Endogenous cannabinoid signaling is required for voluntary exercise-induced enhancement of progenitor cell proliferation in the hippocampus.

Voluntary exercise and endogenous cannabinoid activity have independently been shown to regulate hippocampal plasticity. The aim of the current study was to determine whether the endocannabinoid system is regulated by voluntary exercise and if these changes contribute to exercise-induced enhancement of cell proliferation. In Experiment 1, 8 days of free access to a running wheel increased the agonist binding site density of the cannabinoid CB(1) receptor; CB(1) receptor-mediated GTPgammaS binding; and the tissue content of the endocannabinoid anandamide in the hippocampus but not in the prefrontal cortex. In Experiment 2, the CB(1) receptor antagonist AM251 (1 mg kg(-1)) was administered daily to animals given free access to a running wheel for 8 days, after which cell proliferation in the hippocampus was examined through immunohistochemical analysis of the cell cycle protein Ki-67. Voluntary exercise increased proliferation of progenitor cells, as evidenced by the increase in the number of Ki-67 positive cells in the granule cell layer of the dentate gyrus (DG) in the hippocampus. However, this effect was abrogated by concurrent treatment with AM251, indicating that the increase in endocannabinoid signaling in the hippocampus is required for the exercise-induced increase in cell proliferation. These data demonstrate that the endocannabinoid system in the hippocampus is sensitive to environmental change and suggest that it is a mediator of experience-induced plasticity.

Suppression of amygdalar endocannabinoid signaling by stress contributes to activation of the hypothalamic-pituitary-adrenal axis.

Endocannabinoids inhibit hypothalamic-pituitary-adrenal (HPA) axis activity; however, the neural substrates and pathways subserving this effect are not well characterized. The amygdala is a forebrain structure that provides excitatory drive to the HPA axis under conditions of stress. The aim of this study was to determine the contribution of endocannabinoid signaling within distinct amygdalar nuclei to activation of the HPA axis in response to psychological stress. Exposure of rats to 30-min restraint stress increased the hydrolytic activity of fatty acid amide hydrolase (FAAH) and concurrently decreased content of the endocannabinoid/CB(1) receptor ligand N-arachidonylethanolamine (anandamide; AEA) throughout the amygdala. In stressed rats, AEA content in the amygdala was inversely correlated with serum corticosterone concentrations. Pharmacological inhibition of FAAH activity within the basolateral amygdala complex (BLA) attenuated stress-induced corticosterone secretion; this effect was blocked by co-administration of the CB(1) receptor antagonist AM251, suggesting that stress-induced decreases in CB(1) receptor activation by AEA contribute to activation of the neuroendocrine stress response. Local administration into the BLA of a CB(1) receptor agonist significantly reduced stress-induced corticosterone secretion, whereas administration of a CB(1) receptor antagonist increased corticosterone secretion. Taken together, these findings suggest that the degree to which stressful stimuli reduce amygdalar AEA/CB(1) receptor signaling contributes to the magnitude of the HPA response.

Protracted cannabinoid administration elicits antidepressant behavioral responses in rats: role of gender and noradrenergic transmission.

Research has shown that enhancement of cannabinoid CB(1) receptor activity elicits an antidepressant-like response in the forced swim test (FST); however, the effects of chronic administration of cannabinoid agents in the FST are not well characterized. In Experiment 1, the CB(1) receptor agonist HU-210 (0.1 mg/kg) was administered for 10 days to male rats, following which animals were exposed to the FST. In Experiment 2, the same protocol was utilized; however, prior to the FST animals were co-treated with either prazosin (1 mg/kg; an alpha(1)-adrenoreceptor antagonist) or propranolol (2.5 mg/kg; a beta-adrenoreceptor antagonist). In Experiment 3, the same protocol was employed in both male and female rats, and the role of drug withdrawal was examined by administration of the CB(1) receptor antagonist AM251 (1 mg/kg) prior to the FST. Experiment 1 revealed that HU-210 administration evoked a reduction in immobility and increase in struggling that was identical to that produced by the antidepressant desipramine (10 mg/kg). Experiment 2 revealed that this effect was attenuated by both alpha- and beta-adrenoreceptor antagonists, suggesting noradrenergic involvement in this antidepressant-like profile. Experiment 3 demonstrated that HU-210 administration produced an antidepressant response in both males and females, which was attenuated by the induction of precipitated withdrawal. These results show that protracted administration of a CB(1) receptor agonist produces an antidepressant-like response in the FST in both sexes, which appears to involve the noradrenergic system.

Regional alterations in the endocannabinoid system in an animal model of depression: effects of concurrent antidepressant treatment.

It has been suggested that disturbances in endocannabinoid signaling contribute to the development of depressive illness; however, at present there is insufficient evidence to allow for a full understanding of this role. To further this understanding, we performed an analysis of the endocannabinoid system in an animal model of depression. Male rats exposed to chronic, unpredictable stress (CUS) for 21 days exhibited a reduction in sexual motivation, consistent with the hypothesis that CUS in rats induces depression-like symptoms. We determined the effects of CUS, with or without concurrent treatment with the antidepressant imipramine (10 mg/kg), on CP55940 binding to the cannabinoid CB(1) receptor; whole tissue endocannabinoid content; and fatty acid amide hydrolase (FAAH) activity in the prefrontal cortex, hippocampus, hypothalamus, amygdala, midbrain and ventral striatum. Exposure to CUS resulted in a significant increase in CB(1) receptor binding site density in the prefrontal cortex and a decrease in CB(1) receptor binding site density in the hippocampus, hypothalamus and ventral striatum. Except in the hippocampus, these CUS-induced alterations in CB(1) receptor binding site density were attenuated by concurrent antidepressant treatment. CUS alone produced a significant reduction in N-arachidonylethanolamine (anandamide) content in every brain region examined, which was not reversed by antidepressant treatment. These data suggest that the endocannabinoid system in cortical and subcortical structures is differentially altered in an animal model of depression and that the effects of CUS on CB(1) receptor binding site density are attenuated by antidepressant treatment while those on endocannabinoid content are not.

Endocannabinoid modulation of male rat sexual behavior.

RATIONALE: Synthetic and plant-derived cannabinoid CB(1) receptor agonists have consistently been shown to impair sexual behavior in male rodents; however, the role of the endocannabinoid system in regulating copulatory processes is largely unknown. The aim of this experiment was to determine the effect of pharmacological facilitation or antagonism of endocannabinoid signaling on male rat sexual behavior. MATERIALS AND METHODS: Male Long-Evans rats were administered a single injection of either the cannabinoid CB(1) receptor antagonist AM251 (1, 2, or 5 mg/kg), the fatty acid amide hydrolase (FAAH) inhibitor URB597 (0.1, 0.3, or 0.5 mg/kg), or the anandamide uptake inhibitor/FAAH inhibitor AM404 (1, 2, and 5 mg/kg), or their respective vehicles, and examined on parameters of appetitive and consummatory sexual behavior. RESULTS: Inhibition of anandamide metabolism through URB597 had no effect on any parameter of sexual behavior. However, the highest dose of AM404 increased the latency to engage in intromitting behavior, but had no other effect on sexual behavior, suggesting that this effect may be due to the sedative-suppressive effects of this drug. AM251 produced a dose-dependent facilitation of ejaculation, such that the number of intromissions required to achieve ejaculation and the ejaculation latency were reduced by AM251 administration. CONCLUSIONS: These data suggest that antagonism of the CB(1) receptor facilitates ejaculatory processes, an effect which may be due to interactions with neuropeptidergic systems in the hypothalamus, and further, suggest a novel target for pharmacological agents aimed at treating ejaculatory-based sexual dysfunction.

Local enhancement of cannabinoid CB1 receptor signalling in the dorsal hippocampus elicits an antidepressant-like effect.

Systemic administration of direct cannabinoid CB1 receptor agonists and inhibitors of the hydrolytic enzyme fatty acid amide hydrolase have been shown to elicit antidepressant effects. Moreover, the endocannabinoid system in the hippocampus is sensitive to both chronic stress and antidepressant administration, suggesting a potential role of this system in emotional changes associated with these regimens. The aim of this study was to determine if cannabinoid CB1 receptors in the hippocampus modulate emotionality in rats as assessed via the forced swim test. Male Sprague-Dawley rats were bilaterally implanted with cannulae directed at the dentate gyrus of the dorsal hippocampus and subsequently received three infusions of either the cannabinoid CB1 receptor agonist HU-210 (1 and 2.5 microg), the fatty acid amide hydrolase inhibitor URB597 (0.5 and 1 microg), the cannabinoid CB1 receptor antagonist AM251 (1 and 2.5 microg), or vehicle (dimethyl sulfoxide) and were assessed in the forced swim test. Infusion of both doses of HU-210 resulted in a dramatic reduction in immobility and increase in swimming behaviour, indicative of an antidepressant response, which was partially reversed by coadministration of AM251. No effect of URB597 administration or any effect following the administration of AM251 alone was, however, observed. These data indicate that activation of CB1 receptors in the dentate gyrus of the hippocampus results in an antidepressant-like response. Collectively, these data highlight the potential importance of changes in the hippocampal endocannabinoid system following stress or antidepressant treatment with respect to the manifestation and/or treatment of depression.

Alterations in behavioral flexibility by cannabinoid CB1 receptor agonists and antagonists.

RATIONALE: Cannabinoid CB1 receptors are expressed in the prefrontal cortex, but their role in mediating executive functions such as behavioral flexibility is unclear. OBJECTIVE: The present study examined the effect of pharmacological activation or blockade of the cannabinoid CB1 receptors on behavioral flexibility using a strategy set-shifting task conducted on a cross maze. MATERIALS AND METHODS: In experiment 1, rats initially were trained to turn left or right while ignoring the visual cue to obtain a food; on the second test day, rats had to inhibit the previously learned rule and approach the cue to obtain the food. In experiment 2, the order of discrimination training was reversed. RESULTS: Administration of the cannabinoid CB1 receptor agonist HU-210 before the set-shift on day 2 elicited dose-dependent effects on performance. A 20-microg/kg dose of HU-210 increased perseverative errors, whereas the effects of a lower, 5-microg/kg dose caused differential effects depending on whether rats were required to shift from a response to a visual-cue discrimination strategy or vice versa. Conversely, administration of a 2-mg/kg, but not a 5-mg/kg dose of the CB1 receptor antagonist AM251 reduced perseverative errors. CONCLUSIONS: These data demonstrate a biphasic and dose-sensitive role for the cannabinoid system in behavioral flexibility, which in turn may have clinical implications for the role of the endocannabinoid system in psychiatric disorders where behavioral flexibility is compromised.