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

Abstract

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.

Behavioural and pharmacological characterization of a novel cannabinomimetic adamantane-derived indole, APICA, and considerations on the possible misuse as a psychotropic spice abuse, in C57bl/6J mice

“…APICA administration dose-dependently decreased total distance traveled in the open field test, This result is consistent with preliminary evaluation of APICA cannabinomimetic profile, which showed that APICA dose-dependently induced hypothermia and reduced heart rate at the maximal dose of 10 mg/kg, a similar potency as Δ 9 -THC, but lower than JWH-018, the representative member of cannabinomimetic indoles [4]. Since CB1 agonists have been shown to exert anxiogenic effect [13], we also evaluated APICA activity on behavioural reactivity in the open field. Our results show that APICA strongly decreased the time spent in the center of the arena, as well as the number of transitions in the central area, and this observation is consistent with an overall reduction of locomotor activity and exploration.…”

“…These opposite observations might be explained by the distribution of CB1 receptors in the brain. Rey et al [13] showed a biphasic effects of the synthetic CB1 cannabinoid receptor agonist CP-55,940, demonstrating that the anxiogenic effect exerted by the high doses was mediated via the CB1 receptor activation on the GABAergic terminals. Indeed, the broad distribution of CB1 receptors in the central nervous system [17], together with its modulatory role on neurotransmission [18], account for the controversial activity of cannabinoids on anxiety modulation.…”

“…Melting point was determined by DSC analysis and corresponded to the peak maximum. 1 H NMR spectra was recorded operating at 300 MHz and 13 (25). (Fig.…”

Natural Cannabinoids Improve Dopamine Neurotransmission and Tau and Amyloid Pathology in a Mouse Model of Tauopathy

“…This PK −/− /Tau vlw model showed an elevated level of self-injured wounds on the front of the face, due to their compulsive behavior and repetitive selfscratching [25]. The role of cannabinoids in mood and anxiety disorders has been described [34][35][36]. Each mouse was recorded to evaluate the extent of facial barbering in the different groups of the experiment.…”

“…The nucleic acids were dissolved in 150 l of sterile water. For PCR, 150 ng of genomic DNA was denatured for 3 min at 94 • C and subjected to 35 Twenty-microliter volumes of PCR products were analyzed by electrophoresis on a 1.8% agarose gel that was subsequently stained with ethidium bromide for visualization of DNA bands. DNA molecular weight markers (Roche, Spain) were used to provide a size reference for the test reactions [25,26].…”