3-(2-hydroxy-4-(1-1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol and Chronic-Disease

In many species, adolescence is a critical phase in which the endocannabinoid system can regulate the maturation of important neuronal networks that underlie cognitive function. Therefore, adolescents may be more susceptible to the neural consequences of chronic cannabis abuse. We reported previously that chronically exposing adolescent rats to the synthetic cannabinoid agonist CP55,940 leads to impaired performances in adulthood i.e. long-lasting deficits in both visual and spatial short-term working memories. Here, we examined the synaptic structure and function in the prefrontal cortex (PFC) of adult rats that were chronically treated with CP55,940 during adolescence. We found that chronic cannabinoid exposure during adolescence induces long-lasting changes, including (1) significantly altered dendritic arborization of pyramidal neurons in layer II/III in the medial PFC (2) impaired hippocampal input-induced synaptic plasticity in the PFC and (3) significant changes in the expression of PSD95 (but not synaptophysin or VGLUT3) in the medial PFC. These changes in synaptic structure and function in the PFC provide key insight into the structural, functional and molecular underpinnings of long-term cognitive deficits induced by adolescent cannabinoid exposure. They suggest that cannabinoids may impede the structural maturation of neuronal circuits in the PFC, thus leading to impaired cognitive function in adulthood.

Topics: Animals; Blotting, Western; Cannabinoids; Chronic Disease; Cyclohexanols; Dendrites; Disease Models, Animal; Disks Large Homolog 4 Protein; Hippocampus; Intracellular Signaling Peptides and Proteins; Long-Term Potentiation; Male; Marijuana Abuse; Membrane Proteins; Microelectrodes; Prefrontal Cortex; Pyramidal Cells; Rats, Wistar; Synaptophysin; Vesicular Glutamate Transport Proteins

Hyperactivation of the amygdala following chronic stress is believed to be one of the primary mechanisms underlying the increased propensity for anxiety-like behaviors and pathological states; however, the mechanisms by which chronic stress modulates amygdalar function are not well characterized. The aim of the current study was to determine the extent to which the endocannabinoid (eCB) system, which is known to regulate emotional behavior and neuroplasticity, contributes to changes in amygdalar structure and function following chronic stress. To examine the hypothesis, we have exposed C57/Bl6 mice to chronic restraint stress, which results in an increase in fatty acid amide hydrolase (FAAH) activity and a reduction in the concentration of the eCB N-arachidonylethanolamine (AEA) within the amygdala. Chronic restraint stress also increased dendritic arborization, complexity and spine density of pyramidal neurons in the basolateral nucleus of the amygdala (BLA) and increased anxiety-like behavior in wild-type mice. All of the stress-induced changes in amygdalar structure and function were absent in mice deficient in FAAH. Further, the anti-anxiety effect of FAAH deletion was recapitulated in rats treated orally with a novel pharmacological inhibitor of FAAH, JNJ5003 (50 mg per kg per day), during exposure to chronic stress. These studies suggest that FAAH is required for chronic stress to induce hyperactivity and structural remodeling of the amygdala. Collectively, these studies indicate that FAAH-mediated decreases in AEA occur following chronic stress and that this loss of AEA signaling is functionally relevant to the effects of chronic stress. These data support the hypothesis that inhibition of FAAH has therapeutic potential in the treatment of anxiety disorders, possibly by maintaining normal amygdalar function in the face of chronic stress.

Topics: Amidohydrolases; Amygdala; Animals; Anxiety; Arachidonic Acids; Chronic Disease; Cyclohexanols; Dendrites; Drug Evaluation, Preclinical; Endocannabinoids; Exploratory Behavior; Male; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Knockout; Polyunsaturated Alkamides; Pyramidal Cells; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Restraint, Physical; Stress, Psychological

Cannabinoid receptor agonists have previously been shown to produce antinociceptive effects in rodent models of inflammatory pain. In the present study, we characterized responses of spinal dorsal horn neurons receiving sensory input from the hind paw in rats that had received intraplantar injection of complete Freund's adjuvant (CFA), and examined effects of the nonselective CB1/2 receptor agonist CP55,940 on spinal neuron responses. Systemic (i.v.) administration of CP55,940 failed to attenuate responses of dorsal horn neurons to noxious mechanical stimulation in naïve rats, but significantly reduced responses in CFA-inflamed rats to 25.78+/-13.7% of vehicle control at a cumulative dose of 0.8 mg/kg (ID50=0.28+/-0.02 mg/kg). Additionally, local administration of CP55,940 (10 microM) to the spinal cord reduced responses of mechanosensory dorsal horn neurons in CFA-inflamed rats to 67.15+/-7.1% of vehicle control. The inhibitory action of CP55,940 on spinal dorsal horn neurons in CFA-inflamed rats was mediated by CB1 receptors since local pretreatment with the CB1 receptor antagonist AM251 (10 microM) blocked this effect, while the CB2 receptor antagonist AM630 (10 microM) was ineffective. Our results suggest that following inflammation, the inhibition of spinal nociceptive transmission by CP55,940 is mediated in part by spinal CB1 receptors, and not spinal CB2 receptors.

Topics: Afferent Pathways; Animals; Cannabinoid Receptor Modulators; Cannabinoids; Chronic Disease; Cyclohexanes; Cyclohexanols; Dose-Response Relationship, Drug; Inflammation; Male; Mechanoreceptors; Nociceptors; Pain; Phenols; Posterior Horn Cells; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid

In our previous study, we demonstrated that chronic ethanol (EtOH) exposure down-regulated the cannabinoid receptors (CB1) in mouse brain synaptic plasma membrane (SPM) (Basavarajappa et al., Brain Res. 793 (1998) 212-218). In the present study, we investigated the effect of chronic EtOH (4-day inhalation) on the CB1 agonist stimulated guanosine-5'-O-(3-[35S]thio)-triphosphate ([35S]GTP gamma S) binding in SPM from mouse. Our results indicate that the net CP55,940 stimulated [35S]GTP gamma S binding was increased with increasing concentrations of CP55,940 and GDP. This net CP55,940 (1.5 microM) stimulated [35S]GTP gamma S binding was reduced significantly (-25%) in SPM from chronic EtOH group (175 +/- 5.25%, control; 150 +/- 8.14%, EtOH; P < 0.05). This effect occurs without any significant changes on basal [35S]GTP gamma S binding (152.1 +/- 10.7 for control, 147.4 +/- 5.0 fmol/mg protein for chronic EtOH group, P > 0.05). Non-linear regression analysis of net CP55,940 stimulated [35S]GTP gamma S binding in SPM showed that the Bmax of cannabinoid stimulated binding was significantly reduced in chronic EtOH exposed mouse (Bmax = 7.58 +/- 0.22 for control; 6.42 +/- 0.20 pmol/mg protein for EtOH group; P < 0.05) without any significant changes in the G-protein affinity (Kd = 2.68 +/- 0.24 for control; 3.42 +/- 0.31 nM for EtOH group; P > 0.05). The pharmacological specificity of CP55,940 stimulated [35S]GTP gamma S binding in SPM was examined with CB1 receptor antagonist, SR141716A and these studies indicated that CP55,940 stimulated [35S]GTP gamma S binding was blocked by SR141716A with a decrease (P < 0.05) in the IC50 values in the SPM from chronic EtOH group. These results suggest that the observed down-regulation of CB1 receptors by chronic EtOH has a profound effect on desensitization of cannabinoid-activated signal transduction and possible involvement of CB1 receptors in EtOH tolerance and dependence.

Topics: Analgesics; Animals; Binding, Competitive; Brain Chemistry; Central Nervous System Depressants; Chronic Disease; Cyclohexanols; Dose-Response Relationship, Drug; Down-Regulation; Ethanol; Guanosine 5'-O-(3-Thiotriphosphate); Kinetics; Male; Mice; Piperidines; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Sulfur Radioisotopes; Synaptic Membranes