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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Arachidonic acid ethanolamide (anandamide) is a brain constituent that binds to the brain cannabinoid receptor (CB1). It produces many of the pharmacological effects caused by delta 9-tetrahydrocannabinol (delta 9-THC) in mice. Anandamide parallels delta 9-THC in its specific interaction with the cannabinoid receptor and in inhibition of adenylate cyclase. Two additional fatty acid ethanolamides that bind to the cannabinoid receptor, homo-gamma-linolenylethanolamide and docostetraenylethanolamide, have been identified in the brain. We believe that the anandamides are involved in the coordination of movement and short term memory. Depression of ambulation in an open field and the analgetic response to anandamide are not fully developed until adulthood, possibly due to an age-related increase in the CB1 receptor concentration. This observation has clinical implications in pediatrics. A second cannabinoid receptor (CB2) is present in the spleen. A monoglyceride, 2-arachidonyl-glycerol which binds to both CB1 and CB2 in transfected cells and inhibits andenylate cyclase in spleen cells was found in the gut. Its role is apparently associated with the immune system. These fatty acids amides and esters represent a new family of chemical modulators in the body.
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PMID:Endogenous cannabinoid ligands--chemical and biological studies. 890 44

The objective of the present study was to determine the neurobehavioral effects of the putative endogenous cannabinoid ligand, anandamide, and its influence on cannabinoid (CB1) receptor gene expression. The effect of acute administration of anandamide to C57BL/6, DBA/2, and ICR mice were evaluated in motor function and emotionality tests. The C57BL/6 and ICR mouse strains were more sensitive than the DBA/2 strain to the depression of locomotor activity and stereotyped behavior caused by anandamide. Although anandamide produced catalepsy in all three strains, anandamide induced ataxia in the minus-maze test only in the C57BL/6 animals and only at the lowest dose used. In the plus-maze test system, anandamide produced a mild aversive response, and by the third day of treatment the mouse strains developed an intense aversion to the open arms of the plus-maze. Northern analysis data using the recently cloned mouse cannabinoid receptor cDNA as a probe indicated that there was abundant expression of CB1 gene in the whole brain of the ICR mouse than in the brains of the C57BL/6 and DBA/2 strains with or without pretreatment with anandamide. The anandamide induced neurobehavioral profile does not seem to correspond to the CB1 gene expression in the mouse strains. It is, therefore, unlikely that the CB1 receptor mediates all the cannabinomimetic effects of anandamide in the brain.
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PMID:Neurobehavioral effects of anandamide and cannabinoid receptor gene expression in mice. 943 4

We have found that phosphorylation of a G-protein-coupled receptor by protein kinase C (PKC) disrupts modulation of ion channels by the receptor. In AtT-20 cells transfected with rat cannabinoid receptor (CB1), the activation of an inwardly rectifying potassium current (Kir current) and depression of P/Q-type calcium channels by cannabinoids were prevented by stimulation of protein kinase C by 100 nM phorbol 12-myristate 13-acetate (PMA). In contrast, activation of Kir current by somatostatin was unaffected, and inhibition of calcium channels was only modestly attenuated. The possibility that PKC acted by phosphorylating CB1 receptors was confirmed by demonstrating that PKC phosphorylated a single serine (S317) of a fusion protein incorporating the third intracellular loop of CB1. Mutating this serine to alanine did not affect the ability of CB1 to modulate currents, but it eliminated disruption by PMA, demonstrating that PKC can disrupt ion channel modulation by receptor phosphorylation.
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PMID:Protein kinase C disrupts cannabinoid actions by phosphorylation of the CB1 cannabinoid receptor. 952

Cannabinoids cause an increase in synaptic transmission via gamma-aminobutyric acid (GABA) receptors and this may be the mechanism by which activation of CB1 receptors blocks the induction of long-term potentiation (LTP). To test this hypothesis, we used paired pulse depression (PPD) of CA1 population spike responses recorded in the rat hippocampal slice as an index of GABA-ergic feedback inhibition, to establish whether the effects of a stereoselective CB1 receptor agonist on GABA-ergic transmission and LTP were correlated. The active isomer, WIN55212-2, blocked the induction of LTP and suppressed PPD over the concentration range 250 nM-5 microM, whereas the inactive isomer, WIN55212-3, was inactive at 5 microM. The effects of 5 microM WIN55212-2 on both LTP and PPD were completely blocked by the CB1 receptor antagonist SR141716A (5 microM). The results show that the effects are correlated in that both suppression of PPD and blockade of induction of LTP are probably mediated by CBI receptors. However, the suppression in PPD suggests that WIN55212-2 caused a decrease in GABA-ergic feedback transmission which would be expected to facilitate, rather than block, the induction of LTP. We therefore conclude that the blockade of LTP by cannabinoids is not via upregulation of GABA-ergic synaptic transmission.
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PMID:Correlation between cannabinoid mediated effects on paired pulse depression and induction of long term potentiation in the rat hippocampal slice. 983 42

1. The arachidonic acid derivative arachidonylethanolamide (anandamide) is an endogeneous ligand of cannabinoid receptors that induces pharmacological actions similar to those of cannabinoids such as delta9-tetrahydrocannabinol (THC). We examined whether anandamide can influence excessive neuronal activity by investigating stimulation-induced population spikes and epileptiform activity in rat hippocampal slices. For this purpose, the effects of anandamide were compared with those of the synthetic cannabinoid agonist WIN 55,212-2 and its inactive S(-)-enantiomer WIN 55,212-3. 2. Both anandamide (1 and 10 microM) and WIN 55,212-2 (0.1 and 1 microM) decreased the amplitude of the postsynaptic population spike and the slope of the field excitatory postsynaptic potential (field e.p.s.p.) without affecting the presynaptic fibre spike of the afferents. At a concentration of 1 microM, WIN 55,212-2 completely suppressed the postsynaptic spike, whereas the S(-)-enantiomer WIN 55,212-3 produced only a slight depression. The CB1 receptor antagonist SR 141716 blocked the inhibition evoked by the cannabinoids. SR 141716 had a slight facilitatory effect on neuronal excitability by itself. 3. Anandamide shifted the input-output curve of the postsynaptic spike and the field e.p.s.p. to the right and increased the magnitude of paired-pulse facilitation indicating a presynaptic mechanism of action. 4. Anandamide and WIN 55,212-2, but not WIN 55,212-3, attenuated both stimulus-triggered epileptiform activity in CA1 elicited by omission of Mg2+ and spontaneously occurring epileptiform activity in CA3 elicited by omission of Mg2+ and elevation of K+ to 8 mM. The antiepileptiform effect of these cannabinoids was blocked by SR 141716. 5. In conclusion, cannabinoid receptors of the CB1 type as well as their endogeneous ligand, anandamide, are involved in the control of neuronal excitability, thus reducing excitatory neurotransmission at a presynaptic site, a mechanism which might be involved in the prevention of excessive excitability leading to epileptiform activity.
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PMID:Effects of the endogeneous cannabinoid, anandamide, on neuronal activity in rat hippocampal slices. 1037 27

Although the majority of cannabinoid users smoke marijuana, the preponderance of laboratory animal research is based on administration of Delta9-tetrahydrocannabinol (Delta9-THC) or other cannabinoid agents via injection. The aim of the present study was to evaluate the impact of inhaling marijuana, or ethanol-extracted placebo smoke in the mouse model of cannabinoid activity by assessing inhibition of spontaneous activity, antinociception, catalepsy, and body temperature. In order to determine dosimetry, blood levels of Delta9-THC were obtained following either marijuana exposure or intravenous injection of Delta(9)-THC. Inhalation exposure to marijuana produced dose-related increases in antinociception and catalepsy, with estimated ED50 doses of Delta9-THC of 2.4 and 3.8 mg/kg, respectively. However, hypothermia and locomotor depression occurred in both the placebo- and marijuana-exposed mice. The CB1 receptor antagonist, SR 141716A antagonized the antinociceptive effects of marijuana (AD50 = 0.6 mg/kg), but only slightly decreased marijuana-induced catalepsy, and failed to alter either the hypothermic or locomotor depressive effects. In contrast, SR 141716A antagonized the antinociceptive, cataleptic, and hypothermic effects of intravenously administered Delta9-THC in mice that were exposed to air alone, though all subjects exhibited locomotor depression, possibly related to the restraint. In accordance with reports of others, these data suggest that exposure to smoke alone has pharmacological consequences. Our findings also indicate that marijuana-induced antinociception is mediated through a CB1-receptor mechanism of action and are consistent with the notion that Delta9-THC is mainly responsible for this effect.
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PMID:The pharmacological activity of inhalation exposure to marijuana smoke in mice. 1137 14

Recent studies have demonstrated a loss of cannabinoid CB1 receptors in the postmortem basal ganglia of patients affected by Huntington's disease (HD) and in transgenic mouse models for this disease. These studies have led to the notion that substances that increase the endocannabinoid activity, such as receptor agonists or inhibitors of endocannabinoid uptake and/or metabolism, might be useful in the treatment of hyperkinetic symptoms of this disease. In the present study, we employed a rat model of HD generated by bilateral intrastriatal injections of 3-nitropropionic acid (3-NP), a toxin that selectively damages striatal GABAergic efferent neurons. These rats exhibited biphasic motor disturbances, with an early (1-2 weeks) hyperactivity followed by a late (3-4 weeks) motor depression. Analysis of GABA, dopamine, and their related enzymes, glutamic acid decarboxylase and tyrosine hydroxylase, in the basal ganglia proved marked decreases compatible with the motor hyperkinesia. In addition, mRNA levels for CB1 receptor, neuronal-specific enolase, proenkephalin, and substance P decreased in the caudate-putamen of 3-NP-injected rats. There were also reductions in CB1 receptor binding in the caudate putamen, the globus pallidus, and, to a lesser extent, the substantia nigra. By contrast, mRNA levels for tyrosine hydroxylase in the substantia nigra remained unaffected. Interestingly, the administration of AM404, an inhibitor of endocannabinoid uptake, to 3-NP-injected rats attenuated motor disturbances observed in the early phase of hyperactivity. Administration of AM404 also tended to induce recovery from the neurochemical deficits caused by the toxin in GABA and dopamine indices in the basal ganglia. In summary, morphological, behavioral, and biochemical changes observed in rats intrastriatally lesioned with 3-NP acid were compatible with a profound degeneration of striatal efferent GABAergic neurons, similar to that occurring in the brain of HD patients. As expected, a loss of CB1 receptors was evident in the basal ganglia of these rats. However, the administration of substances that increase endocannabinoid activity, by inhibiting the uptake process, allowed an activation of the remaining population of CB1 receptors, resulting in a significant improvement of motor disturbances and neurochemical deficits. These observations might be relevant to the treatment of hyperkinetic symptoms in HD, a human disorder with unsatisfactory symptomatic treatment for most patients.
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PMID:Alleviation of motor hyperactivity and neurochemical deficits by endocannabinoid uptake inhibition in a rat model of Huntington's disease. 1184 43

Do endocannabinoids (eCBs) participate in long-term synaptic plasticity in the brain? Using pharmacological approaches and genetically altered mice, we show that stimulation of prelimbic cortex afferents at naturally occurring frequencies causes a long-term depression of nucleus accumbens glutamatergic synapses mediated by eCB release and presynaptic CB1 receptors. Translation of glutamate synaptic transmission into eCB retrograde signaling involved metabotropic glutamate receptors and postsynaptic intracellular Ca(2+) stores. These findings unveil the role of the eCB system in activity-dependent long-term synaptic plasticity and identify a mechanism by which marijuana can alter synaptic functions in the endogenous brain reward system.
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PMID:Endogenous cannabinoids mediate long-term synaptic depression in the nucleus accumbens. 1206 Jul 81

It was shown recently that Delta9-tetrahydrocannabinol, like several other drugs eliciting euphoria, stimulates dopaminergic neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens. The aim of the present work was to clarify the mechanism of this stimulatory effect. Our hypothesis was that cannabinoids depress the GABAergic inhibition of dopaminergic neurons in the VTA. Electrophysiological properties of VTA neurons in rat coronal midbrain slices were studied with the patch-clamp technique. GABA(A) receptor-mediated inhibitory postsynaptic currents (IPSCs) were evoked by electrical stimulation in the vicinity of the recorded neurons. The amplitude of IPSCs was depressed by the synthetic mixed CB1/CB2 cannabinoid receptor agonist WIN55212-2 (10(-6) and 10(-5) m). The CB1 cannabinoid receptor antagonist SR141716A (10(-6) m) prevented the inhibition produced by WIN55212-2 (10(-5) m). Two observations showed that IPSCs were depressed with a presynaptic mechanism. WIN55212-2 (10(-5) m) did not change the amplitude of miniature IPSCs recorded in the presence of tetrodotoxin. Currents evoked by pressure ejection of muscimol from a pipette were also not changed by WIN55212-2 (10(-5) m). The results indicate that activation of CB1 cannabinoid receptors inhibits GABAergic neurotransmission in the VTA with a presynaptic mechanism. Depression of the GABAergic inhibitory input of dopaminergic neurons would increase their firing rate in vivo. Accordingly, dopamine release in the projection region of VTA neurons, the nucleus accumbens, would also increase.
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PMID:Inhibition of GABAergic neurotransmission in the ventral tegmental area by cannabinoids. 1209 13

The central cannabinoid receptor (CB(1)) antagonist, SR-141716A, has been used extensively to ascertain that cannabinoids interact with the CB(1) receptor. SR-141716A has been shown to produce effects opposite of cannabinoids when administered alone. It has been theorized that SR-141716A may act as an inverse agonist at the CB(1) receptor or by disinhibiting an endogenous cannabinoid tone. In an effort to ascertain the exact interaction between SR-141716A and the CB(1) receptor, we have conducted a structure-activity relationship study to compare CB(1) receptor affinity of SR-141716A analogs with their ability to produce an increase in locomotor activity. SR-141716A produced a significant increase in locomotor activity in mice within the first hour of administration. Twenty SR-141716A analogs from five different chemical series were also tested. Our data implicate particular regions of the SR-141716A molecule that may be involved in stimulation and depression of locomotor activity. When the K(I) of the analogs was plotted against the percent stimulation that each analog produced, it is evident that there is no correlation between the ability of the analogs to stimulate locomotor activity and their affinity for the CB(1) receptor. [35S]GTPgammaS binding data indicate that SR-141716A and five of the analogs are inverse agonists. However, none of the analogs demonstrating inverse agonism produce stimulation of locomotor activity. It is therefore concluded that the SR-141716A-induced stimulation in locomotor activity is not the result of inverse agonist activity at the CB(1) receptor or by disinhibition of an endogenous tone.
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PMID:SR-141716A-induced stimulation of locomotor activity. A structure-activity relationship study. 1237 50


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