Co-administration of cannabidiol and ketamine induces antidepressant-like effects devoid of hyperlocomotor side-effects.

BACKGROUND AND PURPOSE: Although useful as a rapid-acting antidepressant drug, ketamine is known to induce psychotomimetic effects, which may interfere with its therapeutic use. Cannabidiol (CBD) is a non-psychostimulant compound from Cannabis sativa, which has shown promising antidepressant effects without inducing hyperlocomotion. AMPA receptor activation is involved in the antidepressant effect induced by ketamine, but its relevance for the effects of CBD is not known. Moreover, given that CBD has antipsychotic and antidepressant properties, it is unknown whether adding CBD to ketamine could potentiate the antidepressant properties of ketamine while also attenuating its psychostimulant effects. EXPERIMENTAL APPROACH: S-Ketamine (2.5, 3, 5, 10, 30 mg/kg) and cannabidiol (3, 10, 30 mg/kg) were administered alone or in combination to male Swiss mice. Independent groups received NBQX (AMPA receptor antagonist) 5 min before administration of CBD or S-ketamine. The antidepressant-like effect was assessed in the forced swimming test (FST), and the open field test (OFT) evaluated the psychostimulant effect. KEY RESULTS: CBD induced significant dose-dependent antidepressant effects without causing hyperlocomotion in the OFT. S-ketamine produced an antidepressant effect associated with hyperlocomotion in the higher dose. NBQX inhibited the antidepressant effect of both ketamine and CBD. Pretreatment with CBD (10 mg/kg) attenuated the ketamine-induced hyperlocomotion while preserving its antidepressant effect. CONCLUSION: AND IMPLICATIONS: Similar to ketamine, the antidepressant-like effect elicited by CBD involves AMPA receptor activation. Additionally, CBD prevents the hyperlocomotion induced by S-ketamine without affecting its antidepressant-like effect. Our findings suggest that CBD and ketamine's combined administration can be a promising therapeutic strategy for achieving an appropriate antidepressant effect without unwanted side-effects. This article is part of the special issue on 'Cannabinoids'.

Orexin A injection into the ventral medial prefrontal cortex induces antidepressant-like effects: Possible involvement of local Orexin-1 and Trk receptors.

RATIONALE: Reduced levels of orexin-A (OXA) in the central nervous system (CNS) have been associated with the pathophysiology of depression and its exogenous administration promotes antidepressant-like effect. The mechanisms associated with these effects are, however, not yet known. Herein, we investigated the hypothesis that OXA effects could be associated with orexin 1 receptor (OX1R) and tyrosine receptor kinase B (TrkB) activation, in the ventromedial prefrontal cortex (vmPFC), a brain region that is central to depression neurobiology. OBJECTIVES: 1. To Investigate the effects induced by OXA administration into the vmPFC; 2. Evaluate the participation of OX1R and TrkB in behavioral responses induced by OXA. METHODS: Male Wistar rats received intra-vmPFC injections of OXA (10, 50 and 100 pmol/0.2 µL) and were exposed to the forced swimming test (FST) or the open field test (OFT). Independent groups received an intra-vmPFC injection of SB334867 (OX1R antagonist, 10 nmol/0.2 µL) or K252a (non-selective Trk antagonist, 10 pmol/0.2 µL), before local injection of OXA, and were exposed to the same tests. RESULTS: OXA injection (100 pmol/0.2 µL) into the vmPFC induced antidepressant-like effect, which was prevented by SB334867 and K252a pretreatments. CONCLUSION: OXA signaling in the vmPFC induces antidepressant-like effect in the FST which is dependent on OX1R and Trk receptors.

Impaired emotional response to stress in mice lacking galectin-1 or galectin-3.

Galectin-1 (Gal-1) and galectin-3 (Gal-3) are multifunctional glycan-binding proteins, expressed in the brain and in its limbic structures that are involved in behavioral control. Gal-1 induces the expression of the brain-derived neurotrophic factor (BDNF) and promotes adult neural stem cells proliferation, biological events impaired in stress-related psychiatric disorders, such as depression and anxiety. Despite that, there is no evidence regarding galectin involvement in emotional control during stressful situations. Thus, we analyzed the behavioral phenotype of Gal-1 or Gal-3 knock-out mice (Gal-1 KO or Gal-3 KO) in different experimental models predictive of depressive and compulsive-like behaviors. METHODS: C57BL-6 Gal-1 KO, Gal-3 KO, and wild-type mice (WT) were analyzed under the open field test (OFT) and, 6 h later, under the forced swim test (FST). Additionally, independent groups of male mice, lacking galectins or not, were exposed to the tail suspension test (TST) or to the marble burying test (MBT). The hippocampus and prefrontal cortex (PFC) of the mice submitted to MBT were dissected to access BDNF levels. RESULTS: Both Gal-1 and Gal-3 KO mice showed increased time of immobility in the FST and in the TST compared to WT animals, thus reflecting an impaired stress-coping behavior. Additionally, Gal-1 and Gal-3 KO female mice presented increased compulsive-like behavior in the MBT, without significant changes in the locomotor activity. BDNF levels were found to be decreased in the PFC of Gal-1 KO mice. DISCUSSION: Our results demonstrate that the absence of either endogenous Gal-1 and Gal-3 impairs stress-coping and increases compulsive-like behavior, suggesting that Gal-1 and Gal-3 are involved in the neurobiology of depression and obsessive-compulsive-like disorder.

Involvement of CB1 and TRPV1 receptors located in the ventral medial prefrontal cortex in the modulation of stress coping behavior.

Cannabinoid type-1 (CB1) and transient receptor potential vanilloid type-1 (TRPV1) receptors may have opposite roles in modulating neural activity and, consequently, in regulating the stress response. These receptors are widely expressed in several brain structures, including the ventral medial prefrontal cortex (vmPFC). The functional consequences of the interaction between CB1 and TRPV1, however, have scarcely been explored. Therefore, we investigated if CB1 and TRPV1 receptors located in the vmPFC would be involved in the behavioral changes induced by the stress of the forced swim test (FST). Rats with cannulae implanted into the vmPFC were given the dual blocker of TRPV1 receptors and fatty acid amide hydrolase (FAAH), Arachidonyl serotonin (AA-5HT, 0.125/0.25/0.5nmol), TRPV1 antagonist, SB366791 (0.5/1/10nmol), FAAH inhibitor, URB597 (0.001/0.01/0.1/1nmol), or vehicle and were submitted to the FST, or to the open-field test. Another group received intra-vmPFC injection of SB366791 or vehicle, followed by a second injection of URB597 or vehicle, and was submitted to the FST. Lastly, a group received intra-vmPFC injection of a CB1 antagonist, in sub-effective dose or vehicle, followed by AA-5HT, SB366791 or vehicle. The results showed that AA-5HT, SB366791 and URB597 significantly reduced the immobility time without changing the locomotor activity. Furthermore, the co-administration of URB597 and SB366791 in sub-effective doses induced an antidepressant-like effect in the FST. Additionally, the antidepressant-like effect of AA-5HT was prevented by the CB1 antagonist. Together, these results suggest that both, CB1 and TRPV1 receptors located in the vmPFC are involved in the behavioral responses to stress, although in opposite ways.

Antidepressant-like effect of cannabidiol injection into the ventral medial prefrontal cortex-Possible involvement of 5-HT1A and CB1 receptors.

RATIONALE: Systemic administration of cannabidiol (CBD), the main non-psychotomimetic constituent of Cannabis sativa, induces antidepressant-like effects. The mechanism of action of CBD is thought to involve the activation of 5-HT1A receptors and the modulation of endocannabinoid levels with subsequent CB1 activation. The brain regions involved in CBD-induced antidepressant-like effects remain unknown. The ventral medial prefrontal cortex (vmPFC), which includes the infralimbic (IL) and prelimbic (PL) subregions, receives dense serotonergic innervation and plays a significant role in stress responses. OBJECTIVE: To test the hypothesis that the administration of CBD into the IL or PL would induce an antidepressant-like effect through 5-HT1A and CB1 activation. METHODS: Rats received intra-IL or -PL microinjections of CBD (10-60 nmol/side), 8-OH-DPAT (5-HT1A agonist, 5-10 nmol/side), anandamide (AEA, 0.5 pmol/side) or vehicle (0.2 µl/side) and were submitted to the forced swimming (FST) or to the open field (OFT) tests. Independent CBD-treated groups were pre-treated with WAY100635 (10, 30 nmol/side, 5-HT1A antagonist) or AM251 (10 pmol/side, CB1 antagonist) and submitted to the same tests. An additional group was treated with WAY100635 followed by anandamide. RESULTS: CBD (PL: 10-60 nmol; IL:45-60 nmol) and 8-OH-DPAT (10 nmol) administration significantly reduced the immobility time in the FST, without changing locomotor activity in the OFT. WAY100635 (30 nmol) did not induce effect per se but blocked CBD, 8-OH-DPAT and AEA effects. Additionally, AM251 blocked CBD-effects. CONCLUSION: administration of CBD into the vmPFC induces antidepressant-like effects possibly through indirect activation of CB1 and 5-HT1A receptors.