CB1 receptor stimulation in specific brain areas differently modulate anxiety-related behaviour

Rubino, Tiziana; Guidali, C.; Viganò, Daniela; Realini, Natalia; Valenti, Marta; Massi, Paola; Parolaro, Daniela

doi:10.1016/j.neuropharm.2007.06.024

Cited by 151 publications

(124 citation statements)

References 59 publications

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“…This result supports our previous studies which have provided additional evidence for differential modulation of fear responding by the endocannabinoid system in the presence versus absence of pain [25,69,70]. In addition, and in agreement with the present findings, there are also reports of anxiogenic effects (dependent on dose) of URB597 or the phytocannabinoid and CB 1 receptor agonist Δ 9 -tetrahydrocannabinol (THC) following their direct administration into the vHip [71,72]. Overall then, it is likely that the net effect of endocannabinoid activity on anxiety/fear-related behaviour will depend both on the specific region/subregion and the environmental or aversive context under investigation.…”

Section: Discussionsupporting

confidence: 93%

A role for the ventral hippocampal endocannabinoid system in fear-conditioned analgesia and fear responding in the presence of nociceptive tone in rats

Ford

Kieran

Dolan

et al. 2011

Pain

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Section: Discussionsupporting

confidence: 93%

A role for the ventral hippocampal endocannabinoid system in fear-conditioned analgesia and fear responding in the presence of nociceptive tone in rats

Ford

Kieran

Dolan

et al. 2011

Pain

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“…First of these is anxiety, which is highly comorbid with autism (42-56 %). The eCB system, and cannabidiol in particular, is known to mediate anxiety and related phenotypes [137,138]. Anecdotal reports of cannabis use in autism suggest a reduction in anxiety-related symptoms.…”

Section: Suggested Roles Of the Ecb System In Autismmentioning

confidence: 99%

Endocannabinoid Signaling in Autism

et al. 2015

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Autism spectrum disorder (ASD) is a complex behavioral condition with onset during early childhood and a lifelong course in the vast majority of cases. To date, no behavioral, genetic, brain imaging, or electrophysiological test can specifically validate a clinical diagnosis of ASD. However, these medical procedures are often implemented in order to screen for syndromic forms of the disorder (i.e., autism comorbid with known medical conditions). In the last 25 years a good deal of information has been accumulated on the main components of the Bendocannabinoid (eCB) system^, a rather complex ensemble of lipid signals (Bendocannabinoids^), their target receptors, purported transporters, and metabolic enzymes. It has been clearly documented that eCB signaling plays a key role in many human health and disease conditions of the central nervous system, thus opening the avenue to the therapeutic exploitation of eCB-oriented drugs for the treatment of psychiatric, neurodegenerative, and neuroinflammatory disorders. Here we present a modern view of the eCB system, and alterations of its main components in human patients and animal models relevant to ASD. This review will thus provide a critical perspective necessary to explore the potential exploitation of distinct elements of eCB system as targets of innovative therapeutics against ASD.Key Words Autism spectrum disorder . endocannabinoid system . fragile X syndrome . metabolic regulation . reward system The Endocannabinoid SystemTwenty-five years after the cloning and expression of a complementary DNA that encoded a G protein-coupled receptor, named type-1 cannabinoid (CB 1 ) receptor [1], there is a good deal of information on the main components of the so-called Bendocannabinoid (eCB) system^, as well as on its role in controlling cannabinergic signaling in human health and disease [2][3][4]. Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are the most active eCBs as yet identified, although this family of bioactive lipids includes other arachidonic acid (AA) derivatives with cannabimimetic properties (i.e., noladin ether, virodhamine, N-arachidonoyldopamine, to name but a few). The classical dogma that eCBs are synthesized and released Bon demand^upon (patho)physiological stimuli has been recently revisited on the basis of unexpected evidence for intracellular reservoirs and transporters of eCBs. These new entities have been shown to drive intracellular trafficking of eCBs, adding a new dimension to the regulation of their biological activity [5]. To date, several metabolic routes have B. Chakrabarti, A. Persico and N. Battista are equal first authors.

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“…In this context, the endocannabinoid (eCB) anandamide has been shown to exert its effects on anxiety via the transient receptor potential vanilloid type 1 channel, demonstrating the promiscuity of eCBs and adding a new level of complexity to the study of cannabinoid transmission in the regulation of emotions (Moreira et al, 2012). Additionally, specific brain areas, which are usually involved in emotional homeostasis (ie, prefrontal cortex, hippocampus, and amygdala), seem to have opposite but complementary roles in the regulation of anxiety by cannabinoids (Rubino et al, 2008). These discrepant observations might be explained by the distribution of CB1 receptors in the brain.…”

Section: Introductionmentioning

confidence: 99%

Biphasic Effects of Cannabinoids in Anxiety Responses: CB1 and GABAB Receptors in the Balance of GABAergic and Glutamatergic Neurotransmission

Rey

Purrio

Viveros

et al. 2012

Neuropsychopharmacol

275

198

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Biphasic effects of cannabinoids have been shown in processes such as feeding behavior, motor activity, motivational processes and anxiety responses. Using two different tests for the characterization of anxiety-related behavior (elevated plus-maze and holeboard), we first identified in wild-type C57BL/6N mice, two doses of the synthetic CB1 cannabinoid receptor agonist CP-55,940 with anxiolytic (1 mg/kg) and anxiogenic properties (50 mg/kg), respectively. To clarify the role of CB1 receptors in this biphasic effect, both doses were applied to two different conditional CB1 receptor knockout (KO) mouse lines, GABA-CB1-KO (CB1 receptor inactivation in forebrain GABAergic neurons) and Glu-CB1-KO (CB1 receptor inactivation in cortical glutamatergic neurons). We found that the anxiolytic-like effects of the low dose of cannabinoids are mediated via the CB1 receptor on cortical glutamatergic terminals, because this anxiolytic-like response was abrogated only in Glu-CB1-KO mice. On the contrary, the CB1 receptor on the GABAergic terminals is required to induce an anxiogenic-like effect under a high-dose treatment because of the fact that this effect was abolished specifically in GABA-CB1-KO mice. These experiments were carried out in both sexes, and no differences occurred with the doses tested in the mutant mice. Interestingly, the positive allosteric modulation of GABA B receptor with GS-39783 was found to largely abrogate the anxiogenic-like effect of the high dose of CP-55,940. Our results shed new light in further understanding the biphasic effects of cannabinoids at the molecular level and, importantly, pave the way for the development of novel anxiolytic cannabinoid drugs, which may have favorable effect profiles targeting the CB1 receptor on glutamatergic terminals.

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CB1 receptor stimulation in specific brain areas differently modulate anxiety-related behaviour

Cited by 151 publications

References 59 publications

A role for the ventral hippocampal endocannabinoid system in fear-conditioned analgesia and fear responding in the presence of nociceptive tone in rats

A role for the ventral hippocampal endocannabinoid system in fear-conditioned analgesia and fear responding in the presence of nociceptive tone in rats

Endocannabinoid Signaling in Autism

Biphasic Effects of Cannabinoids in Anxiety Responses: CB1 and GABAB Receptors in the Balance of GABAergic and Glutamatergic Neurotransmission

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