Unraveling the molecular basis of cannabidiolic acid methyl Ester's anti-depressive effects in a rat model of treatment-resistant depression.

Major depressive disorder (MDD) stands as a significant cause of disability globally. Cannabidiolic Acid-Methyl Ester (CBDA-ME) (EPM-301, HU-580), a derivative of Cannabidiol, demonstrates immediate antidepressant-like effects, yet it has undergone only minimal evaluation in psychopharmacology. Our goal was to investigate the behavioral and potential molecular mechanisms associated with the chronic oral administration of this compound in the Wistar Kyoto (WKY) genetic model of treatment-resistant depression. Male WKY rats were subjected to behavioral assessments before and after receiving chronic (14-day) oral doses of CBDA-ME (0.5 mg/kg), 15 mg/kg of imipramine or vehicle. At the end of the study, plasma corticosterone levels and mRNA expression of various genes in the medial Prefrontal Cortex and Hippocampus were measured. Behavioral outcomes from CBDA-ME treatment indicated an antidepressant-like effect similar to imipramine, as oral ingestion reduced immobility and increased swimming duration in the Forced Swim Test. Neither treatment influenced locomotion in the Open Field Test nor preference in the Saccharin Preference Test. The behavioral impact in WKY rats coincided with reduced corticosterone serum levels, upregulated mRNA expression of Cannabinoid receptor 1, Fatty Acid Amide Hydrolase, and Corticotropin-Releasing Hormone Receptor 1, alongside downregulation of the Serotonin Transporter in the hippocampus. Additionally, there was an upregulation of CB1 mRNA expression and downregulation of Brain-Derived Neurotrophic Factor in the mPFC. These findings contribute to our limited understanding of the antidepressant effects of CBDA-ME and shed light on its potential psychopharmacological mechanisms. This discovery opens up possibilities for utilizing cannabinoids in the treatment of major depressive disorder and related conditions.

Abnormally persistent latent inhibition induced by MK801 is reversed by risperidone and by positive modulators of NMDA receptor function: differential efficacy depending on the stage of the task at which they are administered.

RATIONALE: Latent inhibition (LI) is the poorer conditioning to a stimulus resulting from its nonreinforced preexposure. LI indexes the ability to ignore irrelevant stimuli and is used extensively to model attentional impairments in schizophrenia (SZ). We showed that rats and mice treated with the N-methyl-D-aspartic acid (NMDA) receptor antagonist MK801 expressed LI under conditions preventing LI expression in controls. This abnormally persistent LI was reversed by the atypical antipsychotic drug (APD) clozapine and by compounds enhancing NMDA transmission via the glycineB site, but not by the typical APD haloperidol, lending the MK801 LI model predictive validity for negative/cognitive symptoms. OBJECTIVE: To test additional representatives from the two classes of drugs and show that the model can dissociate between atypical APDs and glycinergic drugs are the objectives of the study. MATERIALS AND METHODS: LI was measured in a conditional emotional response procedure. Atypical APD risperidone, selective 5HT2A antagonist M100907, and three glycinergic drugs were administered in preexposure or conditioning. RESULTS: Rats treated with MK801 (0.05 mg/kg) exhibited LI under conditions that disrupted LI in controls. This abnormality was reversed by risperidone (0.25 and 0.067 mg/kg) and M100907 (1 mg/kg) given in preexposure. Glycine (0.8 g/kg), D-cycloserine (DCS;15 and 30 mg/kg), and glycyldodecylamide (GDA; 0.05 and 0.1 g/kg.) counteracted MK801-induced LI persistence when given in conditioning. CONCLUSIONS: These results support the validity of MK801-induced persistent LI as a model of negative/cognitive symptoms in SZ and indicate that this model may have a unique capacity to discriminate between typical APDs, atypical APDs, and glycinergic compounds, and thus, foster the identification of novel treatments for SZ.

A comparison of drug effects in latent inhibition and the forced swim test differentiates between the typical antipsychotic haloperidol, the atypical antipsychotics clozapine and olanzapine, and the antidepressants imipramine and paroxetine.

Current animal models of antipsychotic activity that have the capacity to dissociate between typical and atypical antipsychotic drugs (APDs) have two drawbacks: they require previous administration of a psychotomimetic drug, and they achieve the dissociation by demonstrating effectiveness of atypical but not typical APDs, thus losing specificity and selectivity for APDs. The present experiments were designed to solve these problems by using two non-pharmacological tests: latent inhibition (LI), in which potentiation of the deleterious effects of non-reinforced stimulus pre-exposure on its subsequent conditioning served as a behavioral index for a common action of typical and atypical APDs (antipsychotic), and the forced swim test (FST), in which reduction of immobility served as a behavioral index for a dissimilar action of these drugs (antidepressant). The typical APD haloperidol (0.1 mg/kg), the atypical APDs clozapine (2.5 mg/kg) and olanzapine (0.6 mg/kg), and the antidepressants imipramine (10 mg/kg) and paroxetine (7.0 mg/kg), produced distinct patterns of action in the two tests: haloperidol potentiated LI and increased immobility in the FST, clozapine and olanzapine potentiated LI and decreased immobility in the FST, and imipramine and paroxetine decreased immobility in the FST and did not potentiate LI. Thus, the comparison of drug effects in LI and FST enabled a discrimination between typical and atypical APDs without losing selectivity for APDs.

Systemic administration of MK-801 produces an abnormally persistent latent inhibition which is reversed by clozapine but not haloperidol.

RATIONALE: Latent inhibition (LI) refers to retarded conditioning to a stimulus as a consequence of its inconsequential pre-exposure, and disrupted LI in the rat is considered to model an attentional deficit in schizophrenia. Blockade of NMDA receptor transmission, which produces behavioral effects potentially relevant to schizophrenic symptomatology in several animal models, has been reported to spare LI. OBJECTIVES: To show that systemic administration of the non-competitive NMDA antagonist MK-801 will lead to an abnormally persistent LI which will emerge under conditions that disrupt LI in controls, and that this will be reversed by the atypical neuroleptic clozapine but not by the typical neuroleptic haloperidol, as found for other NMDA antagonist-induced models. METHODS: LI was measured in a thirst-motivated conditioned emotional response (CER) procedure by comparing suppression of drinking in response to a tone in rats which previously received 0 (non-pre-exposed) or 40 tone exposures (pre-exposed) followed by two (experiment 1) or five (experiments 2-5) tone - foot shock pairings. RESULTS: MK-801 at doses of 0.1 and 0.2 mg/kg reduced conditioned suppression while no effect on suppression was seen at the 0.05 mg/kg dose. At the latter dose, intact LI was seen with parameters that produced LI in controls (40 pre-exposures and two conditioning trials). Raising the number of conditioning trials to five disrupted LI in control rats, but MK-801-treated rats continued to show LI, and this abnormally persistent LI was due to the action of MK-801 in the conditioning stage. MK-801-induced LI perseveration was unaffected by both haloperidol (0.1 mg/kg) and clozapine (5 mg/kg) administered in conditioning, and was reversed by clozapine but not by haloperidol administered in pre-exposure. CONCLUSION: MK-801-induced perseveration of LI is consistent with other reports of perseverative behaviors, suggested to be particularly relevant to negative symptoms of schizophrenia, following NMDA receptor blockade. We suggest that LI perseveration may model impaired attentional set shifting associated with negative symptoms of schizophrenia. Moreover, the finding that the action of MK-801 on LI and the action of clozapine are exerted in different stages of the LI procedure suggests that the MK-801-based LI model may provide a unique screening tool for the identification of novel antipsychotic compounds, whereby the schizophrenia-mimicking LI abnormality is drug-induced, but the detection of the antipsychotic action is not dependent on the mechanism of action of the pro-psychotic drug.