Showing papers on "Cannabinoid receptor type 1 published in 2007"

Genetic Dissection of Behavioural and Autonomic Effects of Δ9-Tetrahydrocannabinol in Mice

Abstract: Marijuana and its main psychotropic ingredient Δ9-tetrahydrocannabinol (THC) exert a plethora of psychoactive effects through the activation of the neuronal cannabinoid receptor type 1 (CB1), which is expressed by different neuronal subpopulations in the central nervous system. The exact neuroanatomical substrates underlying each effect of THC are, however, not known. We tested locomotor, hypothermic, analgesic, and cataleptic effects of THC in conditional knockout mouse lines, which lack the expression of CB1 in different neuronal subpopulations, including principal brain neurons, GABAergic neurons (those that release γ aminobutyric acid), cortical glutamatergic neurons, and neurons expressing the dopamine receptor D1, respectively. Surprisingly, mice lacking CB1 in GABAergic neurons responded to THC similarly as wild-type littermates did, whereas deletion of the receptor in all principal neurons abolished or strongly reduced the behavioural and autonomic responses to the drug. Moreover, locomotor and hypothermic effects of THC depend on cortical glutamatergic neurons, whereas the deletion of CB1 from the majority of striatal neurons and a subpopulation of cortical glutamatergic neurons blocked the cataleptic effect of the drug. These data show that several important pharmacological actions of THC do not depend on functional expression of CB1 on GABAergic interneurons, but on other neuronal populations, and pave the way to a refined interpretation of the pharmacological effects of cannabinoids on neuronal functions.

Requirement of cannabinoid receptor type 1 for the basal modulation of hypothalamic-pituitary-adrenal axis function.

Abstract: The endocannabinoid system affects the neuroendocrine regulation of hormone secretion, including the activity of the hypothalamus-pituitary-adrenal (HPA) axis. However, the mechanisms by which endocannabinoids regulate HPA axis function have remained unclear. Here we demonstrate that mice lacking cannabinoid receptor type 1 (CB1-/-) display a significant dysregulation of the HPA axis. Although circadian HPA axis responsiveness is preserved, CB1-/- mice are characterized by an enhanced circadian drive on the HPA axis, resulting in elevated plasma corticosterone concentrations at the onset of the dark as compared with wild-type (CB1+/+) littermates. Moreover, CB1-/--derived pituitary cells respond with a significantly higher ACTH secretion to CRH and forskolin challenges as compared with pituitary cells derived from CB1+/+ mice. Both CBL-/- and CB1+/+ mice properly respond to a high-dose dexamethasone test, but response to low-dose dexamethasone is influenced by genotype. In addition, CB1-/- mice show increased CRH mRNA levels in the paraventricular nucleus of the hypothalamus but not in other extrahypothalamic areas, such as the amygdala and piriform cortex, in which CB1 and CRH mRNA have been colocalized. Finally, CB1-/- mice have selective glucocorticoid receptor mRNA down-regulation in the CA1 region of the hippocampus but not in the dentate gyrus or paraventricular nucleus. Conversely, mineralocorticoid receptor mRNA expression levels were found unchanged in these brain areas. In conclusion, our findings indicate that CB1 deficiency enhances the circadian HPA axis activity peak and leads to central impairment of glucocorticoid feedback, thus further outlining the essential role of the endocannabinoid system in the modulation of neuroendocrine functions.

Role of Cannabinoid Type 1 Receptors in Locomotor Activity and Striatal Signaling in Response to Psychostimulants

Abstract: A single administration of cocaine or D-amphetamine produces acute hyperlocomotion and long-lasting increased sensitivity to subsequent injections. This locomotor sensitization reveals the powerful ability of psychostimulants to induce brain plasticity and may participate in the alterations that underlie addiction. We investigated the role of cannabinoid receptor type 1 (CB1-R) in the effects of a single injection of psychostimulants. The acute locomotor response to cocaine was normal in mice pretreated with the CB1-R inverse agonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251), whereas no sensitization was observed in response to a second administration a week later. Locomotor responses to cocaine and D-amphetamine were decreased in CB1-R-deficient mice, and sensitization was impaired. To determine how CB1-R controls long-lasting effects of psychostimulants, we studied cocaine-activated signaling pathways. Cocaine-induced cAMP-dependent phosphorylation of glutamate receptor 1 was altered in the striatum of CB1-R mutant mice but not of AM251-treated mice. In contrast, cocaine-induced phosphorylation of extracellular signal-regulated kinase (ERK) was blocked in both CB1-R mutant and antagonist-pretreated mice. Conditional deletion of CB1-R in forebrain principal neurons or GABAergic neurons prevented cocaine-induced ERK activation in dorsal striatum and nucleus accumbens. Our results provide strong evidence for the role of the endocannabinoid system in regulating neuronal circuits critical for long-lasting effects of cocaine, presumably by acting on CB1-R located on terminals of striatal medium spiny neurons.

Activation of human T cells induces upregulation of cannabinoid receptor type 1 transcription.

Abstract: Objective: Effects of cannabinoids are mediated by CB1 and CB2 receptors. In addition to neuronal effects, cannabinoids are potent modulators of immune functions. In this report, we

Δ9‐Tetrahydrocannabinol (THC) and AM 404 protect against cerebral ischaemia in gerbils through a mechanism involving cannabinoid and opioid receptors

Abstract: Background and purpose: It has been suggested that the endocannabinoid system elicits neuroprotection against excitotoxic brain damage. In the present study the therapeutic potential of AM 404 on ischaemia-induced neuronal injury was investigated in vivo and compared with that of the classical cannabinoid receptor type 1 (CB1) agonist, Δ9-tetraydrocannabinol (THC), using a model of transient global cerebral ischaemia in the gerbil. Experimental approach: The effects of AM 404 (0.015–2 mg kg−1) and THC (0.05–2 mg kg−1), given 5 min after ischaemia, were measured from 1 h to 7 days in terms of electroencephalographic (EEG) total spectral power, spontaneous motor activity, memory function, rectal temperature and hippocampal CA1 neuronal count. Key results: Over the dose range tested, AM 404 (2 mg kg−1) and THC (1 mg kg−1) completely reversed the ischaemia-induced behavioural, EEG and histological damage. Only THC (1 and 2 mg kg−1) induced a decrease of body temperature. Pretreatment with the selective CB1 receptor antagonist, AM 251 (1 mg kg−1) and the opioid antagonist, naloxone (2 mg kg−1) reversed the protective effect induced by both AM 404 and THC while the TRPV1 vanilloid antagonist, capsazepine (0.01 mg kg−1), was ineffective. Conclusions and implications: Our findings demonstrate that AM 404 and THC reduce neuronal damage caused by bilateral carotid occlusion in gerbils and that this protection is mediated through an interaction with CB1 and opioid receptors. Endocannabinoids might form the basis for the development of new neuroprotective drugs useful for the treatment of stroke and other neurodegenerative pathologies. British Journal of Pharmacology (2007) 152, 1301–1311; doi:10.1038/sj.bjp.0707514; published online 29 October 2007

Functional blockage of the cannabinoid receptor type 1 evokes a kappa-opiate-dependent analgesia.

Abstract: Progress in the control and treatment of pain may be facilitated by a better understanding of mechanisms underlying nociceptive processing. Cannabinoids and opioids are endogenous modulator of pain sensation, but therapies based in these compounds are not completely exploited because of their side effects. To test the role of cannabinoid receptor type 1 (CB1-R) inhibition in nociception, we performed a subchronic administration of the CB1-R antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM281) in mice. This treatment provoked analgesia in peripheral thermal and visceral models of pain. Analysis of genes encoded for the opioid system in the spinal cord showed an increase in the expression of genes encoded for the κ-opioid system in AM281-injected mice compared with vehicle-injected ones. Furthermore, systemic administration of nor-binaltorphimine, a κ-opioid receptor antagonist, blocked AM281-induced analgesia. Finally, c-fos expression in the dorsal spinal cord and higher centers of pain processing after noxious stimulation were significantly lower in AM281-injected mice than in vehicle-injected animals, indicating that dynorphin could block nociceptive information transmission at the spinal cord level. These results indicate the existence of a cross-talk between opioid and cannabinoid systems in nociception. Furthermore, the results suggest that CB1-R antagonists could be useful as a new therapeutic approach for pain relief.

Effects of AM1346, a high-affinity CB1 receptor selective anandamide analog, on open-field behavior in rats.

Abstract: AM1346 is a cannabinoid receptor type 1 (CB1R) anandamide analog [alkoxyacid amide of N-eicosa-(5Z, 8Z, 11Z, 14Z)-tetraenylamine] with high affinity and selectivity for the CB1 vs. CB2 receptor [Ki (CB1)=1.5 nmol/l; Ki (CB2)=152 nmol/l]. The present study characterized the effects of AM1346 (5.6-18 mg/kg) and its interaction with the CB1R antagonist/inverse agonist SR141716 (1-5.6 mg/kg) on open-field behaviors of rats. AM1346 reduced ambulation (horizontal activity), rearing (vertical activity) and increased the degree of circling and the latency to leave the central area of the open-field arena. AM1346 also tended to reduce defecation and to increase vocalization in a dose-dependent manner. In pretreatment studies, SR141716 completely blocked the effects of AM1346 on circling and latency and partially antagonized the effects of 18 mg/kg AM1346 on ambulation and rearing. SR141716 also tended to decrease AM1346-induced vocalization in a dose-dependent manner. Earlier studies have shown that SR141716, given alone, can increase grooming behavior and, as well, produces dose-related increases in scratching. In the present studies, these effects were attenuated in a dose-related manner by AM1346. The present profile of behavioral effects for AM1346 is consistent with its designation as a CB1R agonist. When combined with drug discrimination data (surmountable antagonism of effects of SR141716 by Delta(9)-THC and AM1346 but not by methanandamide, i.e. AM356), these data indicate that the anandamide analog AM1346 may be more behaviorally similar to cannabinoids like Delta(9)-THC than to other anandamide-based molecules such as methanandamide.

Novel pyrazoles highly-selective marijuana acceptor-1antagon and/or reversed activation agent

Abstract: The invention relates to a constitutional formula of receptor antagonist and/or inverse agonist of novel cannabinoid receptor type 1 (CB1) receptor shown in the right formula (I), the preparation method and the application thereof. The compounds can be used for curing, preventing or relieving CB1 receptor mediated diseases. The compounds and the pharmaceutically-acceptable salts thereof can be used for curing, preventing or relieving obesity, diabetes, drug dependence, cognitive deficit, neurological disease, gastrointestinal tract disease and liver cirrhosis.