Article

Very low doses of Δ8-THC increase food consumption and alter neurotransmitter levels following weight loss

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Abstract

We have investigated the effect of 0.001 mg/kg delta(8)-tetrahydrocannabinol (THC) on food consumption, cognitive function, and neurotransmitters in mice. Sabra mice were treated with vehicle, THC, or THC+CB1 antagonist (SR141716A). The mice were fed for 2.5 h a day for 9 or 50 days. In the 9-day schedule, THC-treated mice showed a 16% increase in food intake compared with controls (P<.001). This effect was reversed by the antagonist (P<.01). In the long-term schedule a 22% increase in intake (P<.05) was recorded. During the course of the 9- and 50-day experimental protocol, all mice lost about 20% and 10% of their original weight, respectively, to reach approximately the same weights, which were not significantly different between the different treatment groups. In addition, THC caused an increase in activity (P<.05). Cognitive function showed a tendency to improve (P<.06) in the THC-treated mice, which was reversed by the antagonist for Days 4 and 5 of the maze (P<.01, and P<.05, respectively). Significant decreases in dopamine and serotonin (5-HT) levels were found both in the hypothalamus (P<.01) and the hippocampus (P<.01, P<.05), respectively, while norepinephrine (NE) levels showed tendency to increase in both the hypothalamus and hippocampus. Delta(8)-THC increased food intake significantly more (P<.05) than did delta(9)-THC, while performance and activity were similar. Thus, delta(8)-THC (0.001 mg/kg) caused increased food consumption and tendency to improve cognitive function, without cannabimimetic side effects. Hence, a low dose of THC might be a potential therapeutic agent in the treatment of weight disorders.

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... There remains a need for effective and sustainable treatment for AN (Steinhausen, 2002b) [22]. Several animal models have been developed to investigate AN, including diet restriction (DR), activity wheel, and separation stress [3] [6] [18] [2]. Clearly, no single animal model is a true replica of the human disease, but the various assays are useful for focusing on different aspects of this condition. ...
... In addition, it affects AMPK (Adenosine Monophosphate kinase) [12]. Restoration of these systems by administration of tyrosine or cannabinoids or omega 3 fatty acids may have therapeutic potential [3] [2,9]. Insulin is one of the most powerful anabolic hormones. ...
... In addition, it affects AMPK(Adenosine Monophosphate kinase) [12]. Restoration of these systems by administration of tyrosine or cannabinoids or omega 3 fatty acids or insulin may have therapeutic potential [3] [2]. ...
Article
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Introduction : Anorexia nervosa is a psycho-socio-biological disease, characterized by self-starvation and distorted perception of body weight. Patients often over-exercise. Insulin is an anabolic hormone that increases food intake and restores body fat and is present in low levels in anorexia nervosa patients: thus may have therapeutic potential in treating anorexia nervosa. Aims : to explore whether low levels insulin administration may result in recovery of cerebral function and restoration of metabolic disorder providing a treatment option for anorexia nervosa. Methods : Female Sabra mice maintained on DR of 2.0 hours per day for 32 days, in cages with or without wheel attached to an electronic counter (activity wheel). They were then permitted to eat ad libitum for additional 15 days. On the second week, mice were injected ip with 0.5U/kg long acting Insulin(Lantus) or saline and cognitive function was evaluated. Insulin administered three times a week during days 8-32. Mice euthanized on day 48 and cerebral levels of monoamines, 2-AG and expression of genes associated with metabolic status were evaluated. Results : Activity wheel mice decreased body weight, 2-AG, dopamine levels and 5-HT1A and increased Camkk2 and SIRT1 gene expression compared to mice without it. Insulin increased body weight, decreased revolutions, enhanced NPY and normalized Camkk2, SIRT-1, BDNF, elevated 2-AG and improved cognition in the wheel group. Conclusion : low dose insulin administration to animal model of anorexia associated with exercise, led to alterations and normalization in brain metabolic status and improved cognition. Insulin should be further explored as potential novel treatment for anorexia nervosa.
... weight loss might affect brain function may assist in better understanding the etiology and lead to the development of new therapeutic strategies. In order to accomplish it we have developed three experimental animal models of AN which represent different aspects of the disorder: diet restriction, activity wheel and separation stress (7)(8)(9). ...
... The plant Cannabis sativa and its active ingredient, Δ 9 -tetrahydrocannabinol (Δ 9 -THC) are known appetite stimulators (8,9). Following the discovery of the endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG) (amide and ester of the essential fatty acid arachidonic acid respectively that bind to the cannabinoid receptors), we tested their effects on appetite in these mice models (10,11). ...
... A decrease in dopamine and 5-HT and increase in NE were observed without any addictive effects. SR 141716A reversed these effects (8). AN is also characterized by anhedonia whereby patients experience little pleasure or reward. ...
Article
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Background: Δ9-Tetrahydrocannabinol (Δ9-THC) is the active compound of Cannabis sativa with appetitestimulating properties. This study evaluated the effect of low doses of oral Δ9-THC on self-reported symptoms of patients suffering from chronic anorexia nervosa (AN). Methods: Nine female subjects over 18 years of age participated in the study. Six were diagnosed according to DSM-IV criteria with AN restrictive type and three with active AN binge-purge type. Their mean age was 45.0±3.2 years and their BMI was 16.1±1.6 kg/M2. They completed questionnaires before and after treatment with Δ9-THC (1 mg/day for one week and 2 mg/day for three weeks). The primary outcome was improvement in the way patients perceived their eating behavior. Results: Significant improvements were found in selfreported body care, sense of ineffectiveness, asceticism and depression. There were no significant changes in BMI. Conclusions: Δ9-THC may be an effective component in treating the psychological symptoms of AN.
... Research which has been done thus far in the area has been performed in rats, and the levels of 2-AG involved were relatively high and produced cannabinomimetic side effects. Our goals were to investigate the effects of very low doses (0.001 mg/kg) of 2-AG, which do not produce cannabinomimetic side effects (Sulcova et al., 1998) on cognitive function and food consumption, which were improved following administration of low doses (0.001mg/kg i.p.) of the cannabinoids ANA, THC and noladin and fish oil in diet-restricted mice (Hao et al., 2000) (Avraham et al., , 2004) (Avraham et al., 2011). Food consumption was also shown to be increased by low dose of 2-AG in rats (Kirkham et al., 2002). ...
... Searching for mechanisms downstream to the CB 1 receptor, which may account for the increased food consumption, and since low dose cannabinoids were shown to affect catecholamines in the hypothalamus, which are related to feeding behavior (Hao et al., 2000) (Avraham et al., , 2004, we measured catecholamine levels in the hypothalamus. However, these were not found to change significantly (only a trend of increased NE was noticed). ...
... This improvement was reversed by SR141716A. Experiments with other cannabinoids showed the same results: 0.001mg/kg ANA improved the cognitive performance of mice on diet restriction (Hao et al., 2000), as did 0.001mg/kg THC (Avraham et al., 2004) . ...
Article
We have investigated the effects of 0.001mg/kg 2-arachidonoylglycerol (2-AG) administered in combination with compounds present in the body alongside 2-AG like 2-palmitoylglycerol and 2-linoleylglycerol (also termed “entourage”), on cognitive function,food intake, and neurotransmitter levels in the hippocampus and hypothalamus of mice under diet restriction. Young female Sabra mice were treated with vehicle, 2-AG, 2-AG + entourage, 2-AG + entourage + 5-(4-Chlorophenyl)-1-(2,4-dichloro-phenyl)- 4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide (SR141716A, a CB1 antagonist) and SR141716A. The mice were fed for 2.5h a day for 14 days. Cognitive function was evaluated by the eight arm maze test, and neurotransmitter (norepinephrine, dopamine, L-DOPA and serotonin) levels were measured in the hippocampus and hypothalamus by high-performance liquid chromatography-electrochemical detection. Food intake was increased by 2-AG and, to an even greater extent, by 2-AG + entourage. SR141716A reversed the effect of 2-AG + entourage. The administration of 2-AG + entourage improved cognitive function compared to the vehicle mice, and this improvement was blocked by SR141716A. 2-AG + entourage-treated mice showed an increase in norepinephrine (NE), dopamine and L-DOPA levels in the hippocampus. SR141716A normalized NE and L-DOPA levels. There were no significant changes in hypothalamic neurotransmitter levels. The use of very low doses of the endocannabinoid 2-AG + entourage can improve cognitive function by elevating norepinephrine and L-DOPA levels in the hippocampus, without cannabinomimetic side effects. These findings may have implications for cognitive enhancement in anorexia nervosa.
... Research which has been done thus far in the area has been performed in rats, and the levels of 2-AG involved were relatively high and produced cannabinomimetic side effects. Our goals were to investigate the effects of very low doses (0.001 mg/kg) of 2-AG, which do not produce cannabinomimetic side effects (Sulcova et al., 1998) on cognitive function and food consumption, which were improved following administration of low doses (0.001mg/kg i.p.) of the cannabinoids ANA, THC and noladin and fish oil in diet-restricted mice (Hao et al., 2000) (Avraham et al., , 2004) (Avraham et al., 2011). Food consumption was also shown to be increased by low dose of 2-AG in rats (Kirkham et al., 2002). ...
... Searching for mechanisms downstream to the CB 1 receptor, which may account for the increased food consumption, and since low dose cannabinoids were shown to affect catecholamines in the hypothalamus, which are related to feeding behavior (Hao et al., 2000) (Avraham et al., , 2004, we measured catecholamine levels in the hypothalamus. However, these were not found to change significantly (only a trend of increased NE was noticed). ...
... This improvement was reversed by SR141716A. Experiments with other cannabinoids showed the same results: 0.001mg/kg ANA improved the cognitive performance of mice on diet restriction (Hao et al., 2000), as did 0.001mg/kg THC (Avraham et al., 2004) . ...
Article
Aberrant accumulation and self-assembly of α-synuclein are tightly linked to several neurodegenerative diseases called synucleinopathies, including idiopathic Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Deposition of fibrillar α-synuclein as insoluble inclusions in affected brain cells is a pathological hallmark of synucleinopathies. However, water-soluble α-synuclein oligomers may be the actual culprits causing neuronal dysfunction and degeneration in synucleinopathies. Accordingly, therapeutic approaches targeting the toxic α-synuclein assemblies are attractive for these incurable disorders. The "molecular tweezer" CLR01 selectively remodels abnormal protein self-assembly through reversible binding to Lys residues. Here, we treated young male mice overexpressing human wild-type α-synuclein under control of the Thy-1 promoter (Thy1-aSyn mice) with CLR01 and examined motor behavior and α-synuclein in the brain. Intracerebroventricular administration of CLR01 for 28 days to the mice improved motor dysfunction in the challenging beam test and caused a significant decrease of buffer-soluble α-synuclein in the striatum. Proteinase-K-resistant, insoluble α-synuclein deposits remained unchanged in the substantia nigra, whereas levels of diffuse cytoplasmic α-synuclein in dopaminergic neurons increased in mice receiving CLR01 compared with vehicle. More moderate improvement of motor deficits was also achieved by subcutaneous administration of CLR01, in 2/5 trials of the challenging beam test and in the pole test, which requires balance and coordination. The data support further development of molecular tweezers as therapeutic agents for synucleinopathies.
... Administration induces hyperphagia ( Williams and Kirkham, 2002a) OEA ( Bachur et al., 1965) An endogenously produced lipid involved in the control of fat intake and satiety ( Gaetani et al., 2010) and produced on demand in the gut (Rodriguez de Fonseca et al., 2001). Activates VR 1 ( Ahern, 2003) Phytocannabinoids Δ 8 THC ( Ben-Zvi et al., 1970) Partial agonism at CB 1 R and CB 2 R ( Pertwee, 2001), more stable than Δ 9 THC ( Avraham et al., 2004) Δ 9 THC ( Gaoni and Mechoulam, 1964a) ...
... This early study importantly demonstrated that very low concentrations of orally administered Δ 9 THC could substantially change an animal's motivation to consume; particularly given that a considerable percentage of the administered drug would have undergone first pass metabolism as a result of oral administration. Intriguingly, a later study by Avraham ( Avraham et al., 2004) also showed that extremely low Δ 8 THC doses (a pCB similar to Δ 9 THC but regarded as more stable; 0.001 mg/kg; intraperitoneal; i.p.) increased feeding in mice. These studies suggest that subtle modulation of the eCB system can be achieved without the manifestation of the nonspecific behavioural side effects traditionally associated with C. sativa administration ( Howlett et al., 2004). ...
Article
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The herb Cannabis sativa (C. sativa) has been used in China and on the Indian subcontinent for thousands of years as a medicine. However, since it was brought to the UK and then the rest of the western world in the late 19th century, its use has been a source of controversy. Indeed, its psychotropic side effects are well reported but only relatively recently has scientific endeavour begun to find valuable uses for either the whole plant or its individual components. Here, we discuss evidence describing the endocannabinoid system, its endogenous and exogenous ligands and their varied effects on feeding cycles and meal patterns. Furthermore we also critically consider the mounting evidence which suggests non-Δ(9) tetrahydrocannabinol phytocannabinoids play a vital role in C. sativa-induced feeding pattern changes. Indeed, given the wide range of phytocannabinoids present in C. sativa and their equally wide range of intra-, inter- and extra-cellular mechanisms of action, we demonstrate that non-Δ(9) tetrahydrocannabinol phytocannabinoids retain an important and, as yet, untapped clinical potential.
... We have investigated the effect of very low doses (without canabinomimetic side effects) of synthetic cannabinoids D 8 -THC [40], anandamide [19] and 2-arachidonylglyceryl-ether (noladin) [41] on food consumption, cognitive function and neurotransmitter levels in mice as potential therapeutic options in anorexia. THC-treated mice showed an 18% increase in food intake that was reversed by the CB 1 antagonist SR141716A. ...
Alexandre Steiner – Systemic Inflammation Laboratory, St Joseph's Hospital and Medical Center, Phoenix, AR, USA
... Whereas cannabinoid-induced food consumption is reversed by rimonabant, this is not the case for the effect on mouse activity. This dose of delta(9)-tetrahydrocannabinol decreases dopamine and serotonin levels in the hippocampus, although no significant changes are found with norepinephrine (Avraham et al. 2004). ...
Article
Addiction is a chronic, recurring and complex disorder. It is characterized by anomalous behaviors that are linked to permanent or long-lasting neurobiological alterations. Furthermore, the endocannabinoid system has a crucial role in mediating neurotransmitter release as one of the main neuromodulators of the mammalian central nervous system. The purpose of the present review is to instruct readers about the functional and structural interactions between the endocannabinoid system and the main neurotransmitter systems of the central nervous system in the context of drug addiction. With this aim, we have systematically reviewed the main findings of most of the existing literature that explores cross-talk in the five brain areas that are most traditionally implicated in addiction: amygdala, prefrontal cortex, nucleus accumbens, hippocampus and ventral tegmental area (VTA). The neurotransmission systems influenced by the pharmacology of the endocannabinoid system in these brain areas, which are reviewed here, are gamma-aminobutyric acid (GABA), glutamate, the main biogenic amines (dopamine, noradrenaline and serotonin), acetylcholine and opioids. We show that all of these neurotransmitter systems can be modulated differentially in each brain area by the activation or deactivation of cannabinoid CB1 brain receptors. Specifically, most of the studies relate to the hippocampus and nucleus accumbens. Moreover, the neurotransmitter with the fewest number of related studies is acetylcholine (excepting in the hippocampus), whereas there is a large number that evaluates GABA, glutamate and dopamine. Finally, we propose a possible interpretation of the role of the endocannabinoid system in the phenomenon of addiction.
... Other agonists like 2-arachidonoyl-glycerol (2-AG) [21] and noladin ether [22] have a similar effect. It has recently been described that Δ 8 -THC, a substance with less psychoactive effects than Δ 9 -THC, may have a stronger orexigenic effect [23]. ...
Article
Full-text available
Cannabinoid system is a crucial mechanism in regulating food intake and energy metabolism. It is involved in central and peripheral mechanisms regulating such behavior, interacting with many other signaling systems with a role in metabolic regulation. Cannabinoid agonists promote food intake, and soon a cannabinoid antagonist, rimonabant, will be marketed for the treatment of obesity. It not only causes weight loss, but also alleviates metabolic syndrome. We present a review of current knowledge on this subject, along with data from our own research: genetic studies on this system in eating disorders and obesity and studies locating cannabinoid receptors in areas related to food intake. Such studies suggest cannabinoid hyperactivity in obesity, and this excessive activity may have prognostic implications.
... Williams et al. (1998) have previously reported increased consumption of normal rat chow in animals that were mildly food-deprived (removal of the regular chow for 4 h before D 9 -THC administration). Thus, within a limited, usually low, dose range, it appears that D 9 -THC (as well as D 8 -THC; see Avraham et al., 2004) can produce hyperphagia in rodents. This seems to be the case for the endogenous cannabinoids anandamide and 2-arachidonoylol glycerol (2-AG) as well (Williams and Kirkham, 1999;Hao et al., 2000;Kirkham et al., 2002). ...
Article
This study examined effects of the CB1 receptor antagonist/inverse agonist SR-141716 and the CB1 receptor agonist delta9-tetrahydrocannabinol (delta9-THC) on feeding behavior in male Sprague-Dawley rats. Rats were housed individually with free access to regular pelletized laboratory chow [after a 2 weeks handling phase, animals had access to regular chow for 21 h (Study 1) or 22 h (Study 2); high-fat powder food for 3 h in Study 1 and 2 h in Study 2, respectively], and free access to water. Animals were maintained on a reversed 12-h light/dark cycle (dark beginning at noon). Rats were habituated to this type of feeding and light/dark schedule for 3 weeks until a stable baseline for food intake was achieved. In Study 1, animals were examined after administration of delta9-THC alone (dose range 0.1-1.8 mg/kg), SR-141716 alone (dose range 0.03-0.3 mg/kg), and the two drugs combined; injections were given i.p. at the beginning of the second hour after presenting the high-fat diet and drugs were given twice weekly. There was a dose-related increase in high-fat diet intake, peaking at 0.56-1 mg/kg delta9-THC. SR-141716 alone suppressed the high-fat diet intake below control levels. A combination of 0.3 mg/kg SR-141716 and 0.56 mg/kg delta9-THC counteracted the effects on consumption of either drug alone. In Study 2, experimental rats were treated initially with 0.56 mg/kg delta9-THC for six consecutive days; controls received vehicle. Attenuation of the hyperphagia (high-fat diet) was evident after the second injection. Increasing doses of delta9-THC (1 and 1.8 mg/kg, for two and three consecutive days, respectively) did not reinstate the initial hyperphagia. In conclusion, low-to-moderate doses of delta9-THC produced hyperphagia (to a high-fat food source), which was antagonized by SR-141716. SR-141716 singly suppressed intake of the high-fat diet. Delta9-THC-induced hyperphagia dissipated rapidly upon chronic treatment; however, it is unclear whether this reflects pharmacological tolerance or the emergence of a conditioned taste aversion in Study 2.
... Indeed, oral formulations of D 9 -THC are currently used therapeutically to treat cachexia in cancer and AIDS patients (Beal et al., 1995; Jatoi et al., 2002). In rodents, D 9 -THC and D 8 -THC also increased food intake (present study; Williams et al., 1998; Koch, 2001; Avraham et al., 2004). Further, this effect was selective; that is, the dose range at which D 9 -THC produced this effect did not entirely overlap that at which it decreased locomotor activity. ...
Article
1 Marijuana's appetite-increasing effects have long been known. Recent research suggests that the CB(1) cannabinoid receptor antagonist SR141716A may suppress appetite. This study represents a further, systematic investigation of the role of CB(1) cannabinoid receptors in the pharmacological effects of cannabinoids on food intake. 2 Mice were food-restricted for 24 h and then allowed access to their regular rodent chow for 1 h. Whereas the CB(1) antagonist SR141716A dose-dependently decreased food consumption at doses that did not affect motor activity, Delta(9)-tetrahydrocannabinol (Delta(9)-THC) increased food consumption at doses that had no effect on motor activity. O-3259 and O-3257, structural analogs of SR141716A, produced effects similar to those of the parent compound. 3 Amphetamine (a known anorectic) and diazepam (a benzodiazepine and CNS depressant) decreased food consumption, but only at doses that also increased or decreased motor activity, respectively. The CB(2) cannabinoid receptor antagonist SR144528 and the nonpsychoactive cannabinoid cannabidiol did not affect food intake nor activity. 4 SR141716A decreased feeding in wild-type mice, but lacked pharmacological activity in CB(1) knockout mice; however, basal food intake was lower in CB(1) knockout mice. Amphetamine decreased feeding in both mouse genotypes. 5 These results suggest that SR141716A may affect the actions of endogenous cannabinoids in regulating appetite or that it may have effects of its own aside from antagonism of cannabinoid effects (e.g., decreased feeding behavior and locomotor stimulation). In either case, these results strongly suggest that CB(1) receptors may play a role in regulation of feeding behavior.
... We chose to examine the effects of WIN 55,212-2 and AM 251 on food intake in presatiated rats to further delineate the role of endogenous cannabinoids in energy balance. Our data represent the first attempt to directly examine the effect of cannabinoids on serotonin (5-HT) release; there are few reports in the literature examining the interactions of catecholamine and cannabinoids and the resulting effect on food intake (16) . ...
Article
Full-text available
The effect of intracerebroventricular or intraperitoneal administration of cannabinoid receptor agonist WIN 55,212-2 or inverse agonist AM 251 on food intake and extracellular levels of serotonin and acetic acid 5-hydroxy-indol from presatiated rats was studied. Compared to the vehicle-injected control, the intracerebroventricular administration of WIN 55,212-2 was associated with a significant increase in food intake, whereas the administration of AM 251 caused a significant reduction in this respect. These results were accompanied by considerable reductions or increases in serotonin and acetic acid 5-hydroxy-indol levels compared to the vehicle-injected control and the baseline values for the different experimental groups studied. Intraperitoneal administration of WIN 55,212-2 at doses of 1 and 2 mg/kg promoted hyperphagia up to 6 h after injection, whereas administration of a higher dose (5 mg/kg) significantly inhibited food intake and motor behaviour in partially satiated rats. Administration of any of the AM 251 doses studied (0.5, 1, 2, 5 mg/kg) led to a significant decrease in the amount of food ingested from 2 h after the injection, compared to the vehicle-injected control group, with the most striking effect being observed when the 5 mg/kg dose was injected.
... Otros agonistas como el 2-araquidoni- lglicerol (2-AG) (Kirkham, Williams, Fezza y Di Marzo, 2002) y el noladin eter (Avraham, Menachem, Okun, Zlotarav, Abel, Mechoulam et al. 2005) producen un efecto similar. Recientemente se ha descrito que el ∆ 8 THC, con menos efectos psicoactivos que el ∆ 9 THC, podría tener un efecto orexígeno más potente (Avraham, Ben-Shushan, Breuer, Zolotarev, Okon, Fink et al. 2004). El efecto orexígeno se observa con la administración de agonistas en centros cerebrales relacionados con la regulación de la ingesta, como el núcleo VMH (Jamshidi y Taylor, 2001); en el núcleo accumbens (NAc) (Kirkham et al. 2002 ) o en el cuarto ventrículo por la proximidad del núcleo parabraquial (Miller, Murray, Freeman y Edwards, 2004). ...
Article
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Cada vez disponemos de más información que sugiere que el sistema cannabinoide es un mecanismo crucial en la regulación de la ingesta alimentaria y en el metabolismo energético. De ahí que próximamente se vaya a comercializar un antagonista cannabinoide, el rimonabant, para su uso en obesidad que, además de una pérdida de peso, consigue una mejora del denominado síndrome metabólico, con unos cambios en el metabolismo lipídico y glucídico no observados por otros fármacos antiobesidad actualmente comercializados. Se presenta una revisión de los conocimientos actuales sobre el tema y los datos de estudios propios: estudios genéticos de dicho sistema en los trastornos de la conducta alimentaria y en obesidad y estudios de localización de receptores cannabinoides en sitios relacionados con la ingesta. Dichos estudios apoyan un estado de hiperactividad cannabinoide en la obesidad y, además, dicha hiperactividad puede constituir un factor pronóstico.
... Additionally from day 7, daily THC (0.5 mg kg − 1 ) or vehicle injections were administered for a further 8 days. A wide variety of doses of THC and related cannabinoids have been shown to increase feeding, depending on species, strain, and prior feeding state (pre-fed, fasted or ad libitum) (Avraham et al., 2004;Avraham et al., 2005;Hao et al., 2000;Rahminiwati and Nishimura, 1999;Wiley et al., 2005). However, there have been no previous studies using THC in the ABA model, nor in this strain of mouse in any paradigm. ...
Article
The activity-based anorexia (ABA) paradigm is one of the few animal models of human anorexia nervosa. We present here the translation of this approach to C57/BL6 mice, a common background for genetically modified mice, and investigate the effects of the cannabinoid agonist, Delta(9)-tetrahydrocannabinol (THC) and the endocannabinoid uptake inhibitor, OMDM-2 in this model. The ABA paradigm was optimised so that food-restricted wheel-running mice displayed anorexia, reduced body weight and disrupted activity and circadian cycles. These conditions produced a murine ABA model with a defined stage and stability to allow for pharmacological intervention. Daily Delta(9)-THC (0.5 mg/kg) decreased survival in the ABA animals but increased feeding in the survivors, OMDM-2 (3 mg/kg) increased food intake, but not sufficiently to reverse weight loss. The effects of this model on endocannabinoid tone in the brain remain to be determined. Since the endocannabinoid system may be implicated in anorexia nervosa and in view of the positive modulation by cannabinoids of some aspects of ABA in this study, further investigation of the effects of cannabinoids in ABA is warranted.
... On contrary, it was found to exhibit significant anticonvulsant, sedative and other pharmacological activities by interacting with the effects of THC. Studies have shown that CBN decreases heart rate, intestinal mobility and inhibits platelet aggregation [96,[98][99][100][101]. ...
Article
Cannabinoids are the major chemical constituents of the plant Cannabis sativa L. and are known to exhibit a wide range of pharmacological effects viz., psychotropic, analgesic, anticancer, antiinflammatory, antidiabetic, anticonvulsive, antibacterial and antifungal etc. The use of cannabis, cannabinoids and their products is restricted in several countries due to the high risk of misuse. Recently, cannabinoids have regained the interest of the researchers due to their therapeutic applications. Ever since the discovery of the cannabinoids, most of the studies carried out on the evaluation of their biological activities were limited to only preclinical levels. The quality of the preclinical data still remains only low to moderate, thus, leaving behind an uncertainty in their use for therapeutic applications. Problems associated with the solubility, stability and bioavailability of the cannabinoid drugs are also a major concern in the quality of the study. Nanoparticle based drug delivery system could be a potential method to increase the reliability of the data. While considering the immense pharmacological properties of the cannabinoids, there is an urgency to perform intensive clinical trials and to know their mechanism of action in various disease conditions, evaluate their efficacy and safety, and register them as drug candidates. This review highlights the chemistry, types and biological activities of the cannabinoids such as THC, CBD and CBN in focus with their anticancer activity, neuroprotective effect and nanoformulating the cannabinoid drugs.
... 22−28 Orally administered endocannabinoids can affect food intake and digestive processes via their effects on peristalsis 29 and catecholamines. 26,27 Anandamide (AEA) and the other N-acylethanolamines, e.g., oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and linoleoylethanolamide (LEA) (Figure 1), are formed by several enzymatic pathways from their precursors which are the Nacylated ethanolamine phospholipids. Endogenous OEA and PEA are thought to inhibit food intake by acting on receptors in the intestine. ...
Article
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ABSTRACT Newly synthesized acylethanolamide derivatives: oleoyl-L-valinolamide (1), oleoyl-D-valinolamide (2), elaidoyl-L-valinolamide (3), elaidoyl-D-valinolamide (4) stearoyl-L-valinolamide (5) and palmitoyl-L-valinolamide (6) were investigated in mice as anti-obesity compounds. Compounds 1, 2, 5, 6 significantly decreased body weight by c6.57% following 8 injections of 1mg/kg i.p. during 39 days, while 3 and 4 showed no such activity. Receptor binding indicated that no compound activated CB1, CB2, PPARα or TRPV1 receptors. Hypothalamic RT-PCR showed that mRNA expression of the anorexigenic genes POMC and CART were upregulated by 1, 2, 5 and 1, 2 respectively, while those of the orexigenic genes: NPY and CaMKK2 were downregulated by the respective compounds 1, 5, 6 and 1, 2, 5. Oleoyl-L-valinolamide (1) enhances anorectic pathways and lead to decreased glucose levels, enhanced locomotor activity and improved cognition. Effects of oleoyl-L-valinolamide (1) on weight were dose-dependent and it could be given orally. 1, 2, 4, 5 down regulated FAAH mRNA expression.
... Inhibition of AMPK activity conversely leads to hepatic gluconeogenesis, lipogenesis , and glycogen synthesis (Lim et al., 2010). Acute injections of ghrelin and cannabinoids have been shown to increase appetite in rats (Kirkham, 2003; Wren et al., 2001b) and mice (Avraham et al., 2004; Kola et al., 2008; Sun et al., 2004; Wiley et al., 2005). HU210 is a highly potent synthetic cannabinoid receptor agonist (K i values of 0.061 and 0.52 nM at cloned human CB1 and CB2 receptors respectively – data from Tocris Bioscience). ...
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Introduction: Ghrelin is a potent orexigenic brain-gut peptide with lipogenic and diabetogenic effects, possibly mediated by growth hormone secretagogue receptor (GHS-R1a). Cannabinoids also have orexigenic and lipogenic effects. AMPK is a regulator of energy homeostasis and we have previously shown that ghrelin and cannabinoids stimulate hypothalamic AMPK activity while inhibiting it in the liver and adipose tissue, suggesting that AMPK mediates both the central appetite-inducing and peripheral effects of ghrelin and cannabinoids. Aims: Using GHS-R KO mice, we investigated whether the known ghrelin receptor GHS-R1a is required for the tissue-specific effects of ghrelin on AMPK activity, and if an intact ghrelin signalling pathway is necessary for the effects of cannabinoids on AMPK activity. Methods: Wild-type and GHS-R KO mice were treated intraperitoneally with ghrelin 500 ng/g bodyweight or CB1 agonist HU210 20 ng/g and hypothalamic, hepatic and adipose AMPK activity was studied using a functional kinase assay. Results: Ghrelin and HU210 significantly stimulated hypothalamic AMPK activity in wild-type animals (mean±SEM, 122.5±5.2% and 128±11.6% of control, p<0.05) and inhibited it in liver (55.1±4.8% and 62.2±14.5%, p<0.01) and visceral fat (mesenteric fat (MF): 54.6±16% and 52.0±9.3%, p<0.05; epididymal fat (EF): 47.9±12.1% and 45.6±1.7%, p<0.05). The effects of ghrelin, and interestingly also HU210, on hypothalamic, visceral fat and liver AMPK activity were abolished in the GHS-R KO mice (hypothalamus: 107.9±7.7% and 87.4±13.3%, liver: 100.5±11.6% and 116.7±5.4%, MF: 132.1±29.9% and 107.1±32.7%, EF: 89.8±7.3% and 91.7±18.3%, p>0.05). Conclusions: Ghrelin requires GHS-R1a for its effect on hypothalamic, liver and adipose tissue AMPK activity. An intact ghrelin signalling pathway is necessary for the effects of cannabinoids on AMPK activity.
... Although the observations that marijuana stimulates appetite and food consumption are known for many years (Abel 1971;Foltin et al. 1986), the experimental evidence for CB-induced hyperphagia has been not demonstrated until more recently. In the late 1990s and early 2000s, Williams et al. (1998) showed that Δ 9 -THC exerts hyperphagic action in prefed rats and free-feeding rats (Koch 2001), a similar effect to that reported using Δ8-THC (Avraham et al. 2004). In addition, Kirkham et al. (2002) reported that AEA and 2-AG levels are elevated by after food deprivation in the limbic forebrain, whereas 2-AG is reduced in the hypothalamus during the feeding state but increased during the deprived state, which suggests a role of eCBs in motivation toward food. ...
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... Podíl ostatních kanabinoidů na omamných účincích konopí nebyl dosud uspokojivě objasněn, předpokládá se však, že průběh intoxikace do jisté míry ovlivňují, protože byly zjištěny určité rozdíly při použití konopí a čistého syntetického THC (Galal et al., 2009). Izomer THC, delta-8-THC, již v malých dávkách významně ovlivňuje příjem potravy a vede ke snížení váhy pokusných myší (Avraham et al., 2004). Kanabidiol (CBD) se rovněž vyskytuje téměř ve všech odrůdách konopí od velmi nízkých hodnot až po zhruba 95 % přítomných kanabinoidů. ...
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... Studies of repeated THC dosing have yielded complex, region-specific effects, such as increased total striatal dopamine levels in rats 60 but reduced hippocampal dopamine levels in mice 61 . Reduced dopamine metabolism was found in the medial PFC in two rat studies 60 , an effect that was not observed in the striatum or the NAc 62 . ...
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The effects of Δ9-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, are a pressing concern for global mental health. Patterns of cannabis use are changing drastically owing to legalization, the availability of synthetic analogues (commonly termed spice), cannavaping and an emphasis on the purported therapeutic effects of cannabis. Many of the reinforcing effects of THC are mediated by the dopamine system. Owing to the complexity of the cannabinoid–dopamine interactions that take place, there is conflicting evidence from human and animal studies concerning the effects of THC on the dopamine system. Acute THC administration causes increased dopamine release and neuron activity, whereas long-term use is associated with blunting of the dopamine system. Future research must examine the long-term and developmental dopaminergic effects of THC.
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The Cannabis sativa plant has been used medicinally and recreationally for thousands of years, but recently only relatively some of its constituents have been identified. There are more than 550 chemical compounds in cannabis, with more than 100 phytocannabinoids being identified, including Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD). These phytocannabinoids work by binding to the cannabinoid receptors, as well as other receptor systems. Also within cannabis are the aromatic terpenes, more than 100 of which have been identified. Cannabis and its constituents have been indicated as therapeutic compounds in numerous medical conditions, such as pain, anxiety, epilepsy, nausea and vomiting, and post-traumatic stress disorder. This chapter provides an overview of some of the biological effects of a number of the cannabinoids and terpenes, as well as discussing their known mechanisms of action and evidence of potential therapeutic effects.
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Marijuana is one of the most widely used illicit psychoactive substances in the U.S. Recently, negative perceptions of marijuana as an abused substance have been tempered somewhat by the idea that it may also have medicinal properties. Regardless of perception of marijuana, however, investigation of its active substituents and their mechanism of action led to the discovery of an endocannabinoid system that is activated by marijuana as well as by several endogenous cannabinoids, including anandamide and 2-arachidonylglycerol. In this chapter, we review the pharmacology of marijuana and discuss how its interaction with the endocannabinoid system may have implications for understanding the physiology of this system.
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Since pre-history, Cannabis sativa has been exploited for its potent and manifold pharmacological actions. Amongst the most renowned of these actions is a tendency to provoke ravenous eating. The characterization of the psychoactive principals in cannabis (exogenous cannabinoids) and, more recently, the discovery of specific brain cannabinoid receptors and their endogenous ligands (endocannabinoids) has stimulated research into the physiological roles of endocannabinoid systems. In this review, we critically discuss evidence from the literature that describe studies on animals and human subjects to support endocannabinoid involvement in the control of appetite. We describe the hyperphagic actions of the exogenous cannabinoid, Delta9-tetrahydrocannabinol, and the endogenous CB1 ligands, anandamide and 2-arachidonylglycerol, and present evidence to support a specific role of endocannabinoid systems in appetitive processes related to the incentive and reward properties of food. A case is made for more comprehensive and systematic analyses of cannabinoid actions on eating, in the anticipation of improved therapies for disorders of appetite and body weight, and a better understanding of the biopsychological processes underlying hunger.
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Arachidonylethanolamide, an arachidonic acid derivative in porcine brain, was identified in a screen for endogenous ligands for the cannabinoid receptor. The structure of this compound, which has been named "anandamide," was determined by mass spectrometry and nuclear magnetic resonance spectroscopy and was confirmed by synthesis. Anandamide inhibited the specific binding of a radiolabeled cannabinoid probe to synaptosomal membranes in a manner typical of competitive ligands and produced a concentration-dependent inhibition of the electrically evoked twitch response to the mouse vas deferens, a characteristic effect of psychotropic cannabinoids. These properties suggest that anandamide may function as a natural ligand for the cannabinoid receptor.
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Marijuana and many of its constituent cannabinoids influence the central nervous system (CNS) in a complex and dose-dependent manner. Although CNS depression and analgesia are well documented effects of the cannabinoids, the mechanisms responsible for these and other cannabinoid-induced effects are not so far known. The hydrophobic nature of these substances has suggested that cannabinoids resemble anaesthetic agents in their action, that is, they nonspecifically disrupt cellular membranes. Recent evidence, however, has supported a mechanism involving a G protein-coupled receptor found in brain and neural cell lines, and which inhibits adenylate cyclase activity in a dose-dependent, stereoselective and pertussis toxin-sensitive manner. Also, the receptor is more responsive to psychoactive cannabinoids than to non-psychoactive cannabinoids. Here we report the cloning and expression of a complementary DNA that encodes a G protein-coupled receptor with all of these properties. Its messenger RNA is found in cell lines and regions of the brain that have cannabinoid receptors. These findings suggest that this protein is involved in cannabinoid-induced CNS effects (including alterations in mood and cognition) experienced by users of marijuana.
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The effect of systemically administered delta 9-tetrahydrocannabinol (THC), the psychoactive ingredient in marijuana, on the potassium-evoked release of dopamine (DA) was examined in the neostriatum of the chloral hydrate anesthetized rat. Both in vivo electrochemical and in vivo microdialysis techniques were employed. A low dose of THC (0.5 mg/kg, i.p.) increased the time course of potassium-evoked in vivo electrochemical signals corresponding to released extracellular DA. In vivo microdialysis showed an increase in potassium-evoked DA release following 0.5 and 2.0 mg/kg doses of THC. Potassium-evoked electrochemical signals corresponding to released extracellular DA were augmented in time course following i.p. administration (5.0 mg/kg) of nomifensine, a recognized and potent catecholaminergic reuptake blocker. In addition, in vivo brain microdialysis studies of nomifensine (5.0 mg/kg i.p.) on neostriatal potassium-evoked DA release showed that DA levels were augmented in magnitude over the time course of the microdialysis. Taken together, these studies indicate that THC has a potent presynaptic augmenting effect on at least the neostriatal portions of the mesotelencephalic DA system in the rat, although the possibility that this effect could be mediated transsynaptically cannot be ruled out. Given the previous extensive evidence for an involvement of portions of the mesotelencephalic DA system in mediating the reinforcing and euphorigenic properties of many classes of abused drugs, and in mediating direct electrical brain stimulation reward, we suggest that the presently demonstrated effects of THC on forebrain dopamine function may be related to marijuana's euphorigenic properties and, thus, to its abuse potential.
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In this study, we report the isolation from canine intestines of 2-arachidonyl glycerol (2-Ara-Gl). Its structure was determined by mass spectrometry and by direct comparison with a synthetic sample. 2-Ara-Gl bound to membranes from cells transiently transfected with expression plasmids carrying DNA of either CB1 or CB2--the two cannabinoid receptors identified thus far--with Ki values of 472 +/- 55 and 1400 +/- 172 nM, respectively. In the presence of forskolin, 2-Ara-Gl inhibited adenylate cyclase in isolated mouse spleen cells, at the potency level of delta 9-tetrahydrocannabinol (delta 9-THC). Upon intravenous administration to mice, 2-Ara-Gl caused the typical tetrad of effects produced by THC: antinociception, immobility, reduction of spontaneous activity, and lowering of the rectal temperature. 2-Ara-Gl also shares the ability of delta 9-THC to inhibit electrically evoked contractions of mouse isolated vasa deferentia; however, it was less potent than delta 9-THC.
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The major active ingredient of marijuana, delta 9-tetrahydrocannabinol (delta 9-THC), has been used as a psychoactive agent for thousands of years. Marijuana, and delta 9-THC, also exert a wide range of other effects including analgesia, anti-inflammation, immunosuppression, anticonvulsion, alleviation of intraocular pressure in glaucoma, and attenuation of vomiting. The clinical application of cannabinoids has, however, been limited by their psychoactive effects, and this has led to interest in the biochemical bases of their action. Progress stemmed initially from the synthesis of potent derivatives of delta 9-THC, and more recently from the cloning of a gene encoding a G-protein-coupled receptor for cannabinoids. This receptor is expressed in the brain but not in the periphery, except for a low level in testes. It has been proposed that the nonpsychoactive effects of cannabinoids are either mediated centrally or through direct interaction with other, non-receptor proteins. Here we report the cloning of a receptor for cannabinoids that is not expressed in the brain but rather in macrophages in the marginal zone of spleen.
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Two subtypes of cannabinoid receptors (CB-R) have been identified to date, the CB1-R, essentially located in the CNS, and the CB2-R, found at the periphery. Δ9-Tetrahydrocannabinol (Δ9-THC) is the major active component of Cannabis sativa, anandamide is a putative endogenous ligand, WIN 55,212-2 and CP 55,940, HU-210, are potent synthetic ligands, all are CB1/CB2 non-selective agonists. In animals, they produce a characteristic combination of four symptoms, hypothermia, analgesia, hypoactivity and catalepsy, all reversed by the selective CB1-R antagonist, SR 141716. Anandamide exhibits several differences, compared to other agonists since hypothermia, analgesia and catalepsy are not reversed by SR 141716. Cannabinoid-related processes seem also involved in cognition, memory, anxiety, control of appetite, emesis, intraocular pressure, inflammatory and immune responses. Intriguingly, although Cannabis is widely used as recreational drug in humans, only a few studies revealed an appetitive potential of cannabimimetics in animals, and evidence for aversive effects of Δ9-THC and other agonists is more readily obtained in a variety of tests. SR 141716 impairs the perception of the appetitive value of positive reinforcers (food, cocaine, morphine), and reduces the motivation for sucrose, beer and alcohol consumption, indicating that positive incentive and/or motivational processes could be under a permissive control of CB1-related mechanisms. There is little evidence that cannabinoid systems are activated under basal conditions. However, a tonic involvement of a CB1-mediated cannabinoid link has been demonstrated, notably in animals suffering from chronic pain, faced with anxiogenic stimuli or highly motivational reinforcers. CB1-related mechanisms might also exert a tonic control on cognitive processes.
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• Patients with anorexia nervosa have disturbances of mood, appetite, and neuroendocrine function. Central nervous system monoamine pathways modulate these systems, and alterations in function of these systems may occur in anorexia nervosa. Because monoamine metabolism can be influenced by nutritional intake, we studied anorectics before and at intervals after correction of weight loss. Underweight anorectics had a 30% decrease in CSF homovanillic acid level and a 20% decrease in CSF 5-hydroxyindoleacetic acid concentration; these values returned to normal shortly after weight recovery. The CSF level of norepinephrine (NE) in underweight anorectics and in these patients a few weeks after weight restoration was similar to that in normal subjects. Long-term weight-recovered (20 ± 7 months) anorectics, however, had a 50% decrease in CSF NE level compared with that of controls. Underweight anorectics have state-associated disturbances in dopamine and serotonin metabolism. Changes in NE metabolism are more complex and state independent. These abnormalities in neurotransmitter metabolism are part of the neurobiological syndrome of anorexia nervosa and may contribute to the characteristic changes in mood, behavior, and neuroendocrine function.
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[DELTA]9-Tetrahydrocannabinol ([DELTA]9-THC), the most prominent psychoactive cannabinoid in Cannabis sativa L. (marijuana), has been reported to have properties of appetite stimulation, promotion of weight gain, and antiemetic efficacy in selected patient populations. In this 4-week, double-blind, crossover study, 11 female patients with primary anorexia nervosa (PAN) were evaluated on [DELTA]9-THC and on an active placebo, diazepam. All patients participated in a standardized behavior modification treatment program. The following data were obtained: (1) daily weight, (2) daily caloric intake, and (3) weekly psychiatric assessments. The two groups were comparable on all measures at baseline except for two items on the behavioral rating scales. The only significant differences found between the changes over time on [DELTA]9-THC versus diazepam were more pathology on [DELTA]9-THC for somatization, interpersonal sensitivity, and sleep disturbance. Three patients experienced severe dysphoric reactions consisting of paranoid ideation and feelings of loss of control during [DELTA]9-THC administration. One week after the study ended, each subject was given the highest dose level of [DELTA]8-THC achieved in the study, and periodic blood samples were obtained coincident with self-rated "subjective high" assessments and pulse measurements. Quantitative analyses of these samples indicated peak times of 1 to 5 hours postdose for [DELTA]9- THC and for its primary active metabolite, 11-hydroxy-THC, which generally coincided with peak times for "subjective high" and pulse rate. The results of this clinical investigation suggest that [DELTA]9-THC is not efficacious, in short-term administration, in the treatment of primary anorexia nervosa and is associated with significant psychic disturbance in some PAN patients.
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Tested 24 male albino rats on an 8-arm maze in a paradigm of sampling with replacement from a known set of items until the entire set was sampled. Exps I-III demonstrate that Ss performed efficiently, choosing an average of more than 7 different arms within the 1st 8 choices, and did not utilize intramaze cues or consistent chains of responses in solving the task. Exps IV-VI examined some characteristics of Ss' memory storage. There was a small but reliable recency effect with the likelihood of a repetition error increasing with the number of choices since the initial instance. This performance decrement was due to interference from choices rather than just to the passage of time. No evidence was found for a primary effect. The data also suggest that there was no tendency to generalize among spatially adjacent arms. Results are discussed in terms of the memory processes involved in this task and human serial learning. (27 ref) (PsycINFO Database Record (c) 2012 APA, all rights reserved)
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The existence of an endogenous cannabinoid system was demonstrated conclusively with the discovery of endogenous brain constituents capable of activating the cannabinoid receptors functionally. These compounds are synthesized by neuronal cells and inactivated through re-uptake and enzymatic hydrolysis by both neurons and astrocytes. In analogy with the endorphins they can be referred to as endocannabinoids. Apart from the identification of their metabolic pathways, research carried out in the past six years has focused on the possible cellular and molecular targets for the actions of endocannabinoids. These studies have confirmed a similarity between the endocannabinoids and the psychoactive substance in marijuana, Δ9(−)-tetrahydrocannabinol, and have suggested a role for endocannabinoids in the modulation of neurotransmitter action and release.
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A reproducible behavior correlate of aging in rodents is deficient performance of inhibitory avoidance memory tasks. Impaired performance has been attributed, in part, to age-related changes in brain norepinephrine (NE) system function. To determine whether supplemenation of brain NE can ameliorate avoidanace deficits in aged animals, we transplanted noradrenergic locus coeruleus neurons from fetal rat donors into the cerebral ventricle of 24-month-old male F344 rats. Aged rats that received NE-containing grafts exhibited significant improvement of inhibitory avoidance retention performance compared to both unoperated aged animals and aged animals that received grafts of cerebellar tissue. Improved behavioral performance was prevented by pretreatment of NE graft recipients with the β-adrenergic receptor blocking agent, propranolol, and was mimicked by chronic intraventricular infusion of NE. Taken together, our findings support the view that age-related declines in brain NE content contribute to age-related deficits in inhibitory avoidance performance, and that NE replacement therapy can improve performance of this task in aged rats.
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In this study, we report the isolation from canine intestines of 2-arachidonyl glycerol (2-Ara-Gl). Its structure was determined by mass spectrometry and by direct comparison with a synthetic sample. 2-Ara-Gl bound to membranes from cells transiently transfected with expression plasmids carrying DNA of either CB1 or CB2—the two cannabinoid receptors identified thus far—with Ki values of 472 ± 55 and 1400 ± 172 nM, respectively. In the presence of forskolin, 2-Ara-Gl inhibited adenylate cyclase in isolated mouse spleen cells, at the potency level of Δ9-tetrahydrocannabinol (Δ9-THC). Upon intravenous administration to mice, 2-Ara-Gl caused the typical tetrad of effects produced by THC: antinociception, immobility, reduction of spontaneous activity, and lowering of the rectal temperature. 2-Ara-Gl also shares the ability of Δ9-THC to inhibit electrically evoked contractions of mouse isolated vasa deferentia; however, it was less potent than Δ9-THC.
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The effect of the cannabinoid CB1 receptor antagonist, SR 141716, on food intake and body weight was assessed in adult, non-obese Wistar rats. The daily administration of SR 141716 (2.5 and 10 mg/kg; i.p.) reduced dose-dependently both food intake and body weight. Tolerance to the anorectic effect developed within 5 days; in contrast, body weight in SR 141716-treated rats remained markedly below that of vehicle-treated rats throughout the entire treatment period (14 days). The results suggest that brain cannabinoid receptors are involved in the regulation of appetite and body weight.
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This investigation reports the possible role of the endocannabinoid anandamide on modulating the behavioral and neurochemical consequences of semi-starvation. We studied the effect of very low dose anandamide (0.001 mg/kg) administration on food intake, cognitive function and catecholaminergic and serotonergic pathways in two murine brain areas concerned with appetite (hypothalamus) and learning (hippocampus), and the peripheral corticosterone response to the stress of 40% diet restriction. Anandamide-treated mice consumed 44% more food (P<0.05) during 1 week of 2.5-h feeding each day. In the hypothalamus, there were significantly increased concentrations of norepinephrine (P<0.01), dopamine (P<0.05) and 5-hydroxytryptamine (5-HT) (P<0.001). In the hippocampus, anandamide increased significantly norepinephrine and dopamine, but decreased 5-HT (all at P<0.001). Diet restriction was accompanied in both areas by a significant decrease in all neurotransmitter concentrations that were partially restored by anandamide for dopamine and 5-HT, but not for norepinephrine. In animals on diet restriction, anandamide significantly improved impaired maze performance. Norepinephrine turnover and plasma corticosterone levels were also raised significantly by anandamide. The fact that low dose anandamide improved food intake, cognitive function and reversed some of the neurotransmitter changes caused by diet restriction, might have implications for the treatment of cachexia associated with acquired immunodeficiency syndrome (AIDS) and cancer, for mood changes sometimes associated with dieting, and in the extreme case, of patients with anorexia.
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The involvement of cannabinoid processes in positive reinforcement was studied using an unbiased, one-compartment, conditioned place preference (CPP) procedure in rats. This was achieved by examining the ability of the selective antagonist of the CB1 cannabinoid receptor subtype, SR 141716, to counteract the CPP supported by classical reinforcers. The acquisition of CPP induced by cocaine (2 mg/kg), morphine (4 mg/kg) and food (standard chow and sucrose pellets) was dose-dependently blocked by pre-pairing administration of SR 141716 (0.03-3 mg/kg). However, SR 141716 (up to 10 mg/kg) did not significantly counteract the expression of cocaine-induced CPP. On the other hand, the synthetic CB receptor agonist, WIN 55212-2 (0.3-1 mg/kg), established a robust place aversion (CPA), as already described with other agonists, and CPP was never observed, even at 100-fold lower doses. The aversive effect of WIN 55212-2 was reversed by SR 141716 (0.3-1 mg/kg), suggesting that it was accounted for by the stimulation of CB1 receptors. These findings indicate that, on their own, CB receptor agonists are unable to generate the processes necessary to induce a pleasurable state in animals, as assessed in place conditioning procedures. Nevertheless, a cannabinoid link may be involved in the neurobiological events, allowing the perception of the rewarding value of various kinds of reinforcers. However, a permanent endogenous cannabinoid tone seems unlikely to be necessary to ensure the organism a basal hedonic level since, given alone, SR 141716 supported neither CPP nor CPA.
Article
The determination and characterization of a cannabinoid receptor from brain are reported. A biologically active bicyclic cannabinoid analgetic CP-55,940 was tritium-labeled to high specific activity. Conditions for binding to rat brain P2 membranes and synaptosomes were established. The pH optimum was between 7 and 8, and specific binding could be eliminated by heating the membranes to 60 degrees. Binding to the P2 membranes was linear within the range of 10 to 50 micrograms of protein/ml. Specific binding (defined as total binding displaced by 1 microM delta 9-tetrahydrocannabinol (delta 9-THC) or 100 nM desacetyllevonantradol) was saturable. The Kd determined from Scatchard analysis was 133 pM, and the Bmax for rat cortical P2 membranes was 1.85 pmol/mg of protein. The Hill coefficient for [3H]CP-55,940 approximated 1, indicating that, under the conditions of assay, a single class of binding sites was determined that did not exhibit cooperativity. The binding was rapid (kon approximately 2.6 x 10(-4) pM-1 min-1) and reversible (Koff approximately 0.016 min-1) and (koff' greater than 0.06 min-1). The two Kd values estimated from the kinetic constants approximately 55 pM and exceeded 200 pM, respectively. The binding of the agonist ligand [3H]CP-55,940 was decreased by the nonhydrolyzable GTP analog guanylylimidodiphosphate. The guanine nucleotide induced a more rapid dissociation of the ligand from the binding site, consistent with an allosteric regulation of the putative receptor by a G protein. The binding was also sensitive to MgCl2 and CaCl2. Binding of [3H]CP-55,940 was displaced by cannabinoid drugs in the following order of potency: CP-55,940 greater than or equal to desacetyllevonantradol greater than 11-OH-delta 9-THC = delta 9-THC greater than cannabinol. Cannabidiol and cannabigerol displaced [3H]CP-55,940 by less than 50% at 1 microM concentrations. The (-)-isomer of CP-55,940 displaced with 50-fold greater potency than the (+)-isomer. This pharmacology is comparable to both the inhibition of adenylate cyclase in vitro and the analgetic activity of these compounds in vivo. The criteria for a high affinity, stereoselective, pharmacologically distinct cannabinoid receptor in brain tissue have been fulfilled.
Article
The activity of tyrosine hydroxylase (TH), the rate-limiting enzyme in norepinephrine synthesis, was determined in the mediobasal hypothalamus of adult male rats during acute and semistarvation. 3,4-Dihydroxyphenylalanine (DOPA) formed by TH was measured using high-performance liquid chromatography (HPLC). Acute starvation, as well as 3 weeks of semistarvation on a high-protein low-carbohydrate diet (CST PR) reduced TH activity significantly. Three weeks of a low-protein high-carbohydrate diet (CST KH) did not affect TH activity. While maximal velocity (Vmax) is significantly diminished in acute starvation and in semistarvation with a high-protein low-carbohydrate diet, Kd-values for tyrosine were not changed. These results suggest that TH activity in the brain contributes to decreased norepinephrine (NE) turnover in starvation.
Article
Adult female rats received daily oral doses of delta 9-tetrahydrocannabinol (delta 9-THC), delta 8-THC and cannabidiol (CBD) throughout gestation and lactation. The offspring were sacrificed at various ages and tissue samples of cerebral cortex and striatum were assayed for alpha 1-adrenergic and D2-dopaminergic receptors, respectively. In addition, tyrosine hydroxylase activity was determined in the striatum. The Kd for ligand binding to alpha 1 receptors in the cerebral cortex was significantly increased in 10-day-old offspring exposed to CBD. Significant increases in the Bmax of these receptors occurred at 20 days of age following perinatal exposure to delta 9-THC or delta 8-THC. Exposure to CBD increased the Kd of D2 receptors in the striatum of 10 and 20-day-old offspring compared to control. There were no significant treatment effects on the Bmax of D2 receptors in the striatum at any age. Tyrosine hydroxylase activity was significantly decreased only at 60 days of age in offspring exposed to delta 8-THC or CBD. These results differ from those previously reported with a crude marihuana extract, suggesting that changes in the development of brain catecholamine mechanisms resulting from perinatal exposure to marihuana extracts may be due to an additional constituent of the extract, interactions between specific cannabinoids or other unknown factors.
Article
The effects of chronic administration of delta 9-tetrahydrocannabinol (delta 9-THC) on the plasma and brain catecholamine (CA) levels were measured using high performance liquid chromatography-electrochemical detection (LC-EC) system. Intact male rats were injected daily with vehicle (50 microliter oil) or with delta 9-THC (3 mg/kg body wt) over a period of 25 days. Trunk plasma and tissue from preoptic area (POA) and mediobasal hypothalamus (MBH) were collected and catecholamine levels were detected by LC-EC system coupled to an electronic integrator. Alumina extract of tissue and plasma samples, spiked with the internal standard (dihydroxybenzylamine), were injected into the LC-EC system; the CA were chromatographed and eluted within 12 minutes using sodium phosphate buffer as the mobile phase. delta 9-THC treatment resulted in a significant decrease in plasma and MBH levels of norepinephrine (NE), epinephrine (E), POA levels of NE; and significant increases in MBH levels of dopamine (DA) and dihydroxyphenylacetic acid (DOPAC). Our study indicates for the first time that delta 9-THC treatment significantly alters not only the POA and MBH CA levels, but also the plasma CA levels.
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Repeated oral administration of the non-psychoactive cannabinol (CBN; 5 or 50 mg/kg) significantly reduced the concentration of norepinephrine (NE) in median eminence and greatly reduced NE levels 1 and 2 hrs after administration of alpha-methylparatyrosine (alpha-MPT). The levels of dopamine (DA) in median eminence were significantly different, as indicated by the differences in slopes obtained in CBN- treated and control mice before and after alpha-MPT. Plasma levels of luteinizing hormone (LH) were significantly reduced in CBN-exposed mice before alpha-MPT, elevated at 1 hr post-injection, but were also reduced 2 hrs post-injection at 50 mg/kg CBN. Follicle-stimulating hormone (FSH) levels were increased at 1 hr post-alpha-MPT in mice receiving 50 mg/kg CBN. Oral administration of CBN at 50 mg/kg for 4 days enhanced testicular testosterone (T) production in response to intratesticular in vivo injection of 2.5 or 25 mIU human chorionic gonadotropin (hCG). A single oral dose of the psychoactive delta 9-tetrahydrocannabinol (THC) enhanced the production of T 15 min after intratesticular LH (10 ng) injection. However, at 45 or 60 min post-THC treatment, the response to LH was significantly attenuated. These studies demonstrate that both psychoactive and non-psychoactive components of marihuana alter testicular responsiveness to gonadotropins in vivo. These effects may be biphasic, involving stimulation and inhibition of responsiveness, and appear to be correlated with alterations in plasma LH levels. Alterations in plasma gonadotropins may be mediated by cannabinoid effects on catecholamine concentrations in median eminence and THC-induced alterations in testicular responsiveness to gonadotropin probably also involve direct effects of THC at the gonadal level.
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The present study was designed to examine the influence of delta 9-tetrahydrocannabinol (THC) on the central dopaminergic system using circling behavior. THC 5 mg/kg i.p. produced ipsilateral circling in rats with unilateral nigral lesion by 6-hydroxy-dopamine. THC-induced ipsilateral circling was completely antagonized by 0.2 mg/kg of haloperidol. These findings suggest that THC may cause a presynaptic stimulation of nigrostriatal dopaminergic neurons.
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Studies performed during the past decade have shown that the rates at which certain neurons produce and release their neurotransmitters can be affected by precursor availability, and thus by the changes in plasma composition that occur after ingestion of the precursors in purified form or as constituents of foods. Thus, tryptophan administration or a plasma ratio of tryptophan to other large neutral amino acids, thereby raising brain tryptophan levels, increasing the substrate saturation of tryptophan hydroxylase, and accelerating the synthesis and release of serotonin. Tyrosine administration or a high-protein meal similarly elevates brain tyrosine and can accelerate catecholamine synthesis in the CNS and sympathoadrenal cells, while the consumption of lecithin or choline increases brain choline levels and neuronal acetylcholine synthesis. The physiologic and biochemical mechanisms that must exist in order for nutrient consumption to affect neurotransmitte synthesis have been characterized and include: 1) the lack of significant feedback control of plasma levels of the precursor; 2) the lack of a real "bloodbrain barrier" for the precursor, i.e. the ability of the plasma level of the precursor to control its influx into, or efflux from, the CNS; 3) the existence of a low-affinity (and thus unsaturated) transport system mediating the flux of the precursor between blood and brain; 4) low-affinity kinetics for the enzyme that initiates the conversion of the precursor to the transmitter; and, 5) the lack of end-product inhibition of the enzyme, in vivo, by its ultimate product, the neurotransmitter. The extent to which neurotransmitter synthesis in any particular aminergic neuron happens to be affected by changes in the availability of its precursor probably varies directly with the neuron's firing frequency. This relationship allows precursor administration to produce selective physiologic effects by enhancing neurotransmitter release from some but not all of the neurons potentially capable of utilizing the precursor for this purpose. It also allows the investigator to predict when administering the precursor might be useful for amplifying a physiologic process, or for treating a pathologic state. (for example, tyrosine administration raises blood pressure in hypotensive rats, lowers it in hypertensive animals, and has little effect on blood pressure in normotensive animals; the elevation in blood pressure probably reflects enhanced catecholamine release from sympathoadrenal cells, while the reduction in hypertensive animals probably results from increased catecholamine release within the brain-stem.) Such predictions are now being tested clinically in many institution. Available evidence suggests that lecithin or cholie administration can diminish the frequency of abnormal movements in patients with tardive dyskinesia...
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Patients with anorexia nervosa have disturbances of mood, appetite, and neuroendocrine function. Central nervous system monoamine pathways modulate these systems, and alterations in function of these systems may occur in anorexia nervosa. Because monoamine metabolism can be influenced by nutritional intake, we studied anorectics before and at intervals after correction of weight loss. Underweight anorectics had a 30% decrease in CSF homovanillic acid level and a 20% decrease in CSF 5-hydroxyindoleacetic acid concentration; these values returned to normal shortly after weight recovery. The CSF level of norepinephrine (NE) in underweight anorectics and in these patients a few weeks after weight restoration was similar to that in normal subjects. Long-term weight-recovered (20 +/- 7 months) anorectics, however, had a 50% decrease in CSF NE level compared with that of controls. Underweight anorectics have state-associated disturbances in dopamine and serotonin metabolism. Changes in NE metabolism are more complex and state independent. These abnormalities in neurotransmitter metabolism are part of the neurobiological syndrome of anorexia nervosa and may contribute to the characteristic changes in mood, behavior, and neuroendocrine function.
Article
CSF tyrosine, tryptophan, 5-hydroxyindoleacetic acid, 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), gamma-aminobutyric acid, choline, and calcium were compared in 33 anorexic and 14 normal women. The only significant difference between groups was a lower tyrosine level in the anorexic patients; their MHPG level was nonsignificantly higher. No significant group differences in body weight or depressive subgroup were found. HVA levels were positively related to body weight, and choline was negatively correlated with anorexia severity. The role of tyrosine requires further research, but these findings do suggest that HVA and choline increase with some recovery measures and MHPG is increased with this illness.
Article
The effects of delta 9-tetrahydrocannabinol (THC) on the conversion of [3H]tyrosine (TYR) to [3H]dopamine (DA) and [3H]norepinephrine (NE) by mouse brain synaptosomes were studied. The active uptake of TYR and its conversion to DA and NE were found to be concentrated in a synaptosomal subfraction prepared by using differential and density gradient centrifugation. Therefore, drug studies were performed by using the less pure P2 fraction. THC was administered in vitro by using a polyvinylpyrrolidone vehicle. DA synthesis was examined both in synaptosomes prepared from whole brain and from corpus striatum. THC produced increases in the conversion of TYR to DA in both preparations. Synthesis was stimulated maximally by 10 microns THC in both preparations. Higher concentrations produced either no further increase (whole brain) or a decrease in the synthesis of DA. NE synthesis was measured in synaptosomes prepared from whole brain and from brainstem. A concentration-dependent biphasic response was observed in both preparations. Peak increases in NE synthesis were observed with a 10 micron concentration of THC in synaptosomes from whole brain and a 3 micro concentration in the brainstem. THC also inhibited the active uptake of TYR into synaptosomes in all preparations studied. The lC50 in whole brain was 12.2 microns. The decrease in precursor uptake may be the cause of the decreased DA and NE synthesis observed at the higher concentrations of THC. The data from these studies suggest that delta 9-THC can have a direct effect upon catecholamine-containing neurons in the brain.
Article
Δ9-Tetrahydrocannabinol (Δ9-THC), the most prominent psychoactive cannabinoid in Cannabis sativa L. (marijuana), has been reported to have properties of appetite stimulation, promotion of weight gain, and antiemetic efficacy in selected patient populations. In this 4-week, double-blind crossover study, 11 female patients with primary anorexia nervosa (PAN) were evaluated on Δ9-THC and on an active placebo, diazepam. All patients participated in a standardized behavior modification treatment program. The following data were obtained daily weight, daily caloric intake, and weekly psychiatric assessments. The two groups were comparable on all measures at baseline except for two items on the behavioral rating scales. The only significant differences found between the changes over time on Δ9-THC versus diazepam were more pathology on Δ9-THC for somatization, interpersonal sensitivity, and sleep disturbance. Three patients experienced severe dysphoric reactions consisting of paranoid ideation and feelings of loss of control during Δ0-THC administration. One week after the study ended, each subject was given the highest dose level of Δ9-THC achieved in the study, and periodic blood samples were obtained coincident with self-rated 'subjective high' assessments and pulse measurements. Quantitative analyses of these samples indicated peak times of 1 to 5 hours postdose for Δ9-THC and for its primary active metabolite, 11-hydroxy-THC, which generally coincided with peak times for 'subjective high' and pulse rate. The results of this clinical investigation suggest that Δ9-THC is not efficacious, in short-term adinistration, in the treatment of primary anorexia nervosa and is associated with significant psychic disturbance in some PAN patients.
Article
In vitro effects of delta 9-tetrahydrocannabinol (delta 9-THC), delta 8-tetrahydrocannabinol (delta 8-THC), cannabinol (CBN) and cannabidiol (CBD) have been studied on the uptake and release of 3H-labeled dopamine (DA) and norepinephrine (NE) in the synaptosomal preparation of rat brain corpus striatum and hypothalamus. The uptake of both DA and NE in these two regions was stimulated at low concentrations of delta 9-THC (1 x 10(-7) and 2 x 10(-7) M) and delta 8-THC (5 x 10(-9) and 1 x 10(-8) M), whereas at higher concentrations (1 x 10(-5) and 1 x 10(-4) M) both delta 9-THC and its delta 8-isomer inhibited the uptake of DA and NE. Similarly, the release of DA and NE from the preloaded synaptosomes of these two brain regions were inhibited at low concentrations of delta 9-THC (1 x 10(-7) M) and delta 8-THC (1 x 10(-8) M) and stimulated at high concentrations of both isomers (1 x 10(-5) and 1 x 10(-4) M). High concentrations of both CBN and CBD were needed to produce only an inhibitory effect on the uptake and the stimulation on the release of DA and NE in synaptosomes of the two brain regions. No significant effect was found at lower concentrations of CBN and CBD. These results demonstrate that 1) delta 9- and delta 8-THC, but not CBN and CBD, produce a biphasic effect on the uptake and release of DA and NE in the corpus striatum and hypothalamic regions of brain and 2) delta 8-THC is more potent than delta 9-THC on both uptake and release of DA and NE in these two brain regions.
Article
The purpose of the present study was to investigate the disruptive effects of cannabinoids on working memory as assessed in the eight-arm radial-maze. Systemic administration of delta 9-THC, WIN-55,212-2, and CP-55,940 increased the number of errors committed in the radial-maze. CP-55,940 was the most potent cannabinoid in impairing memory (ED50 = 0.13 mg/kg). delta 9-THC and WIN-55,212-2 disrupted maze-choice accuracy at equipotent doses (ED50 values = 2.1 and 2.2 mg/kg, respectively). In addition, systemic administration of each of these agents retarded completion time. Whereas the doses of delta 9-THC and CP-55,940 required to retard maze performance were higher than those needed to increase error numbers, WIN-55,212-2 was equipotent in both of these measures. On the other hand, neither anandamide, the putative endogenous cannabinoid ligand, nor cannabidiol, an inactive naturally occurring cannabinoid, had any apparent effects on memory. A second aim of this study was to elucidate the neuroanatomical substrates mediating the disruptive effects of cannabinoids on memory. Intrahippocampal injections of CP-55,940 impaired maze performance in a dose-dependent manner (ED50 = 8 micrograms/rat), but did not retard the amount of time required to complete the maze. The effects of intrahippocampal CP-55,940 were apparently specific to cognition because no other cannabinoid pharmacological effects (e.g., antinociception, hypothermia, and catalepsy) were detected. This dissociation between choice accuracy in the radial-maze and other cannabinoid pharmacological effects suggests that the working memory deficits produced by cannabinoids may be mediated by cannabinoid receptors in the hippocampus.
Article
The present study has been designed to test whether the recently described endogenous ligand for the cannabinoid receptor, arachidonylethanolamide, termed anandamide, can mimic the effects produced by exogenous cannabinoids on motor behavior and to test possible neurochemical substrates for this potential effect. To this end, adult male rats were submitted to an acute i.p. injection of anandamide, delta 9-tetrahydrocannabinol (THC) or vehicle. Animals were behaviorally tested ten minutes after injection of the drug and, then, sacrificed and their brains used for dopaminergic analyses. Ambulation was not significantly affected by the treatment with either THC or anandamide, but a very pronounced increase was observed in the time spent in inactivity in rats treated with either THC or anandamide. This was accompanied by a marked decrease in the frequency of spontaneous non-ambulatory activities, such as grooming and rearing, although only the administration of THC decreased shaking behavior. The anandamide-induced decrease in grooming was dose-dependent, but the decrease in rearing was higher with the dose of 3 mg/kg than with the dose of 10 mg/kg. The administration of anandamide also caused a dose-dependent decrease in the activity of tyrosine hydroxylase and in the ratio between the number of D1 and D2 receptors in the striatum. Moreover, the administration of 3 mg/kg of anandamide significantly decreased the contents of dopamine and L-3,4-dihydroxyphenylacetic acid in the striatum although lesser and higher doses were less effective. THC only tended to decrease these parameters. No changes were seen in dopaminergic activity in the limbic forebrain after either cannabimimetics. In summary, anandamide, as well as THC, decreases motor behavior. This effect was paralleled by reduction in the activity of nigrostriatal dopaminergic neurons. However, subtle differences in the behavioral and neurochemical effects between anandamide and THC could be observed.
Article
1. THC, PCP, and MK-801 increased DOPAC in rat olfactory tubercle and prefrontal cortex without affecting DA levels, suggesting increased DA release. 2. Effects on NE and MHPG were not evident. 3. These two classes of drugs can effect dopaminergic systems independently of noradrenergic systems.
Article
Cannabinoid consumption has been reported to affect several neurotransmitter systems and their related behaviors. The present study has been designed to examine cannabinoid effects on certain behaviors, which have been currently located in the limbic forebrain, in parallel to their effects on mesolimbic dopaminergic neurons. To this end, male rats treated with an oral dose of delta 9-tetrahydrocannabinol (THC) or vehicle were used 1 h after treatment for two different behavioral tests or neurochemical analyses of mesolimbic dopaminergic activity. Treatments, behavioral tests and sacrifice were performed in the dark phase of photoperiod because it corresponds to the maximum behavioral expression in the rat. Behavioral tests were a dark-light emergence test, which allows measurements of emotional reactivity, and a socio-sexual approach behavior test, which allows measurements of sexual motivation and also of spontaneous and stereotypic activities. Neurochemical analyses consisted of measurements of dopamine (DA) and L-3,4-dihydroxyphenylacetic acid (DOPAC) contents, tyrosine hydroxylase activity, in vitro DA release and number and affinity of D1 receptors in the limbic forebrain. Results were as follows. THC exposure markedly altered the pattern executed by the animals in both tests. Concretely, THC-exposed animals exhibited a low number of visits to an incentive female in addition to high time spent in the vicinity of an incentive male, both observed in the socio-sexual approach behavior test, and an increased emergence latency to go out of a dark compartment in the dark-light emergence test. However, the fact that THC also decreased spontaneous activity and the frequency of rearing and self-grooming behaviors, in addition to the observations of either low total number of visits to both incentive sexual areas or high escape latency to go out of a light compartment, when the animal is placed in this compartment, also suggest the possible existence of an accompanying motor deficit. These behavioral effects were accompanied by increases in DA and DOPAC contents and in D1 receptor density in the limbic forebrain and to a slight decrease in the pattern of K(+)-evoked DA release in vitro from perifused limbic fragments, with no changes in the remaining neurochemical parameters. Collectively, these results allow us to conclude that acute THC markedly altered the behavioral pattern executed by the animals in a socio-sexual approach behavior test and in a dark-light emergence test, presumably indicating loss of sexual motivation and increased emotionality, although also accompanied by motor deficiencies.(ABSTRACT TRUNCATED AT 400 WORDS)
Article
Exposure to cannabinoids has been reported to affect several neurotransmitter systems and their related behaviors. The present study has been designed to further explore the effects of cannabinoids on motor behavior and test the involvement of nigrostriatal dopaminergic neurotransmission and other neurotransmitters as possible neurochemical targets for these cannabinoid effects. Male rats treated with an oral dose of delta 9-tetrahydrocannabinol (THC), the main psychoactive ingredient of cannabinoid derivatives, or vehicle were used 1 h after treatment for analyses of spontaneous motor and stereotypic activities together with neurochemical analyses of the nigrostriatal dopaminergic activity. Treatments and analyses were performed in the dark phase of photoperiod because it corresponds to the maximum behavioral expression in the rat. Neurochemical analyses were measurements of presynaptic activity--dopamine (DA) and L-3,4-dihydroxyphenylacetic acid (DOPAC) contents, tyrosine hydroxylase (TH) activity, and in vitro DA release--and postsynaptic sensitivity--number and affinity of D1 and D2 receptors--in the striatum. In addition, measurements of 5-hydroxytryptamine (5-HT) and 5-hydroxyindolacetic acid (5-HIAA) contents were also performed to evaluate serotoninergic activity in the striatum. An oral dose of THC produced a loss of spontaneous motor activity, measured in both actimeter and open-field test, and a decrease in the frequency of several stereotypic behaviors, such as rearing and self-grooming. This decrease was correlated to a low number of D1-dopaminergic receptors in the striatum, although neither DA and DOPAC contents nor TH activity and D2 receptors were altered.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
Rats fed on a restricted feeding (RF) schedule of 4 h day-1 to produce a 15-20% reduction in body weight were killed before (starved) and after (fed) the presentation of food on the sixth day to compare 5-hydroxytryptamine (5-HT; serotonin) metabolism and synthesis rate in the hypothalamus with freely feeding (FF) controls. The RF rats showed lower 5-HT concentration and synthesis rate than FF controls. Restricted feeding did not decrease tryptophan concentration in the hypothalamus. However, RF-fed rats had lower tryptophan concentration than RF starved rats. 5-HIAA concentration was comparable in RF fed rats and FF controls but higher in RF starved rats. Possible implications of the findings in the pathogenesis of the food deprivation/starvation-related disease anorexia nervosa are discussed.
Article
We have investigated the effect of tyrosine administration on the cognitive and neurochemical alterations caused by diet restriction (DR) in mice, as a possible model for some of the behavioral symptoms of patients with anorexia nervosa. Young female mice were fed to 100, 60, and 40% of the calculated daily nutritional requirements for a period of up to 18 days. Cognitive function was evaluated using a modified eight-arm maze with water as a reward. Animals fed to 60% of controls showed significantly improved maze performance while this was impaired in animals on DR to 40%. However, in these animals, injections of tyrosine (100 mg/kg/day) restored performance. Improved maze performance in the 60% DR and 40% DR + tyrosine animals was related to increased beta:alpha tone in the hippocampus- an area, together with the septum, responsible for spatial learning. This was associated with changes in alpha- and beta-receptor density (Bmax), without affecting affinity (Kd); and increased norepinephrine (NE) in the 40% DR + tyrosine group, and methoxyhydroxyphenylglycol (MHPG) in both groups. In the hypothalamus, the brain area responsible for energy metabolism, there was a progressive increase in alpha:beta tone with increasing DR associated with changes in Bmax. Tyrosine treatment reversed these alterations. Tyrosine improves some of the neurobiological disturbances of DR without causing an increase in body weight. Such a strategy might have important implications for the possible treatment of patients with anorexia nervosa.
Article
The effects of delta 9-tetrahydrocannabinol on single-unit activity in the subpostremal division of the nucleus tractus solitarii were investigated by extracellular recording in rat brain slices. The spontaneous firing rate of 54.8% of the recorded neurons was significantly changed after bath applications of delta 9-tetrahydrocannabinol. Putative nutrition-related neurons responding to a moderate increase in glucose concentration were selectively sensitive to delta 9-tetrahydrocannabinol. The delta 9-tetrahydrocannabinol-sensitive neurons were depressed by clonidine and are therefore likely to be adrenergic or noradrenergic. These observations suggest that some catecholaminergic, glucose-responsive neurons in the subpostremal nucleus tractus solitarii might mediate the influence of cannabinoids on feeding behaviour. Furthermore, most delta 9-tetrahydrocannabinol-sensitive neurons in the nucleus tractus solitarii showed opposite responses to delta 9-tetrahydrocannabinol and the 5-HT3 receptor agonist 1-phenylbiguanide, and might therefore be involved in the nausea-reducing effects of cannabinoids.
Article
We have recently described the dose-response effect of anandamide (AEA), the N-amide derivative of arachidonic acid that acts as an endogenous ligand for the cannabinoid receptor, on extrapyramidal function. The present study has been designed to examine the time-course of this effect. To this end, adult male rats were submitted to an acute i.p. injection of AEA, delta9-tetrahydrocannabinol (THC) or vehicle and examined at different times after drug administration. Animals were tested in an open-field test, then sacrificed and their striata used for analyses of dopaminergic indices. Results were as follows. The administration of AEA or THC produced the expected inhibition of motor behavior. Thus, the administration of AEA decreased the ambulation and the frequency of stereotypic movements (in particular, the number of rears) and increased the time spent by the rats in inactivity. These effects were evident at 10 and 30 min after the administration of the cannabinoid agonist, but mostly disappeared at 60 min. Interestingly, motor inhibition was observed again around 2 or 3 h after the administration of AEA. This was a small but persistent effect (decreased ambulation followed by increased inactivity), because it was observed until at least 6 h after AEA administration. The other cannabimimetic, THC, was always able of decreasing the ambulation and the frequency of rearing and grooming behavior, and of increasing the time spent in inactivity. This effect was usually something more marked than the effect of AEA, but the most characteristic fact was its persistence at all times studies, even at 6 h after administration. These motor disturbances were accompanied by changes in the activity of nigrostriatal dopaminergic neurons. Thus, the administration of AEA decreased the activity of tyrosine hydroxylase (TH) in the striatum at 10 and 30 min after treatment, suggesting a decreased nigrostriatal activity parallel to the motor deficit observed at these times. This was followed by an increase in TH activity and dopamine and L-3,4-dihydroxyphenylacetic acid contents at 60 min after treatment, which would likely reflect a compensatory stimulation of these neurons, whereas restoration of control values was found at 180 min after AEA administration, suggesting that the motor deficit observed at this time was not dependent on dopaminergic influence. Paradoxically, the administration of THC only produced changes in dopaminergic activity at 60 min after treatment, similar to those seen with AEA, but was ineffective at the other times. In summary, A-EA inhibits motor behavior in parallel to reductions in the activity of nigrostriatal dopaminergic neurons. However, this effect was of short duration, disappearing at 60 min after treatment, as compared with the inhibitory effect of THC on motor behavior which was observed at all times studied. Interestingly, a new AEA-induced inhibition of motor behavior, which was not accompanied by dopaminergic changes, appeared at longer times although its meaning remains to be determined.
Article
SR 141716, a selective central CB1 cannabinoid receptor antagonist, markedly and selectively reduces sucrose feeding and drinking as well as neuropeptide Y-induced sucrose drinking in rats. SR 141716 also decreases ethanol consumption in C57BL/6 mice. In contrast, blockade of CB1 receptors only marginally affects regular chow intake or water drinking. The active doses of SR 141716 (0.3-3 mg/kg) are in the range known to antagonize the characteristic effects induced by cannabinoid receptor agonists. These results suggest for the first time that endogenous cannabinoid systems may modulate the appetitive value of sucrose and ethanol, perhaps by affecting the activity of brain reward systems.
Article
There are at least two types of cannabinoid receptors, CB1 and CB2, both coupled to G-proteins. CB1 receptors are present in the central nervous system and CB1 and CB2 receptors in certain peripheral tissues. The existence of endogenous cannabinoid receptor agonists has also been demonstrated. These discoveries have led to the development of selective cannabinoid CB1 and CB2 receptor ligands. This review focuses on the classification, binding properties, effector systems and distribution of cannabinoid receptors. It also describes the various cannabinoid receptor agonists and antagonists now available and considers the main in vivo and in vitro bioassay methods that are generally used.
Article
Effects of the endogenous cannabimimetic anandamide were assessed over a wide dose range in a series of physiological and behavioral assays. These included the tetrad of tests in mice commonly used to assess cannabinoid-induced effects (motor activity, ring catalepsy, hypothermia, and analgesia tests), as well as a model for agonistic behavior on dyadic interactions of singly housed males with nonaggressive group-housed partners. Anandamide-induced effects on leukocyte phagocytosis were measured in a chemiluminescence assay. Results indicated that the higher doses tested (10-100 mg/kg) produced the well-known inhibitory effects in all of the above parameters as well as inhibition of phagocytosis. The lowest dose of anandamide tested (0.01 mg/kg) stimulated behavioral activities in the open field, on the ring and aggressive behavior in timid singly housed mice. This dose of 0.01 mg/kg, also stimulated phagocytosis. We suggest several possible mechanisms to explain these findings such as a differential involvement of a Gs and a Gi protein activated at low and high doses, respectively, allosteric modulation of the cannabinoid, and activation of presynaptic cannabinoid receptors by low doses of anandamide.