 9-THC. Although CB 1 (–/–) mice exhibited supersensitivity to muscimol-induced water maze deficits compared with wild type control mice, muscimol elicited virtually identical effects in SR 141716-treated and vehicle-treated wild type mice.Conclusions This is the first demonstration of which we are aware showing that GABA A receptors may play a necessary role in 9-THC-induced memory impairment in whole animals. 相似文献
13.
Delta9-tetrahydrocannabinol (Δ 9-THC) is the major psychoactive component of the cannabis plant. Δ 9-THC has been used in the active ingredient of Marinol as an appetite stimulant for AIDS patients. Its impact on progression of HIV-1 infection, however, remains debatable. Previous studies indicated that Δ 9-THC administration enhanced HIV-1 infection in huPBL-SCID mice but seemingly decreased early mortality in simian immunodeficiency virus (SIV) infected male Indian-derived rhesus macaques. Here, we determine the chronic effect of Δ 9-THC administration using 0.32 mg/kg or placebo (PBO), i.m., twice daily for 428 days on SIV mac251 infected male Chinese-derived rhesus macaques. Sixteen animals were divided into four study groups: Δ 9-THC +SIV +, Δ 9-THC +SIV ?, PBO/SIV + and PBO/SIV ? ( n = 4/group). One-month after daily Δ 9-THC or PBO administrations, macaques in groups one and three were challenged intravenously with pathogenic SIV mac251/CNS, which was isolated from the brain of a Chinese macaque with end-staged neuroAIDS. No significant differences in peak and steady state plasma viral loads were seen between Δ 9-THC +SIV + and PBO/SIV + macaques. Regardless of Δ 9-THC, all infected macaques displayed significant drop of CD4/CD8 T cell ratio, loss of CD4 + T cells and higher persistent levels of Ki67 +CD8 + T cells compared with uninfected animals. Moreover, long-term Δ 9-THC treatment reduced significantly the frequency of circulating IgE +B cells. Only one Δ 9-THC +SIV + macaque died of simian AIDS with paralyzed limbs compared with two deaths in the PBO/SIV + group during the study period. These findings indicate that chronic Δ 9-THC administration resulted in reduction of IgE +B cells, yet it unlikely enhanced pathogenic SIV mac251/CNS infection in male Rhesus macaques of Chinese origin. 相似文献
14.
Evidence indicates that blockade of cannabinoid receptors increases acetylcholine (ACh) release in brain cortical regions. Although it is assumed that this type of effect is mediated through CB1 receptor (CB1R) antagonism, several in vitro functional studies recently have suggested non-CB1R involvement. In addition, neither the precise neuroanatomical site nor the exact mechanisms underlying this effect are known. We thoroughly examined these issues using a combination of systemic and local administration of CB1R antagonists, different methods of in vivo microdialysis, CB1R knockout (KO) mice, tissue measurements of ACh, and immunochemistry. First, we showed that systemic injections of the CB1R antagonists N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR-141716A) and N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) dose-dependently increased hippocampal ACh efflux. Likewise, local hippocampal, but not septal, infusions of SR141716A or AM251 increased hippocampal ACh release. It is noteworthy that the stimulatory effects of systemically administered CB1R antagonists on hippocampal ACh release were completely abolished in CB1R KO mice. CB1R KO mice had similar basal but higher stress-enhanced hippocampal ACh levels compared with wild-type controls. It is interesting that dopamine D1 receptor antagonism counteracted the stimulatory effect of CB1R blockade on hippocampal ACh levels. Finally, immunohistochemical methods revealed that a high proportion of CB1R-positive nerve terminals were found in hippocampus and confirmed the colocalization of CB1 receptors with cholinergic and dopaminergic nerve terminals. In conclusion, hippocampal ACh release may specifically be controlled through CB1Rs located on both cholinergic and dopaminergic neuronal projections, and CB1R antagonism increases hippocampal ACh release, probably through both a direct disinhibition of ACh release and an indirect increase in dopaminergic neurotransmission at the D1 receptors. 相似文献
15.
Early-onset marijuana use has been associated with short- and long-term deficits in cognitive processing. In human users, self-selection bias prevents determination of the extent to which these effects result only from drug use. This study examined the long-term effects of Δ 9-tetrahydrocannabinol (Δ 9-THC), the major psychoactive constituent of marijuana, in a delayed nonmatch-to-position task (DNMP). Male Long-Evans rats were injected daily with 10 mg/kg Δ 9-THC during or after adolescence [postnatal days (PN) 21-50 or PN50-79, respectively] or with vehicle. On PN91, training in DNMP was initiated. Successful acquisition and pharmacological challenge began on approximately PN300. Decreases in accuracy were observed at lower doses of Δ 9-THC in Δ 9-THC-treated rats (versus vehicle-treated rats). Administration of chronic Δ 9-THC at a younger age tended to enhance this effect. While anandamide did not decrease accuracy in any group, rats treated with Δ 9-THC during adolescence initiated fewer trials at the 30 mg/kg dose of anandamide than did rats in the other two groups. To the extent tested, these differences were pharmacologically selective for cannabinoids, as scopolamine (positive control) decreased accuracy at the same dose in all groups and amphetamine (negative control) did not affect accuracy in any of the groups at doses that did not impair overall responding. These results suggest that repeated administration of a modest dose of Δ 9-THC during adolescence (PN21-50) or shortly thereafter (PN50-79) produces a long-term increase in latent sensitivity to cannabinoid-induced impairment of performance in a complex operant task. 相似文献
16.
The effects on body temperature produced by graded doses of Δ 9-tetrahydrocannabinol (Δ 9-THC) and phenylbutazone were compared in both normal and pyretic rats. Dose related hypothermic responses were produced by the oral administration of Δ 9-THC in normal animals. Moreover, Δ 9-THC significantly reduced elevated temperatures in yeast-induced pyretic rats to near normal levels at doses which exhibited little hypothermic activity in normal rats. The oral antipyretic potency of Δ 9-THC was approximately 2 times that of phenylbutazone. The comparative oral antinociceptive activity of Δ 9-THC and selected narcotic and non-narcotic analgesics was determined by the increase in response latency to pressure applied to normal and yeast-inflamed paws. Δ 9-THC administered orally was essentially inactive at dose levels below those producing pronounced central nervous system depression. The oral anti-inflammatory efficacy of Δ 9-THC was compared to phenylbutazone and acetylsalicylic acid. Δ 9-THC was ineffective in inhibiting carrageenin-induced edema of the rat paw following acute or chronic administration. 相似文献
17.
1 The effects of γ-aminobutyric acid (GABA) and related substances were examined in guinea-pig ileum longitudinal muscle. 2 GABA at doses ranging from 10-7 M to 3 × 10-6 M elicited a relaxation while at higher doses (3 × 10-6 M — 10-4 M), as previously described, it caused a contraction followed by relaxation. 3 GABA-induced relaxation was bicuculline-insensitive, was mimicked by (-)-baclofen but not by homotaurine and muscimol. The effect of baclofen was stereospecific. GABA- and (-)-baclofen-induced relaxations were dose-dependent and their ED50 values were similar. A specific cross-desensitization occurred between GABA and (-)-baclofen. 4 The bicuculline-insensitive relaxation induced by GABA and (-)-baclofen was prevented by tetrodotoxin and hyoscine but not by phentolamine plus propranolol, naloxone or theophylline. 5 In preparations in which the muscle tone was raised by histamine or prostaglandin F2α, GABA and (-)-baclofen induced relaxation to the same extent as before increasing the tone. If the tone was raised by DMPP, a greater bicuculline-insensitive relaxation occurred. 6 Contraction caused by GABA was bicuculline-sensitive and was mimicked by homotaurine and muscimol. Contraction was dose-dependent and muscimol was about three times more potent than GABA or homotaurine. A specific cross-desensitization occurred between the contractile effects of GABA and those of homotaurine or muscimol. 7 Bicuculline competitively antagonized the contractile effects of GABA, homotaurine and muscimol and gave closely similar pA2 values. The slope of the Schild plot for the above drugs was near 1, confirming the competitive nature of the antagonism. 8 The bicuculline-sensitive contraction induced by GABA, homotaurine and muscimol was abolished by tetrodotoxin and was non-competitively antagonized by hyoscine, while it was unaffected by hexamethonium, mepyramine and methysergide. 9 It is concluded that two receptors mediate the GABA effects in guinea-pig ileum: a bicuculline-sensitive GABAA receptor, which elicits contraction through an excitatory action on cholinergic post-ganglionic neurones; and a bicuculline-insensitive GABAB receptor which causes relaxation through an inhibitory presynaptic action on cholinergic post-ganglionic neurones. We confirm that GABA, homotaurine and muscimol are GABAA agonists, while GABA and (-)-baclofen are GABAB agonists. 相似文献
18.
Background and aims A family history (FH) of alcoholism accounts for approximately 50 % of the risk of developing alcohol problems. Several lines of preclinical evidence suggest that brain cannabinoid receptor (CB 1R) function may mediate the effects of alcohol and risk for developing alcoholism including the observations that reduced CB 1R function decreases alcohol-related behaviors and enhanced CB 1R function increases them. In this first human study, we probed CB 1R function in individuals vulnerable to alcoholism with the exogenous cannabinoid Δ 9-tetrahydrocannabinol (Δ 9-THC). Design, setting, and participants Healthy volunteers ( n?=?30) participated in a three test day study during which they received 0.018 and 0.036 mg/kg of Δ 9-THC, or placebo intravenously in a randomized, counterbalanced order under double-blind conditions. Measurements Primary outcome measures were subjective “high,” perceptual alterations, and memory impairment. Secondary outcome measures consisted of stimulatory and depressant subjective effects, attention, spatial memory, executive function, Δ 9-THC and 11-hydroxy-THC blood levels, and other subjective effects. FH was calculated using the Family Pattern Density method and was used as a continuous variable. Findings Greater FH was correlated with greater “high” and perceptual alterations induced by Δ 9-THC. This enhanced sensitivity with increasing FH was specific to Δ 9-THC’s rewarding effects and persisted even when FH was calculated using an alternate method. Conclusions Enhanced sensitivity to the rewarding effects of Δ 9-THC in high-FH volunteers suggests that alterations in CB 1R function might contribute to alcohol misuse vulnerability. 相似文献
19.
1. One isotopic and three non-isotopic methods were used to determine the effect of an acute intravenous dose of Δ 9-tetrahydrocannabinol (Δ 9-THC, 2 mg/kg) on the rat brain turnover rate of serotonin. 2. In control animals the turnover rate of serotonin was about 2 nmol/g per h. This rate was not altered by Δ 9-THC when it was calculated from the rise of 5-hydroxyindoleacetic acid following probenecid or from the rise of serotonin following pargyline. 3. Δ 9-THC did not alter the serotonin turnover rate when it was calculated from the conversion of 3H-tryptophan to 3H-serotonin. 4. The serotonin turnover rate was significantly increased by Δ 9-THC when the rate was calculated from the decline of 5-hydroxyindoleacetic acid following pargyline. 5. These results suggest that Δ 9-THC does not alter the turnover of rat brain serotonin. The previously reported Δ 9-THC-induced changes in body temperature and increased brain levels of 5-hydroxyindoleacetic acid may be mediated by some other mechanism such as interference by Δ 9-THC of the vesicular binding of serotonin. 相似文献
20.
The effects of various doses of l-trans-Δ 9-tetrahydrocannabinol (Δ 9-THC) on naloxone-induced withdrawal were studied in mice rendered dependent on morphine by the pellet implantation procedure. When administered i.p., 30 min prior to naloxone, Δ 9-THC, inhibited the naloxone-induced withdrawal jumping response. Two other signs of morphine withdrawal (defecation and rearing behavior) were also suppressed by Δ 9-THC. It is suggested that Δ 9-THC or some of its derivatives may have potential use in narcotic detoxification. 相似文献
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