Article

Effects of cannabinoids on levels of acetylcholine and choline and on turnover rate of acetylcholine in various regions of the mouse brain

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Abstract

The psychoactive cannabinoids, delta 9-tetrahydrocannabinol (delta 9-THC), delta 8-tetrahydrocannabinol (delta 8-THC), 11-hydroxy-delta 9-tetrahydrocannabinol (11-OH-delta 9-THC) and 9-nor-9 beta-hydroxyhexahydrocannabinol (beta-HHC), as well as the nonpsychoactive cannabinoids, cannabinol (CBN), cannabidiol (CBD), abnormal CBD, delta 8-THC methyl ether (1-OCH3-delta 8-THC) and 9-nor-9 alpha-hydroxyhexahydrocannabinol (alpha-HHC), were used to assess the role of cholinergic mechanisms in the different behavioral actions of these cannabinoids. Their effects on mouse brain choline and acetylcholine (ACh) levels and on ACh turnover were determined in cortex, hippocampus, striatum, midbrain and medulla-pons. delta 9-THC (30 mg/kg) caused a significant elevation of ACh in all five brain areas. 11-OH-delta 9-THC (30 mg/kg) increased ACh in hippocampus, striatum and midbrain. delta 8-THC (30 mg/kg) increased ACh in cortex and hippocampus. delta 9-THC and 11-OH-delta 9-THC increased choline in midbrain and cortex, whereas beta-HHC increased choline in all areas, except hippocampus, at a dose of 30 mg/kg. Also at this dose, delta 9-THC, 11-OH-delta 9-THC, delta 8-THC and beta-HHC decreased ACh turnover in the hippocampus, as did CBN (10-30 mg/kg), 1-OCH3-delta 8-THC (100 mg/kg) and alpha-HHC (100 mg/kg). ACh turnover was also decreased in midbrain by 1-OCH3-delta 8-THC and in the striatum by alpha-HHC. Thus, the most consistent effects of cannabinoids, both psychotomimetic and nonpsychotomimetic, were to increase ACh and decrease ACh turnover in the hippocampus.(ABSTRACT TRUNCATED AT 250 WORDS)

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... Interestingly, cannabinoid agonists modulate the release and the turnover of Ach in various brain areas. Thus, cannabinoid agonists cause an elevation of Ach release in hippocampus, cortex and striatum ( Tripathi et al., 1987;Acquas et al., 2000), and decreased Ach turnover in these structures ( Revuelta et al., 1978;Tripathi et al., 1987). However, this modulation remains controversial since cannabinoid agonists have been also reported to produce an inhibition of the electrically evoked release of Ach in hippocampal slices and in hippocampal and cortical synaptosomes (Gi€ord & Ashby, 1996, Gi€ord et al., 1997, and to decrease in vivo Ach release in the prefrontal cortex and hippocampus (Carta et al., 1998;Gessa et al., 1998a;Nava et al., 2000). ...
... Interestingly, cannabinoid agonists modulate the release and the turnover of Ach in various brain areas. Thus, cannabinoid agonists cause an elevation of Ach release in hippocampus, cortex and striatum ( Tripathi et al., 1987;Acquas et al., 2000), and decreased Ach turnover in these structures ( Revuelta et al., 1978;Tripathi et al., 1987). However, this modulation remains controversial since cannabinoid agonists have been also reported to produce an inhibition of the electrically evoked release of Ach in hippocampal slices and in hippocampal and cortical synaptosomes (Gi€ord & Ashby, 1996, Gi€ord et al., 1997, and to decrease in vivo Ach release in the prefrontal cortex and hippocampus (Carta et al., 1998;Gessa et al., 1998a;Nava et al., 2000). ...
... A more likely explanation could be an interaction between cannabinoid and nicotine receptor/ neurotransmitter systems. Thus, cannabinoid agonist administration modulates Ach release in several brain structures, such as hippocampus, cortex and striatum ( Revuelta et al., 1978;Tripathi et al., 1987;Acquas et al., 2000), which participate in some behavioural e€ects induced by THC. In agreement with this hypothesis, the cholinesterase inhibitor physostigmine has been reported to potentiate the cataleptic e€ects of THC, suggesting the involvement of central Achrelease in this behavioural response induced by cannabinoids (Pertwee & Ross, 1991). ...
Article
Behavioural and pharmacological effects of Δ9-tetrahydrocannabinol (THC) and nicotine are well known. However, the possible interactions between these two drugs of abuse remain unclear in spite of the current association of cannabis and tobacco in humans. The present study was designed to analyse the consequences of nicotine administration on THC-induced acute behavioural and biochemical responses, tolerance and physical dependence. Nicotine strongly facilitated hypothermia, antinociception and hypolocomotion induced by the acute administration of THC. Furthermore, the co-administration of sub-threshold doses of THC and nicotine produced an anxiolytic-like response in the light–dark box and in the open-field test as well as a significant conditioned place preference. Animals co-treated with nicotine and THC displayed an attenuation in THC tolerance and an enhancement in the somatic expression of cannabinoid antagonist-precipitated THC withdrawal. THC and nicotine administration induced c-Fos expression in several brain structures. Co-administration of both compounds enhanced c-Fos expression in the shell of the nucleus accumbens, central and basolateral nucleus of the amygdala, dorso-lateral bed nucleus of the stria terminalis, cingular and piriform cortex, and paraventricular nucleus of the hypothalamus. These results clearly demonstrate the existence of a functional interaction between THC and nicotine. The facilitation of THC-induced acute pharmacological and biochemical responses, tolerance and physical dependence by nicotine could play an important role in the development of addictive processes. British Journal of Pharmacology (2002) 135, 564–578; doi:10.1038/sj.bjp.0704479
... Thus, while it seems that CBD exerts effects on adenosine and monoamines contents, it is not clear whether this cannabinoid might also affect an additional neurochemical related to wakefulness, such as acetylcholine (ACh). Data regarding the role of CBD on ACh modulation are limited [27][28][29]. To determinate whether systemic administrations of CBD would enhance the extracellular contents of ACh, we first injected this phytocannabinoid (0, 5, 10 or 30 mg/kg, i.p.) at the beginning of the lights-on period of animals. ...
... Due to its promising therapeutic role, several studies describing the effects of CBD on neurochemical function have been published, including the characterization of the influence of this phytocannabinoid on wake-related compounds, such as adenosine [24] as well as monoamines [25,26]. Although significant discoveries in neurochemical changes after CBD injection have been described, limited evidence is available regarding the relationship between this phytocannabinoid and additional wake-related compounds, such as ACh [27][28][29]. Here, we demonstrated that CBD-treated rats showed an enhancement on ACh contents collected from the basal forebrain, a brain area linked to wake control [30,44,45]. In addition, a significant dose-response increase was found in CBDtreated animals. ...
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Cannabis sativa is a plant that contains more than 500 components, of which the most studied are Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD). Several studies have indicated that CBD displays neurobiological effects, including wake promotion. Moreover, experimental evidence has shown that injections of CBD enhance wake-related compounds, such as monoamines (dopamine, serotonin, epinephrine, and norepinephrine). However, no clear evidence is available regarding the effects of CBD on additional wake-related neurochemicals such as acetylcholine (ACh). Here, we demonstrate that systemic injections of CBD (0, 5, 10 or 30 mg/kg, i.p.) at the beginning of the lights-on period, increase the extracellular levels of ACh collected from the basal forebrain and measured by microdialysis and HPLC means. Moreover, the time course effects on the contents of ACh were present 5 h post-injection of CBD. Altogether, these data demonstrate that CBD increases ACh levels in a brain region related to wake control. This study is the first to show the effects of ACh levels in CBD-treated rats and suggests that the basal forebrain might be a site of action of CBD for wakefulness modulation.
... Subchronic nicotine exposure results in region-dependent increases in cannabinoid receptor (CB1) hippocampal expression that persists for one month following nicotine cessation [9]. Similarly, animals chronically exposed to nicotine have increased endocannabinoid levels in the limbic forebrain and brain stem [10], and cannabinoid agonists produce greater release and lower turnover of acetylcholine in the hippocampus, cortex and striatum [11][12][13][14]. Behaviorally, co-administration of marijuana and nicotine in vivo results in acute changes in locomotion, heart rate and body temperature [15], with marijuana's depressant effects potentiated even by subclinical doses of nicotine [16]. ...
... More specifically, although there was an overall effect for marijuana worsening WM, WM was comparable to nonuse occasions when marijuana and tobacco were used simultaneously. These findings, alongside data from animal models on functional interactions between cannabinoid and cholinergic systems [11][12][13]71], together provide convincing preliminary evidence in favor of a compensatory theory. This theory, which hypothesizes that tobacco counteracts marijuana-induced WM decrements, is based largely on the fact that marijuana and tobacco target similar neuroanatomical structures that are central to WM, namely the hippocampus and prefrontal cortex [72,73], and exert opposing independent influences on memory and WM (e.g. ...
Article
Background and aims: The neuropsychological correlates of simultaneous marijuana and tobacco use are largely unknown, which is surprising as both substances have similar neural substrates and have opposing influences on working memory (WM). This study examined the effects of marijuana alone, tobacco alone and simultaneous marijuana and tobacco use on WM. Design: Primary aims were tested using a within-subject design, controlling for multiple subject- and momentary-level confounds via ecological momentary assessment (EMA). Setting: Data collection occurred in the Chicago, USA area in participants' natural environments. Participants: Participants were 287 community young adults from a larger natural history study, oversampled for ever smoking, all of whom event-recorded at least one substance use occasion during the study week. Measurements: Momentary tobacco, marijuana and alcohol use were recorded during multiple EMA across 1 week of data capture. WM was assessed at the end of each EMA assessment. Contextual variables that may influence WM were recorded via EMA. Findings: There were main effects for marijuana and tobacco: WM was poorer with marijuana [odds ratio (OR) = 0.91, 95% confidence interval (CI) = 0.84-0.99] and better with tobacco (OR = 1.11, 95% CI = 1.04-1.18). These effects were not qualified by an interaction (OR = 1.03, 95% CI = 0.84-1.26). Alcohol also reduced WM (OR = 0.87, 95% CI = 0.79-0.95), and the tobacco × alcohol interaction was significant (OR = 0.81, 95% CI = 0.66-0.99), indicating that the facilitative effect of tobacco disappeared with concurrent alcohol use. Conclusions: Relative to when individuals did not use these substances, working memory decreased with acute marijuana and alcohol use and increased with acute tobacco use. However, the putative effect of marijuana on working memory and the facilitative effect of tobacco on working memory were no longer present when used simultaneously with tobacco and alcohol, respectively. Data suggest that tobacco use may compensate for working memory decrements from marijuana among young adults and highlight the importance of investigating further the negative impact of alcohol use on cognition.
... Naranjo et al. [29] observed the influence of CBD on the muscarinic neurotransmission in particular sites of the rat brain involved in memory processes, in the prefrontal cortex and hippocampus, in which CBD (10 mg/kg for three weeks) caused a normalizing effect in the expression of the choline acetyltransferase and binding density of muscarinic M1/M4 receptor, which may have positive outputs in case of memory deficits. It has already been observed that various cannabinoids can increase acetylcholine and decrease its turnover in the cortex and hippocampus of the mouse brain [30]. ...
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As the major nonpsychotropic constituent of Cannabis sativa, cannabidiol (CBD) is regarded as one of the most promising therapeutic agents due to its proven effectiveness in clinical trials for many human diseases. Due to the urgent need for more efficient pharmacological treatments for several chronic diseases, in this review, we discuss the potential beneficial effects of CBD for Alzheimer’s disease, epilepsy, multiple sclerosis, and neurological cancers. Due to its wide range of pharmacological activities (e.g., antioxidant, anti-inflammatory, and neuroprotective properties), CBD is considered a multimodal drug for the treatment of a range of neurodegenerative disorders, and various cancer types, including neoplasms of the neural system. The different mechanisms of action of CBD are here disclosed, together with recent progress in the use of this cannabis-derived constituent as a new therapeutic approach.
... Particularly, an overlapping distribution of cannabinoid and nicotinic acetylcholine receptors was reported in several brain areas including the hippocampus and the amygdala [22]. Also, cannabinoid receptor activation has been shown to modulate the release and turnover of acetylcholine in various brain regions [23,24,25] . In addition, converging experimental evidence indicates that these two systems facilitate each other's pharmacological and rewarding effects. ...
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Evidence shows that the endocannabinoid system modulates the addictive properties of nicotine. In the present study, we hypothesized that spontaneous withdrawal resulting from removal of chronically implanted transdermal nicotine patches is regulated by the endocannabinoid system. A 7-day nicotine dependence procedure (5.2 mg/rat/day) elicited occurrence of reliable nicotine abstinence symptoms in Wistar rats. Somatic and affective withdrawal signs were observed at 16 and 34 hours following removal of nicotine patches, respectively. Further behavioral manifestations including decrease in locomotor activity and increased weight gain also occurred during withdrawal. Expression of spontaneous nicotine withdrawal was accompanied by fluctuation in levels of the endocannabinoid anandamide (AEA) in several brain structures including the amygdala, the hippocampus, the hypothalamus and the prefrontal cortex. Conversely, levels of 2-arachidonoyl-sn-glycerol were not significantly altered. Pharmacological inhibition of fatty acid amide hydrolase (FAAH), the enzyme responsible for the intracellular degradation of AEA, by URB597 (0.1 and 0.3 mg/kg, i.p.), reduced withdrawal-induced anxiety as assessed by the elevated plus maze test and the shock-probe defensive burying paradigm, but did not prevent the occurrence of somatic signs. Together, the results indicate that pharmacological strategies aimed at enhancing endocannabinoid signaling may offer therapeutic advantages to treat the negative affective state produced by nicotine withdrawal, which is critical for the maintenance of tobacco use.
... Furthermore, the coadministration of subthreshold doses of D9-THC and nicotine produced anxiolytic-like responses and conditioned place preference (Valjent et al., 2002), whereas nicotine rewarding effects were absent in CB 1 knockout mice (Castañé et al., 2002). These findings could be explained by a possible interaction between cannabinoid and nicotine receptor ⁄ neurotransmitter systems (Tripathi et al., 1987; Acquas et al., 2000). In addition, a possible modulation in the activity of heterologous systems such as the dopaminergic and the opioid system could also be involved in these interactions (Di Chiara & Imperato, 1988; Szabo et al., 1999; Valjent & Maldonado, 2000). ...
Article
The possible interactions between Delta9-tetrahydrocannabinol (Delta9-THC) and nicotine remain unclear in spite of the current association of cannabis and tobacco in humans. The aim of the present study was to explore the interactions between these two drugs of abuse by evaluating the consequences of Delta9-THC administration on the somatic manifestations and the aversive motivational state associated with nicotine withdrawal in mice. Acute Delta9-THC administration significantly decreased the incidence of several nicotine withdrawal signs precipitated by mecamylamine or naloxone, such as wet-dog-shakes, paw tremor and scratches. In both experimental conditions, the global withdrawal score was also significantly attenuated by acute Delta9-THC administration. This effect of Delta9-THC was not due to possible adaptive changes induced by chronic nicotine on CB1 cannabinoid receptors, as the density and functional activity of these receptors were not modified by chronic nicotine administration in the different brain structures investigated. We also evaluated the consequences of Delta9-THC administration on c-Fos expression in several brain structures after chronic nicotine administration and withdrawal. c-Fos was decreased in the caudate putamen and the dentate gyrus after mecamylamine precipitated nicotine withdrawal. However, acute Delta9-THC administration did not modify c-Fos expression under these experimental conditions. Finally, Delta9-THC also reversed conditioned place aversion associated to naloxone precipitated nicotine withdrawal. Taken together, these results indicate that Delta9-THC administration attenuated somatic signs of nicotine withdrawal and this effect was not associated with compensatory changes on CB1 cannabinoid receptors during chronic nicotine administration. In addition, Delta9-THC also ameliorated the aversive motivational consequences of nicotine withdrawal.
... In several recent in vivo and behavioral investigations, influences of CB receptor activation on the nicotine-induced behavioral responses and the mechanisms of interaction between CBs and nicotinic receptors have been studied in detail (for a review, see Muldoon et al. (2013)). Cannabinoid receptor agonists have been shown to modulate the release and the turnover of acetylcholine in various brain areas involved in nicotine-induced behavioral responses (Tripathi et al., 1987; Gessa et al., 1998; Acquas et al., 2000). Similarly, memory-related effects of nicotine in the mouse elevated plus maze experiments were significantly suppressed by WIN, 55-212-2 a synthetic cannabinoid receptor agonist (Biala and Kruk, 2008). ...
... In several recent in vivo and behavioral investigations, influences of CB receptor activation on the nicotine-induced behavioral responses and the mechanisms of interaction between CBs and nicotinic receptors have been studied in detail (for a review, see Muldoon et al. (2013)). Cannabinoid receptor agonists have been shown to modulate the release and the turnover of acetylcholine in various brain areas involved in nicotine-induced behavioral responses (Tripathi et al., 1987;Gessa et al., 1998;Acquas et al., 2000). Similarly, memory-related effects of nicotine in the mouse elevated plus maze experiments were significantly suppressed by WIN, 55-212-2 a synthetic cannabinoid receptor agonist (Biala and Kruk, 2008). ...
... Inconsistent results have been reported however, as regards the effect of cannabinoids on acetylcholine release in the striatum. For example, ∆ 9 -THC 5 mg/kg and cannabiodiol 20 mg/kg produced a significant decrease in ACh turnover in the striatum (Revuelta et al., 1978), while ∆ 9 -THC (30 mg/kg) caused a significant elevation of ACh in cortex, hippocampus, striatum, mid brain and medulla-pons (Tripathi et al., 1987). Other researchers, however, reported inhibition by ∆ 8 -THC and ∆ 9 -THC of the synthesis of 3H-ACh in cortex, hypothalamus, and striatum rat brain (Friedman et al., 1976). ...
Article
Haloperidol is a classic antipsychotic drug known for its propensity to cause extrapyramidal symptoms due to blockade of dopamine D2 receptors in the striatum. Interest in medicinal uses of cannabis is growing. Cannabis sativa has been suggested as a possible adjunctive in treatment of Parkinson's disease. The present study aimed to investigate the effect of repeated administration of an extract of Cannabis sativa on catalepsy and brain oxidative stress in-duced by haloperidol administration in mice. Cannabis extract was given by subcutaneous route at 5, 10 or 20 mg/kg (expressed as ∆ 9 -tetrahydrocannabinol) once daily for 18 days and the effect on haloperidol (1 mg/kg, i.p.)-induced catalepsy was examined at selected time in-tervals using the bar test. Mice were euthanized 18 days after starting cannabis injection when biochemical assays were carried out. Malondialdehyde (MDA), reduced glutathione (GSH) and nitric oxide (the concentrations of nitrite/nitrate) were determined in brain and liver. In saline-treated mice, no catalepsy was observed at doses of cannabis up to 20 mg/kg. Mice treated with haloperidol at the dose of 1 mg/kg, exhibited significant cataleptic response. Mice treated with cannabis and haloperidol showed significant decrease in catalepsy duration, compared with the haloperidol only treated group. This decrease in catalepsy duration was evident on days 1-12 after starting cannabis injection. Later the effect of cannabis was not ap-parent. The administration of only cannabis (10 or 20 mg/kg) decreased brain MDA by 17.5 and 21.8 %, respectively. The level of nitric oxide decreased by 18 % after cannabis at 20 mg/kg. Glucose in brain decreased by 20.1 % after 20 mg/kg of cannabis extract. The ad-ministration of only haloperidol increased MDA (22.2 %), decreased GSH (25.7 %) and in-creased brain nitric oxide by 44.1 %. The administration of cannabis (10 or 20 mg/kg) to haloperidol-treated mice resulted in a significant decrease in brain MDA and nitric oxide as well as a significant increase in GSH and glucose compared with the haloperidol-control group. Cannabis had no significant effects on liver MDA, GSH, nitric oxide in saline or haloperidol-treated mice. It is concluded that cannabis improves catalepsy induced by haloperidol though the effect is not maintained on repeated cannabis administration. Cannabis alters the oxidative status of the brain in favor of reducing lipid peroxidation, but reduces brain glucose, which would impair brain energetics.
... D 9 -THC is known to interact with Ach and glycine receptors (Xiong et al. 2011). A higher level of choline and Ach were shown in the five brain regions of mouse exposed to D 9 -THC (Tripathi et al. 1987). However, there are also contradictory reports on the D 9 -THC modulated effects on Ach release in vivo studies (Acquas et al. 2001;Gessa et al. 1998;Pisanu et al. 2006). ...
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... Pharmacological evidence has also implicated cholinergic dysfunction in the manifestation of psychotic symptoms. Muscarinic ACh receptors (AChRs) play important roles in animal models that are used to examine sensory gating, which is known to be disrupted in schizophrenic patients, and the activation of muscarinic AChRs was suggested as an alternative to classical antipsychotics for the treating of psychotic symptoms 23 . Chrm3 knockout mice treated with the antipsychotic drug oxotremorine that acts as a selective muscarinic ACh receptor agonist 24-26 displayed increased dopamine release, which is consistent with Chrm3 playing an inhibitory role in dopamine release 24 . ...
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Twenty-one male regular long distance runners participated in two 10 km runs one week apart. Their beta-endorphin-like immunoreactivity (beta-EIR) was assayed in plasma before and immediately after running. Mood was monitored by an adjective check list (Eigenschaftswörterliste, EWL) pre- and post-run. beta-EIR was significantly elevated post-run. Self-reliance and good mood scored higher after running. Both mood elevation and plasma beta-EIR increase showed a considerable individual variability but there was a significant correlation in the mean values of the two runs between individual beta-EIR increases (delta beta-EIR) and the changes of ratings in feeling of pleasantness (delta FP). High delta beta-EIR corresponded to positive mood change post-run.
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Aus den beiden Ketonen (Ia) und (Ib) werden mit Boranat die isomeren Carbinole (II) hergestellt, die gaschromatographisch getrennt werden können und überwiegend aus der äquatorialen Form (III) bestehen, während mit Kalium-tris-sek.-butylboranat überwiegend die axiale Verbindung (IV) erhalten wird.
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Administration of pure 1-δ9-tetrahydrocannabinol to mice had the following dose-dependent nzeurochemical and behavioral effects: a slight but significant increase in concentrations of 5-hydroxytryptamine in whole brain; a decrease in concentration of norepinephrine in brain after administration of low doses and an increase after high doses; diminished spontaneous activity, mloderate hypothermnia, hypersetisitivity to tactile and auditory stimiuli, and ataxia after low doses; and sedation, pronounced hypothermia, and markedly diminished spon taneous activity and reactivity after high doses. The duration of the effects on body temperature and spontaneous activity correlated generally with the changes in brain amines. The characteristic changes in brain amines do not correspond exactly to those observed with other psychotropic drugs.
Article
THERE have been few reports concerning the chemistry and pharmacology of marijuana and its constituents1,2, and most investigators have studied the natural product or a crude extract. Mechoulam and co-workers3 isolated Δ9-tetrahydrocannabinol, which is believed to be the most active constituent of marijuana and has been shown to have marijuana-like activity in man4. Subsequently, Δ8-tetrahydrocannabinol was purified and now both isomers have been prepared synthetically and are available in small quantities for pharmacological experimentation. These substances are somewhat unique in that there are few agents which have such a profound effect on the central nervous system yet do not contain either a sulphur or nitrogen atom in the molecule. We report here some preliminary pharmacological results with pure synthetic Δ8 and Δ9-tetrahydrocannabinol (Δ9-THC), and also describe the effect of the insertion of a heterocyclic atom in ring C on the pharmacology of these agents. The nitrogen analogue of Δ9-THC (I in Fig. 1) was synthesized by Pars and co-workers5 and the sulphur analogue (II) by R. K. R. (unpublished data).
Article
59 undergraduates were placed in 1 of 3 groups based on ability and commitment to running. Each group completed the Profile of Mood States (POMS) over a 6-hr period that centered on the time of day at which Ss ran; all Ss completed a commitment to running scale. Runners had significantly more positive POMS profiles than nonrunners. Mood changes over time suggest that the activity of running may improve one's mood and that moderate levels of running result in positive mood profiles comparable to those of advanced runners. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
The responses to brief maximal exercise of 10 male subjects have been studied. During 30 s of exercise on a non-motorised treadmill, the mean power output (meanSD) was 424.841.9 W, peak power 653.3103.0 W and the distance covered was 167.39.7 m. In response to the exercise blood lactate concentrations increased from 0.600.26 to 13.461.71 mmoll–1 (p<0.001) and blood glucose concentrations from 4.250.45 to 5.590.67 mmoll–1 (p<0.001). The severe nature of the exercise is indicated by the fall in blood pH from 7.380.02 to 7.160.07 (p<0.001) and the estimated decrease in plasma volume of 11.53.4% (p<0.001). The plasma catecholamine concentrations increased from 2.20.6 to 13.46.4 nmoll–1 (p<0.001) and 0.20.2 to 1.40.6 nmoll–1 (p<0.001) for noradrenaline (NA) and adrenaline (AD) respectively. The plasma concentration of the opioid-endorphin increased in response to the exercise from <5.0 to 10.23.9 p moll–1. The post-exercise AD concentrations correlated with those for lactate as well as with changes in pH and the decrease in plasma volume. Post-exercise-endorphin levels correlated with the peak speed attained during the sprint and the subjects peak power to weight ratio. These results suggest that the increases in plasma adrenaline are related to those factors that reflect the stress of the exercise and the contribution of anaerobic metabolism. In common with other situations that impose stress,-endorphin concentrations are also increased in response to brief maximal exercise.
1.1. Potential therapeutic applications of various naturally occurring cannabinoids, their metabolites and synthetic derivatives have been described.2.2. They include analgesic, antipyretic, anti-inflammatory, appetite stimulant, antitussive, antispasmodic, antihypertensive, antiemetic, anticonvulsant, antiasthmatic, antidepressant, antiglaucoma, sedative, hypnotic, anticancer, treatment of alcoholism and narcotic addiction.3.3. More promising areas appear to include antiemetic and appetite-stimulant effects in cancer patients following chemotherapy; anticonvulsant effect of nonpsychoactive cannabinoids; treatment of glaucoma; management of asthmatic and alcoholics.4.4. Potential problems with short- and long-term use of some natural cannabinoids are discussed.5.5. Further studies with natural cannabinoids and their chemical congeners are suggested.
Article
Serum cortisol and plasma beta-endorphin/beta-lipotrophic hormone (LPH) immunoreactivity were measured in five males before and after endurance exercise (treadmill) and burst activity resistance exercise (weight lifting). Mean beta-endorphin/beta-LPH immunoactivity increased significantly following treadmill testing (p < .05) and weight training (p < .06). Post-exercise hormonal values were similar for the two activities. The hormonal changes previously reported with endurance activities also occur with burst activity exercise.
Article
Mice chronically exposed to lead during initial periods of development demonstrate increased levels of spontaneous motor activity. Their behavioral responses to a number of drugs indicate a decrease in central cholinergic activity. Studies utilizing peripheral nervous tissue have shown a decreased evoked and an elevated spontaneous release of ACh by lead. The possibility was examined, therefore, that the evoked and spontaneous ACh release in brain tissue might be similarly altered by chronic lead treatment in vivo. The results indicate that chronic lead administration inhibits the potassium-induced release of both choline and ACh from cortical minces. Potassium-induced release of labeled ACh synthesized from labeled choline is also significantly impaired in the lead-treated animals. Administration of methylphenidate to lead-treated animals, previously reported to suppress leadinduced hyperactivity, reverses the inhibition of potassium-induced choline and ACh release. Spontaneous release of ACh in lead-treated animals is significantly increased. Omission of calcium significantly inhibits the potassium-induced release of ACh without significantly altering choline release. No changes were found in the steady state levels of choline and ACh nor in the activities of choline acetyltransferease, choline phosphokinase, and acetylcholinesterase in the brains of lead-treated animals during development. The results suggest that the inhibition of potassium-induced release of ACh by lead may occur by two different mechanisms: (1) lead may reduce the availability of choline for ACh synthesis, and (2) lead may interfere with the role of calcium in the evoked release of ACh. The present work indicates that chronic lead exposure, at doses previously shown in mice to elicit hyperactivity, also disrupts central ACh function. Also, the results indicate that lead may be a valuable tool in elucidating the dynamic processes involved in central ACh metabolism.
Article
— Acetylcholine turnover has been determined in whole mouse brain using a newly available high specific activity [3H]choline (70 Ci/mmol). Animals were killed at various time points (0.25–10 min) after pulse adminstration of [3H]choline (Ch) by microwave irradiation of the head. Steady-state levels of ACh were determined by radioenzymatic analysis as described by Goldberg & McCaman (1973) as modified by McCaman & Stetzer, 1977. Ch levels were determined by a modification of the method of McCaman & Stetzer (1977). Radiolabelled metabolites of [3H]Ch were separated by selective extraction of [3H]Ch and [3H]ACh inio tetraphenylboron in 3-heptanone (Carrollet al., 1977) coupled with an enzymatic separation of [3H]Ch from [3H]ACh. A precursor-product relationship was verified for Ch and ACh specific activities. Acetylcholine turnover rate was determined by the biosynthesis ratio method (Schuberthet al., 1969, Method 1) and by the finite-differences method (Neffet al., 1971, Method 2). Both methods of kinetic analysis revealed two distinct turnover rates for acetylcholine. In the first phase (0.25–1.5 min post-[3H]Ch), the ACh turnover rate averaged 22nmol/g/min (both methods). During the second phase, (2–10 min) acetylcholine turnover rates were significantly (P < 0.05 and P < 0.01) lower; i.e. 7nmol/g/min (Method 1) and 5.9 nmol/g/min (Method 2). The data are consistent with a 2-compartment model for ACh turnover in whole mouse brain. Additionally, the method described for the separation of radiolabelled metabolites of [3H]Ch allows an accurate determination of ACh turnover in as little as 2 mg of tissue.
Article
The effects of delta9-tetrahydrocannabinol (delta9-THC), the major psychoactive compound of marijuana, and cannabidiol (CBD), a non-psychoactive component, on the acetylcholine (ACh) concentration and the turnover rate of ACh (TRACh) have been studied in various regions of the rat brain. Neither delta9-THC 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, delta9-THC (doses from 0.2 to 10 mg/kg) causes a marked dose-related decrease in the TRACh in hippocampus whereas CBD is without effect in this brain region even when 20 mg/kg is given. Furthermore, high doses of delta9-THC (5 mg/kg) and CBD (20 mg/kg) that produce a significant decrease in the TRACh of striatum fail to change the TRACh in parietal cortex. The low doses of delta9-THC required to reduce hippocampal TRACh suggest that an action on these cholinergic mechanisms may play a role in the psychotomimetic activity of delta9-THC.
Article
A radiochemical method for the determination of picomole levels of ACh has been described previously. This procedure involves the conversion of ACh to choline 32PO4 in the presence of AT32P and the enzymes, acetylcholinesterase and choline kinase (ATP:choline phosphotransferase, EC 2.7.1.32). With this procedure levels of ACh in mammalian brain have been determined in as little as 200 μg of wet tissue. The present report describes recent modifications of the assay which have resulted in a substantial increase in sensitivity (to 0.04 pmol), primarily by increasing the specific activity of the [γ32P]ATP and decreasing the reagent blank. Values for ACh are proportional to tissue over a 500 fold range, from approx 0.1-50 μg protein. Comparison of ACh content of individual soma with both procedures is also given.
Article
Abnormal-delta8-tetrahydrocannabinol (ABN-delta8-THC) failed to elicit central nervous system and cardiovascular effects in laboratory animals. Abnormal-cannabidiol (ABN-CBD) was also devoid of overt behavioral effects but produced marked hypotension with only slight bradycardia in anesthesized dogs.
Article
The effects of delta8- and delta9-tetrahydrocannabinol on the biosynthesis of 3H-acetylcholine (ACh) from 3H-choline in cortical, hypothalamic and striatal rat brain slices were examined. The two cannabinols were found to inhibit the synthesis of 3H-ACh in the three brain regions. Treatment with cannabidiol did not alter ACh synthesis. Delta8-tetrahydrocannabinol was approximately twice as effective as the delta9-isomer. This effect was not associated with alterations in striatal and cortical choline acetyltransferase or with an impaired high-affinity uptake system for choline in the striatum. Treatment with delta8- and delta9-cannabinols, likewise, did not change striatal choline and ACh levels. Antagonism of the ACh biosynthesis inhibition occurred when slices from treated animals were incubated in depolarizing concentration of K+ ion. These results suggest that the inhibition of ACh synthesis observed in tetrahydrocannabinol-treated rats may be related to interference with the propagated action potential or with the depolarization process in cholinergic neurons.
Article
In contrast to our previous studies on the submersion of scuba divers in a state of neutral buoyancy, neither plasma beta-endorphin-like immunoreactivity (beta-EIR) nor affective feelings were significantly changes in scuba divers by mimicking diving pressures of 2 feet (0.6 m) and 50 feet (15.2 m) for 20 min in a hyperbaric chamber. It is concluded that the submersion-induced increase in plasma beta-EIR and accompanying changes in affect reported previously are not due solely to changes in pressure.
Article
Plasma beta-endorphin (beta-EP) and beta-lipotropin (beta-LPH) levels were measured in 15 healthy trained marathon runners. These hormones were evaluated in two different conditions: 1-before (1h) and after a marathon race (n = 10); 2-before, during and after a prolonged (90 min) submaximal exercise (bicycle ergometer at 50% VO2 max) (n = 5). In these latter group plasma beta-EP and beta-LPH levels were measured every 15 min for 165 min. In all the athletes, both plasma beta-EP and beta-LPH levels were significantly higher after the end of the marathon race than in basal conditions (p less than 0.01). The prolonged exercise with bicycle ergometer significantly stimulated plasma beta-EP and beta-LPH levels. Starting 60 min after the beginning of the exercise, plasma beta-EP and beta-LPH levels resulted significantly higher than basal values until the end of the exercise (p less than 0.01 at 60, 75 and 90 min). These data confirming that marathon running is a potent stress stimulus, showed that the duration and related factors but not the work load may be considered critical in stimulating beta-EP and beta-LPH release during physical exercise.
Article
To investigate the hypothesis that endurance exercise may lead to a decrease in ventilatory chemosensitivity as possibly mediated by an increase in endogenous beta-endorphins, we measured hypercapnic ventilatory responsiveness (HCVR) and circulating beta-endorphin immunoreactivity in six runners before and after a marathon (42.2 km) race and after administration of 10 mg iv naloxone. Similar testing was performed at identical time periods on the day before the marathon as control data. On each occasion, HCVR was measured twice 15 min apart, and the mean value was used for analysis. Six active (training distance 50-104 km/wk) and experienced (no. of marathons completed, 1-25) runners participated in the study. There were no significant changes in beta-endorphin activity or HCVR on the control day. All runners experienced a rise in beta-endorphin activity from premarathon (21.3 +/- 16.0 pg/ml) to immediate postmarathon (89.6 +/- 84.9 pg/ml) values (P less than 0.05). However, HCVR showed no significant change at any of the three testing periods on the marathon day. To investigate whether a time delay may have affected the lack of response to naloxone, additional testing was performed in five subjects, except that 10 mg iv naloxone was given within 10 min after completion of the marathon, and then HCVR was measured. Although there was a greater than fourfold increase in beta-endorphin immunoreactivity after the marathon, there was no significant change in HCVR after naloxone administration. We conclude that natural increases in endogenous beta-endorphin activity associated with marathon running do not modulate central chemosensitivity.
beta-endorphin (beta-EP) and beta-lipotropin (beta-LPH) concentrations were measured in the basal state and after acute exercise for 15 min or until exhaustion in 6 physically conditioned male volunteers. Serum concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone and prolactin were also measured in the basal state. In addition, the concentrations of the gonadotropins (LH and FSH) were determined after exercise and the gonadotropin response to gonadotropin releasing hormone was assessed before and after exercise. The data show that acute exercise stimulates the release of both beta-EP and beta-LPH which return to base-line levels within 60 min after exercise. This is in contrast to our previously described results in physically unconditioned male volunteers in whom only beta-LPH release was noted after exercise. Serum LH concentrations declined after exercise reaching nadir values between 60 to 150 min after exercise. As we previously reported in physically unconditioned male volunteers, serum FSH concentrations did not change with exercise and the gonadotropin response to LRH stimulation was uninfluenced by exercise. Serum testosterone and prolactin concentration were within the normal range for healthy adult males. We speculate that the difference in beta-EP release with exercise in physically conditioned and unconditioned males represents a difference in processing of the opioid precursor molecule (pro-opiomelanocortin, POMC) in the two groups.
Article
1. Endogenous opioids have been implicated in the control of breathing in neonates, but their role in ventilatory control in adults remains unclear. 2. We studied the relationship between circulating immunoreactive β-endorphin and the ventilatory and mouth occlusion pressure responses to hypercapnia in 12 healthy male subjects. In addition, we examined the effect of repetitive hypercapnia on plasma β-endorphin and Cortisol levels. 3. A weak but significant negative relationship between the ventilatory response to hypercapnia and basal plasma β-endorphin levels was observed (r = −0.35, P < 0.01). A similar negative relationship was noted between mouth occlusion pressure response to hypercapnia and basal plasma β-endorphin levels (r = −0.36, P < 0.01). 4. Repetitive hypercapnia prevented the fall in plasma Cortisol that occurred under control conditions (P < 0.02) but had no effect on plasma β-endorphin. 5. We conclude that plasma β-endorphin may play a role in the central chemical control of breathing in man.
Article
The purpose of this study was to examine the effects of three different run training programs on plasma responses of beta-endorphin (beta-EP), adrenocorticotropin (ACTH), and cortisol to maximal treadmill exercise. Subjects were randomly assigned to one of three training groups: sprint intervals (SI) (N = 8), endurance (E) (N = 10), or combination (C) (N = 7). Training was monitored for 10 wk, and maximal treadmill exercise tests were administered pre-training and after 2, 4, 6, 8, and 10 wk of training. Blood samples were obtained (pre-training and after 10 wk) before, immediately after, and 5 and 15 min following the maximal exercise tests. All groups significantly (P less than 0.05) increased maximal oxygen consumption values at 8 and 10 wk of the training period. Significant exercise-induced increase in plasma beta-EP, ACTH, cortisol, and blood lactate were observed for both pre- and post-training tests in all training groups. The SI group demonstrated significant post-training increases in beta-EP, ACTH, cortisol, and 5 min post-exercise blood lactate concentrations in response to maximal exercise. No training-induced hormonal changes were observed for the E group. While exercise-induced increases were observed, the C group exhibited significant post-training reductions in plasma responses of beta-EP, ACTH, and blood lactate concentrations in response to maximal exercise. Still, resting and post-exercise increases in plasma cortisol concentrations were significantly higher in magnitude in the post-training test. Lactate was significantly correlated with beta-EP (r = 0.72), ACTH (r = 0.70), and cortisol (r = 0.64).(ABSTRACT TRUNCATED AT 250 WORDS)
Article
An experiment was conducted to examine the acute emotional and psychophysiological effects of a single bout of aerobic exercise. Forty active and 40 inactive college students were randomly assigned to an aerobic exercise or a waiting-period control condition. Self-report measures of mood and cardiovascular response measures to challenging cognitive tasks were collected before and after the 20-min exercise/control period to examine any exercise-induced changes. The results indicated that mood was significantly altered by the exercise activity, with reductions in tension and anxiety specifically evident. Exercise was not found to have any effects on cardiovascular reactivity. A test of aerobic fitness confirmed fitness differences between active and inactive participants, but no mood or reactivity effects related to activity status were obtained. These results suggest that both active and inactive individuals experience acute reductions in anxiety following single bouts of exercise, even in the absence of changes in cardiovascular reactivity. Implications for the continued investigation of the acute effects of exercise are discussed.
Article
The response of plasma beta-endorphin (beta-EP) and adrenocorticotropin (ACTH) was studied in seven well-trained (T) young endurance athletes and seven untrained (UT) age- and weight-matched males during treadmill exercise. Subjects ran continuously for 7 min at 60% VO2max, 3 min at 100% VO2max and 2 min at 110% VO2max. Arterialized blood was obtained periodically from a cannulated heated (41 degrees C) hand vein. Plasma beta-EP was measured by radio-immunoassay (RIA) which incorporated an antibody that did not cross-react (less than 1.5%) with beta-lipotropin. Plasma beta-EP was similar between groups at rest (T = 4.3 +/- 0.8 fmol ml-1, mean +/- SE, UT = 3.3 +/- 0.6 fmol ml-1) and did not change at the 60% VO2max stage. Beta-endorphin significantly increased at 100% VO2max with both groups responding similarly. A further increase occurred at 110% VO2max (T = 10.8 + 2.0 and UT = 6.6 + 1.0 fmol ml-1, P less than 0.05 for between group differences). This between group difference persisted 1 min after exercise when the highest beta-EP levels were reached (T = 18.7 +/- 4.7 and UT = 12.8 +/- 3.1 fmol ml-1, P less than 0.05). Plasma ACTH responses were similar to beta-EP with the highest values (T = 61.5 +/- 7.2, UT = 45.7 +/- 6.8 fmol ml-1, P less than 0.05 for between group differences) occurring at 1 min post-exercise. A positive correlation, r = 0.85, P less than 0.05, was found between beta-EP and ACTH using the 1 min post-exercise values. The enhanced response of beta-EP and ACTH in T may indicate a training-induced adaptation which increases the response capacity to extreme levels of stress.
Article
We studied the responses of plasma concentrations of beta-endorphin, beta-lipotropin, and corticotropin to an exhaustive graded treadmill exercise, to an anaerobic treadmill exercise, and to a sub-maximal outdoor running exercise in 5 male and in 5 female endurance athletes. During the graded treadmill exercise, the mean plasma level (+/- SE) of beta-endorphin in men rose from 1.2 +/- 0.1 to 8.1 +/- 0.7 pmol.l-1, beta-lipotropin rose from 1.6 +/- 0.5 to 7.4 +/- 1.4 pmol.l-1, and corticotropin rose from 4.9 +/- 1.0 to 31 +/- 3.3 pmol.l-1. In women, the mean level of beta-endorphin rose from 1.2 +/- 0.2 to 8.2 +/- 1.8 pmol.l-1, beta-lipotropin rose from 1.4 +/- 0.1 to 8.1 +/- 2.0 pmol.l-1, and corticotropin rose from 3.3 +/- 0.4 to 28 +/- 7.9 pmol.l-1. Concentrations of endorphins and corticotropin increased significantly also during the anaerobic exercise test. In response to sub-maximal running exercise, no significant change was found. These results showed a relationship between the intensity of exercise and the secretion of pro-opiomelanocortin-related peptides, and there were no differences between the groups of trained men and women.
Article
Stressful social interactions have been shown to elicit increases in heart rate as well as in plasma levels of epinephrine, norepinephrine, and cortisol in humans. We sought to determine whether a competitive oral examination would affect plasma levels of the pituitary hormones ACTH, beta-endorphin, beta-lipotrophic hormone, and prolactin in a group of healthy young males. Seven min after beginning the examination, heart rate increased 27% and plasma levels of ACTH, beta-endorphin, beta-lipotropic hormone and prolactin rose 59%, 79%, 42%, and 46%, respectively, compared to values shortly before the examination. These hormone values returned to initial levels after the subjects returned to the waiting room. Plasma cortisol changes were similar in direction to those of ACTH but occurred about 15 min later. The present study demonstrates that a stressful social interaction can elicit rapid increases in plasma levels of the proopiomelanocortin derived peptide hormones and prolactin in man.
Article
Seven women undergoing abdominal hysterectomy under halothane and nitrous oxide analgesia had plasma samples taken before, during and after surgery for assay of adrenocorticotrophin (ACTH), beta-endorphin, beta-lipotrophin and methionine (Met)-enkephalin immunoreactivity. Plasma ACTH, beta-endorphin and beta-lipotrophin all rose in parallel from the start of surgery and were unaffected by postoperative opiate analgesia. Plasma Met-enkephalin concentrations did not change significantly during the course of the surgery and immediate post-operative period, although the variance of the samples increased at the time of the first skin incision. These data indicate that the stress of surgery and post-operative pain, while producing marked elevations of proopiomelanocortin-derived peptides, are not associated with changes in plasma Met-enkephalin. These data exclude a role for circulating Met-enkephalin in the modulation of surgical pain but do not exclude such a role for beta-endorphin.
Article
The plasma beta-endorphin (beta-EP) and beta-lipotropin (beta-LPH) response of men, eumenorrheic women, and amenorrheic women (n = 6) to 1 h of rest or to a bicycle ergometer test [20 min at 30% maximum O2 uptake (VO2max), 20 min at 60% VO2max, and at 90% VO2max to exhaustion] was studied in both normal (22 degrees C) and cold (5 degrees C) environments. beta-EP and beta-LPH was measured by radioimmunoassay in venous samples collected every 20 min during rest or after each exercise bout. Exhaustive exercise at ambient temperature (Ta) 22 degrees C induced significant increases in plasma beta-EP and beta-LPH in all subjects as did work at 60% VO2max in amenorrheic and eumenorrheic women. During work at Ta 5 degrees C, the relative increase in beta-EP and beta-LPH was suppressed in eumenorrheic women and completely prevented in amenorrheic women. Although significant lowering of beta-EP and beta-LPH was observed in men and eumenorrheic women during rest at 5 degrees C, amenorrheic women maintained precold exposure levels. These findings suggest that plasma beta-EP and beta-LPH may reflect a thermoregulatory response to heat load. There appears to be a sexual dimorphism in exercise- and cold-induced release of beta-EP and beta-LPH and amenorrhea may be accompanied by alterations in these responses.
Plasma met-enkephalin, beta-endorphin, cortisol and lactic acid concentrations were measured in seventeen volunteer male subjects at rest and after a long-distance nordic ski race. Immediately after the race, mean plasma met-enkephalin did not show any significant change, but significant rises in beta-endorphin, cortisol and lactic acid were noted in all skiers. The change in beta-endorphin with exercise was significantly related to the change in cortisol (r = 0.68; p less than 0.001) and to the change in plasma lactic acid (r = 0.60; p less than 0.001). Furthermore, the experienced skiers training over 150 km X week-1 of nordic ski had significantly faster skiing times in this event and showed greater beta-endorphin, cortisol and lactic acid levels than the recreational skiers who trained for 20 km X week-1. Our results imply that the changes in plasma beta-endorphin depend on the intensity of exercise. However the significance of higher levels of skiing training or previous nordic ski experience in the release of beta-endorphin is expected and cannot be excluded.
Article
The present study was undertaken to define the response of plasma beta-endorphin immunoreactivity (ir-BE) to exercise of increasing intensity. Nineteen healthy males performed continuous exercise for 32 min on a cycle ergometer, comprised of 8-min bouts at %VO2max approximating 25, 50, and 75% of maximal exercise. Venous blood samples were collected before exercise (T = -20 and 0 min), during exercise (T = 8, 16, 24, and 32 min), and in recovery (T = +15, +30 min). Ir-BE in plasma was measured by radioimmunoassay using Immuno Nuclear assay kits. Plasma ir-BE level (pg X ml-1) was not altered from pre-exercise (18.3 +/- 1.3) after 8 min of exercise at 25 and 50% VO2max intensity; however, ir-BE rose significantly after 8 min of 75% VO2max work intensity (27.1 +/- 2.4) and was further elevated at maximal exercise (74.1 +/- 8.6). Ir-BE level remained elevated 15 min (60.9 +/- 8.1) and 30 min (35.2 +/- 5.2) post-exercise. The response pattern was further characterized by a significant (P less than 0.05) inter-individual variation, both at rest and during exercise; also, regression analysis indicated the ir-Be levels attained at maximal exercise were inversely related to the relative VO2max (ml X kg-1 X min-1) of the subject (predicted ir-BE = 248.2 - 3.39 VO2max; r = -0.397, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Plasma beta-endorphin, prolactin (PRL), FSH and LH were measured in 17 volunteer male subjects at rest and under the stress caused by a long-distance nordic ski race. The race induced increased levels of beta-endorphin and PRL in all skiers. The changes in PRL with exercise were significantly related to the changes in beta-endorphin (r = 0.69, p less than 0.001). Furthermore, the highly trained skiers training over 150 km.week-1 of nordic ski showed consistently higher post-exercise beta-endorphin and PRL levels than the moderately trained skiers who trained for 20 km.week-1. In addition the race induced slight falls in FSH and LH; however plasma gonadotropin levels did not show any correlation with plasma beta-endorphin concentrations and did not differ between the two groups of skiers. These results suggest that endogenous opioid peptides may modulate PRL secretion in heavy exercise, since they are of minor importance in the release of FSH and LH in such a situation. The observations also suggest that the degree of previous training and the exercise intensity do seem to be responsible for the hormonal changes.
Beta-endorphin (beta-End) and adrenocorticotrophic hormone (ACTH) were determined in the peripheral blood of 14 human volunteers exercising on a bicycle ergometer. After 1 h of submaximal work below anaerobic threshold (AT), defined as the 4 mmol X l-1 lactic acid level in arteriolar blood (Kindermann 1979; Mader 1980), beta-End and ACTH levels did not change from control conditions. Eleven of the same 14 subjects performed an uninterrupted graded exercise test on the same bicycle ergometer until exhaustion. This time beta-End and ACTH levels increased concomitantly with exercise of high intensity: at each moment, during and after this maximal test, a highly significant correlation (P less than 0.0001) was noted between the levels of beta-End and ACTH. The peak values of these hormones were reached within 10 min after stopping maximal exercise, and coincided with lactic acid peak levels. A rise in lactic acid levels above the anaerobic threshold always preceded the exercise-induced rise in beta-End and ACTH. Within the population tested, two subgroups could be distinguished: one comprising individuals whose hormonal response nearly coincided with the rise in lactic acid (rapid responders) and a second group composed of subjects whose normal response appeared delayed with respect to the lactic acid rise (slow responders). These results support the view that beta-End and ACTH are secreted in equimolar quantities into the blood circulation in response to exercise, and suggest that metabolic changes of anaerobiosis play a key role in the regulation of stress-hormone release.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
Despite the extensive knowledge about the pharmacological actions of cannabinoids, the two most promising therapeutic areas of Δ9-THC, i.e., antiemetic and antiglaucoma activities, were discovered serendipitously without any preclinical pharmacology. This emphasizes the importance of early studies in humans and the difficulties encountered in correlating animal activity with activity in man for this class of compounds. The role of cannabinoids as antinauseants to patients undergoing cancer chemotherapy is now well established. Δ9-THC has recently been approved by the Food and Drug Administration (FDA) for marketing in the USA, and a synthetic analog, Nabilone, is already marketed in Europe. In the antiglaucoma field, the utility of Δ9-THC as a novel agent has been established, and several synthetic analogs are presently in the developmental stage. From pharmacological screening of cannabinoids, a separation of several specific pharmacological actions has been noted in different derivatives, but the relevance of these to humans is not presently clear. Hopefully, with the introduction of more sophisticated pharmacological screens and with the extended clinical usage of Δ9-THC and Nabilone, there will be a resurgence of interest in this field. Other areas of therapeutic use will become evident, and the potential of this class of novel drugs will begin to emerge. A parallel can be drawn between the opioid and the cannabinoids, since morphine and Δ9-THC both are drugs of abuse. To use the opioid work as a guide, the cannabinoids are at present in their early stages of development, comparable to morphine before the discovery of nalorphine. However, it should be emphasized that the concept of drug development from THCs and cannabinoids is based on very sound foundations, since, unlike morphine, Δ9-THC has a remarkably low toxicity in animals and humans. In addition, it has practically no respiratory-depressant activity, none or very low physical dependence liability, and, finally, a unique pharmacological profile compared to other psychoactive drugs.
Article
The effects of the expectancy of an official race (22000 m) and the performance of this last event on plasma levels of beta-Endorphin (B-End) and ACTH have been assessed. In a group of nine athletes, samples were obtained first in basal conditions; second in the day of the run before the warming up period and third after running. B-End immunoactivity was increased from 15.7 +/- 2.0 pg/ml to 23.4 +/- 2.5 pg/ml before the run and up to 30.6 +/- 2.9 pg/ml after the trial. ACTH levels were increased from 8.4 +/- 1.2 pg/ml to 17.9 +/- 2.3 pg/ml before running and up to 36.2 +/- 3.9 pg/ml after running. The results suggest that psychological and physical stress act synergically to increase the levels of B-End and ACTH during the practice of physical exercise.
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Vigorous exercise is associated with a sensation of well-being, and this subjective state has been objectively quantified with psychometric, cardiovascular, and neurophysiological data. Reductions in state anxiety have been demonstrated to follow acute physical activity, and this response persists for 2-5 h. Chronic physical activity has been associated with reductions in anxiety and depression, as well as increases in self-esteem. This research has been limited to designs of a correlational nature, and the issue of causality vs mere association has not been resolved or addressed. Three hypotheses based upon distraction, monoamine metabolism, and endorphin release are discussed in this paper. Investigators have traditionally attempted to illustrate the mechanism involved in improved mood following exercise by testing one of these or related hypotheses, but it is likely that advances will not be made in this area until these hypotheses are examined in a multiple or synergistic manner. It is concluded that each of the hypotheses reviewed remains tenable.
Article
The pharmacology of the cannabinoids is characterized by at least two very provocative phenomena. First, the multiplicity of effects. As I have mentioned throughout this review, most of these effects are due to actions on the central nervous system. The major problem in the search for a therapeutic agent in this series has been due to the inability to find a cannabinoid with the therapeutic action at doses below those that produce side effects. The high lipid solubility of the cannabinoids allows them to be distributed throughout the brain at reasonable doses. The second aspect of their pharmacology worthy of special mention is their low toxicity. Throughout this review, I have indicated that the minimal effective dose of delta 9-THC for a particular pharmacological effect in animals was higher than that usually consumed by man. Yet, in almost all cases, it was much lower than the dose which produced toxic effects in the same species. These two characteristics of the animal pharmacology of cannabinoids carry over to humans. For instance, each of the cannabinoids tested in man causes many side effects at active doses and lethal effects of overdose by humans are nonexistent or rare. Toxicity following chronic use may be a different issue. A great deal of work has been carried out in an attempt to characterize the pharmacological effects of cannabinoids. It is clear from the material reviewed in this article that most if not all of the predominant effects of cannabinoids in whole animals are due to the direct effects of these compounds on the central nervous system. Our state of knowledge is too limited to rule out the possibility that they also produce effects on certain peripheral organs. It is expected that the majority of these effects will be shown to be due to the interaction of the cannabinoids with the neuronal innervation of the organ rather than directly with the organ tissue itself. Very high doses of cannabinoids just like all active drugs have an effect on many organ systems. These are toxicologic not pharmacologic and are nonspecific. The effects of cannabinoids at the molecular level have been reviewed by Martin (182a) in this series. This type of research is expected to elucidate the mechanism of action of cannabinoids at the cellular level. It is clear that the cannabinoids produce a unique behavioral syndrome in laboratory animals and in man.(ABSTRACT TRUNCATED AT 400 WORDS)
Article
Increased plasma beta-endorphin immunoreactivity in scuba divers after submersion. Med. Sci. Sports Exerc., Vol. 19, No. 2, pp. 87-90, 1987. After submersion under water in a motionless state of neutral buoyancy, scuba divers frequently report feelings of well-being or euphoria similar to those reported after strenuous exercise. Since strenuous exercise is associated with a stress-related increase in plasma beta-endorphin immunoreactivity (beta-EIR), this study was undertaken to measure plasma beta-EIR after submersion in a state of neutral buoyancy under conditions that do not involve strenuous exercise or other extreme stresses. Plasma beta-EIR was measured by radioimmunoassay in male scuba divers before and immediately after remaining motionless 10 ft under water in a state of neutral buoyancy. A significant (P less than 0.01) increase in plasma beta-EIR was found under these conditions. Venipuncture and scuba breathing out of the water did not alter beta-EIR levels. These results indicate that the milder stress associated with submersion in a state of neutral buoyancy involves an increase in plasma beta-EIR similar to that caused by severe stress.
Article
Serum beta-endorphin levels during a graded exercise test to exhaustion. Med. Sci. Sports Exerc., Vol. 19, No. 2, pp. 78-82, 1987. Nine untrained college age males completed a graded exercise protocol to maximal capacity on a bicycle ergometer to determine if there was a relationship between intensity of exercise and serum beta-endorphin (beta-EP) levels. Subjects fasted for 12 h and abstained from physical activity at least 24 h prior to testing. Subjects completed the Multiple Affect Adjective Check List prior to and following exercise to ascertain if psychological state would be associated with beta-EP levels. The initial workload was 150 kilopond meters and was increased 150 kilopond meters every 3 min until VO2max or leg fatigue occurred. Expired gases were continuously analyzed, and a venous blood sample was drawn from an indwelling catheter during the final 30 s of each stage and 5-min post-exercise. beta-EP levels were determined from serum using a radioimmunoassay technique and corrected for cross-reactivity with beta-lipotropin using affinity chromatography. Resting beta-EP levels were 25.3 +/- 4.1 pg X ml-1 and did not demonstrate significant changes during any stage of exercise. A correlation analysis (r = 0.30) revealed no significant relationship between exercise intensity and beta-EP levels. Following exercise, beta-EP levels were significantly increased compared to resting values (38.8 +/- 4.8 pg X ml-1). In addition, psychological state was unaffected by exercise despite significant increases in recovery beta-EP levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
Clinical studies of a variety of cannabis constituents and THC isomers, homologs and metabolites have elucidated some structure activity relationships. The fundamental structure of THC is required for pharmacological activity, but potency may be altered greatly among different double bond isomers, by changing length of side chain or by metabolic hydroxylations. No material has been found in nature, either in cannabis itself or in the metabolites of THC, which differs qualitatively from THC.
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The hypothesis is advanced that marihuana and espedaily Δ9-tetrahydrocannabinol, impair certain aspects of hippocampal neural functioning which are necessary for normal cognitive operations. It is suggested that many of the cognitive alterations induced by cannabinoids may be attributable to interference with cholinergic mechanisms. Both pharmacological and behavioral evidence are cited to support this hypothesis.
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— —A method to measure the rate of acetylcholine turnover in mouse brain in vivo has been developed. It is based on the formation of labelled acetylcholine from intravenously injected labelled choline. The isotopic dilution of choline in the brain has been measured by assaying endogenous choline in the brain by an enzymatic method using tritium-labelled acetyl-CoA and purified choline acetyltransferase.The rate of acetylcholine turnover in the brain could be calculated at 50 n-moles acetylcholine/g/min in conscious mice. In anaesthetized mice and in mice treated with oxotremorine, a decrease of acetylcholine turnover to about 10 n-moles/g/min was found.