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Journal Article

Cannabinoids: influence on neurotransmitter uptake in rat brain synaptosomes.

01 Jul 1975-Journal of Pharmacology and Experimental Therapeutics (American Society for Pharmacology and Experimental Therapeutics)-Vol. 194, Iss: 1, pp 74-81
TL;DR: Hydroxylation of C-7 in delta6-THC does not alter inhibitory potency, but its oxidation to an acid and aromatization of ring A greatly reduce affinity, which is critical for inhibition of NE, 5-HT and GABA uptake.
Abstract: We have examined the effect of Delta1-tetrahydrocannabinol (delat1-THC) and 12 of its derivatives on the uptake of 3H-labeled norepinephrine (NE), dopamine (DA), serotonin (5-HT) gamma-aminobutyric acid (GABA) into synaptosomes in homogenates of various regions of rat brain. Delta1-THC inhibits the accumulation of NE and 5-HT into hypothalamic preparations and DA into the corpus striatum with Ki values of about 12 to 25 muM while GABA uptake into cerebral cortical preparations is inhibited less (Ki = 140 muM). The affinities of delta6-THC, 7-hydroxy-delta1-THC, 7-hydroxy-delta6-THC and cannabidiol for 5-HT, NE and GABA transports are similar to values for delta1-THC, while cannabigerol, cannabinol and delta6-THC-7-oic acid have substantially less affinity. Thus, hydroxylation of C-7 in delta6-THC does not alter inhibitory potency, but its oxidation to an acid and aromatization of ring A greatly reduce affinity. The hydroxyl at C-3(1) of ring C is critical for inhibition of NE, 5-HT and GABA uptake, since its acetylation or methylation abolishes activity. Inhibition of NE, DA, 5-HT and GABA uptake by all cannabinoids examined is noncompetitive. Only about 1% of delta1-THC and delta6-THC and 5% of cannabidiol are fully soluble under our experimental conditions.
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Journal ArticleDOI
TL;DR: It is considered premature to rename cannabinoid receptors after an endogenous agonist as is recommended by the International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification, because pharmacological evidence for the existence of additional types of cannabinoid receptor is emerging and other kinds of supporting evidence are still lacking.
Abstract: Two types of cannabinoid receptor have been discovered so far, CB(1) (2.1: CBD:1:CB1:), cloned in 1990, and CB(2) (2.1:CBD:2:CB2:), cloned in 1993. Distinction between these receptors is based on differences in their predicted amino acid sequence, signaling mechanisms, tissue distribution, and sensitivity to certain potent agonists and antagonists that show marked selectivity for one or the other receptor type. Cannabinoid receptors CB(1) and CB(2) exhibit 48% amino acid sequence identity. Both receptor types are coupled through G proteins to adenylyl cyclase and mitogen-activated protein kinase. CB(1) receptors are also coupled through G proteins to several types of calcium and potassium channels. These receptors exist primarily on central and peripheral neurons, one of their functions being to inhibit neurotransmitter release. Indeed, endogenous CB(1) agonists probably serve as retrograde synaptic messengers. CB(2) receptors are present mainly on immune cells. Such cells also express CB(1) receptors, albeit to a lesser extent, with both receptor types exerting a broad spectrum of immune effects that includes modulation of cytokine release. Of several endogenous agonists for cannabinoid receptors identified thus far, the most notable are arachidonoylethanolamide, 2-arachidonoylglycerol, and 2-arachidonylglyceryl ether. It is unclear whether these eicosanoid molecules are the only, or primary, endogenous agonists. Hence, we consider it premature to rename cannabinoid receptors after an endogenous agonist as is recommended by the International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. Although pharmacological evidence for the existence of additional types of cannabinoid receptor is emerging, other kinds of supporting evidence are still lacking.

2,619 citations


Cites background from "Cannabinoids: influence on neurotra..."

  • ...Thus, (9)-THC acetate, when tested in vitro, shows negligible activity in biochemical reactions in which (9)-THC is active (Banerjee et al., 1975)....

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Journal ArticleDOI
TL;DR: Particular focus will be placed on phytocannabinoid‐terpenoid interactions that could produce synergy with respect to treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections (including methicillin‐resistant Staphylococcus aureus).
Abstract: Tetrahydrocannabinol (THC) has been the primary focus of cannabis research since 1964, when Raphael Mechoulam isolated and synthesized it. More recently, the synergistic contributions of cannabidiol to cannabis pharmacology and analgesia have been scientifically demonstrated. Other phytocannabinoids, including tetrahydrocannabivarin, cannabigerol and cannabichromene, exert additional effects of therapeutic interest. Innovative conventional plant breeding has yielded cannabis chemotypes expressing high titres of each component for future study. This review will explore another echelon of phytotherapeutic agents, the cannabis terpenoids: limonene, myrcene, α-pinene, linalool, β-caryophyllene, caryophyllene oxide, nerolidol and phytol. Terpenoids share a precursor with phytocannabinoids, and are all flavour and fragrance components common to human diets that have been designated Generally Recognized as Safe by the US Food and Drug Administration and other regulatory agencies. Terpenoids are quite potent, and affect animal and even human behaviour when inhaled from ambient air at serum levels in the single digits ng·mL−1. They display unique therapeutic effects that may contribute meaningfully to the entourage effects of cannabis-based medicinal extracts. Particular focus will be placed on phytocannabinoid-terpenoid interactions that could produce synergy with respect to treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections (including methicillin-resistant Staphylococcus aureus). Scientific evidence is presented for non-cannabinoid plant components as putative antidotes to intoxicating effects of THC that could increase its therapeutic index. Methods for investigating entourage effects in future experiments will be proposed. Phytocannabinoid-terpenoid synergy, if proven, increases the likelihood that an extensive pipeline of new therapeutic products is possible from this venerable plant. LINKED ARTICLES This article is part of a themed issue on Cannabinoids in Biology and Medicine. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.163.issue-7

1,113 citations


Cites background from "Cannabinoids: influence on neurotra..."

  • ...GABA uptake inhibitor (Banerjee et al., 1975) Phytol, linalool...

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  • ...Older work supports gamma aminobutyric acid (GABA) uptake inhibition greater than THC or CBD (Banerjee et al., 1975) that could suggest muscle relaxant properties....

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Journal ArticleDOI
TL;DR: Delta-9-tetrahydrocannabinol is associated with transient exacerbation in core psychotic and cognitive deficits in schizophrenia, and this data do not provide a reason to explain why schizophrenia patients use or misuse cannabis.

566 citations

Journal ArticleDOI
TL;DR: Findings demonstrate that endogenous cannabinoids through the activation of CB1 receptors are implicated in the control of emotional behaviour and participate in the physiological processes of learning and memory.
Abstract: RATIONALE: Endogenous and exogenous cannabinoids acting through the CB1 cannabinoid receptors are implicated in the control of a variety of behavioural and neuroendocrine functions, including emotional responses, and learning and memory processes. Recently, knockout mice deficient in the CB1 cannabinoid receptor have been generated, and these animals result in an excellent tool to evaluate the neurophysiology of the endogenous cannabinoid system. OBJECTIVES: To establish the role of the CB1 cannabinoid receptor in several emotional-related behavioural responses, including aggressiveness, anxiety, depression and learning models, using CB1 knockout mice. METHODS: We evaluated the spontaneous responses of CB1 knockout mice and wild-type controls under different behavioural paradigms, including the light/dark box, the chronic unpredictable mild stress, the resident-intruder test and the active avoidance paradigm. RESULTS: Our findings showed that CB1 knockout mice presented an increase in the aggressive response measured in the resident-intruder test and an anxiogenic-like response in the light/dark box. Furthermore, a higher sensitivity to exhibit depressive-like responses in the chronic unpredictable mild stress procedure was observed in CB1 knockout mice, suggesting an increased susceptibility to develop an anhedonic state in these animals. Finally, CB1 knockout mice showed a significant increase in the conditioned responses produced in the active avoidance model, suggesting an improvement of learning and memory processes. CONCLUSIONS: Taken together these findings demonstrate that endogenous cannabinoids through the activation of CB1 receptors are implicated in the control of emotional behaviour and participate in the physiological processes of learning and memory.

472 citations

Journal ArticleDOI
TL;DR: CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent with modulation of such targets that would derive a therapeutically beneficial outcome.

392 citations


Additional excerpts

  • ...Work in the 1970s utilized rat brain synaptosomes to determine the effect of CBD on the activity of various transporters (Table 4) [115]....

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Trending Questions (1)
Cannabinoids inhibit the synaptic uptake of adenosine and dopamine in the rat and mouse striatum

The paper does not mention the inhibition of adenosine uptake by cannabinoids. It only mentions the inhibition of dopamine uptake in the corpus striatum.