Modulating D1 rather than D2 receptor-expressing spiny-projection neurons corresponds to optimal antipsychotic effect

Overactive dopamine transmission in psychosis is predicted to unbalance striatal output via D1- and D2-dopamine receptor-expressing spiny-projection neurons (SPNs). Antipsychotic drugs are thought to re-balance this output by blocking D2-receptor signaling. Here we imaged D1- and D2-SPN Ca2+ dynamics in mice to determine the neural signatures of antipsychotic effect. Initially we compared effective (clozapine and haloperidol) antipsychotics to a candidate drug that failed in clinical trials (MP-10). Clozapine and haloperidol normalized hyperdopaminergic D1-SPN dynamics, while MP-10 only normalized D2-SPN activity. Clozapine, haloperidol or chemogenetic manipulations of D1-SPNs also normalized sensorimotor gating. Given the surprising correlation between clinical efficacy and D1-SPN modulation, we evaluated compounds that selectively target D1-SPNs. D1R partial agonism, antagonism, or positive M4 cholinergic receptor modulation all normalized the levels of D1-SPN activity, locomotion, and sensorimotor gating. Our results suggest that D1-SPN activity is a more relevant therapeutic target than D2-SPN activity for the development of effective antipsychotics.

Pitfalls of NMDA Receptor Modulation by Neuroactive Steroids. The Effect of Positive and Negative Modulation of NMDA Receptors in an Animal Model of Schizophrenia

Evidence from clinical and preclinical studies implicates dysfunction of N-methyl-D-aspartate receptors (NMDARs) in schizophrenia progression and symptoms. We investigated the antipsychotic effect of two neuroactive steroids in an animal model of schizophrenia induced by systemic application of MK-801. The neuroactive steroids differ in their mechanism of action at NMDARs. MS-249 is positive, while PA-Glu is a negative allosteric NMDAR modulator. We hypothesized that the positive NMDA receptor modulator would attenuate deficits caused by MK-801 co-application more effectively than PA-Glu. The rats were tested in a battery of tests assessing spontaneous locomotion, anxiety and cognition. Contrary to our expectations, PA-Glu exhibited a superior antipsychotic effect to MS-249. The performance of MS-249-treated rats in cognitive tests differed depending on the level of stress the rats were exposed to during test sessions. In particular, with the increasing severity of stress exposure, the performance of animals worsened. Our results demonstrate that enhancement of NMDAR function may result in unspecific behavioral responses. Positive NMDAR modulation can influence other neurobiological processes besides memory formation, such as anxiety and response to stress.

Cannabidiol modulation of hippocampal glutamate in early psychosis

Background: Emerging evidence supports the antipsychotic effect of cannabidiol, a non-intoxicating component of cannabis, in people with psychosis. Preclinical findings suggest that this antipsychotic effect may be related to cannabidiol modulating glutamatergic signalling in the brain. Aim: The purpose of this study was to investigate the effects of cannabidiol on the neurochemical mechanisms underlying psychosis. Methods: We investigated the effects of a single oral dose of cannabidiol (600 mg) in patients with psychosis, using a double-blind, randomised, placebo-controlled, repeated-measures, within-subject cross-over design. After drug administration, 13 patients were scanned using proton magnetic resonance spectroscopy to measure left hippocampal glutamate levels. Symptom severity was rated using the Positive and Negative Syndrome Scale 60 min before drug administration (pre-scan), and 270 min after drug administration (post-scan). Effects of cannabidiol on hippocampal glutamate levels, symptom severity, and correlations between hippocampal glutamate and symptoms were investigated. Results: Compared to placebo, there was a significant increase in hippocampal glutamate ( p=0.035), and a significantly greater decrease in symptom severity ( p=0.032) in the psychosis patients under cannabidiol treatment. There was also a significant negative relationship between post-treatment total Positive and Negative Syndrome Scale score and hippocampal glutamate ( p=0.047), when baseline Positive and Negative Syndrome Scale score, treatment (cannabidiol vs placebo), and interaction between treatment and glutamate levels were controlled for. Conclusions: These findings may suggest a link between the increase in glutamate levels and concomitant decrease in symptom severity under cannabidiol treatment observed in psychosis patients. Furthermore, the findings provide novel insight into the potential neurochemical mechanisms underlying the antipsychotic effects of cannabidiol.

O5.2. CBD MODULATION OF HIPPOCAMPAL GLUTAMATE IN PSYCHOSIS

Background Emerging evidence supports the antipsychotic effect of cannabidiol (CBD), a non-intoxicating component of cannabis, in people with psychosis. However, how CBD might exert its antipsychotic effect remains unclear. While current antipsychotic medications typically target the dopaminergic neurotransmitter system, preclinical findings suggest that CBD may directly or indirectly affect multiple distinct modes of neural signalling, including both glutamate and dopamine. However, no study has as yet investigated the effect of CBD on brain glutamate levels in patients with psychosis as a potential mechanism underlying its antipsychotic effects. Methods We investigated the effects of a single oral dose of CBD (600mg), compared to a matched placebo, in patients within 5 years of onset of psychosis, using a double-blind, randomized, placebo-controlled, repeated-measures, within-subject cross-over design, with at least a one-week interval between scans to allow washout of CBD. After drug administration, 13 patients (mean age 27.73, 66.7% male) were scanned using proton magnetic resonance spectroscopy to measure left hippocampal glutamate levels. Symptom severity was assessed using the Positive and Negative syndrome scale (PANSS) 60mins before drug administration (T1, pre scan), and 270mins after drug administration (T2, post scan). Effects of CBD on left hippocampal glutamate levels, symptoms, and correlations between hippocampal glutamate and symptoms were investigated. Results Compared to placebo, there was a significant increase in left hippocampal glutamate in the psychosis patients under CBD treatment (z= -1.80; p=0.035). Under placebo treatment, change in positive psychotic symptoms (as indexed using the T1 minus T2 PANSS positive symptoms subscale scores) was directly correlated with left hippocampal glutamate levels (rho= 0.69, p=0.004), such that symptoms increased as hippocampal glutamate levels decreased. This significant relationship was not observed under the CBD treatment (rho= 0.102, p=0.72). Discussion This suggests that positive psychotic symptoms may be driven by abnormal hippocampal glutamate concentration, which is sensitive to modulation by CBD. These findings are in keeping with the purported antipsychotic effects of CBD in psychosis, and provide novel insight into the neurochemical interactions underlying these effects.

SYSTEMATIC REVIEW OF THE OCCURRENCE OF PSYCHOTIC SYMPTOMS IN THE TRAMADOL AND OXYCODONE WITHDRAWAL .

Objetives: To begin with, this systematic review arises from the interest to know about the appearance of psychotic and opioid symptomatology. Therefore, the main objective of this research is to establish the appearance of psychotic symptoms in the removal of oxycodone and tramadol. Methods: As far as the research procedure is concerned, a systematic review has been carried out which focuses on the relation of the psychotic symptoms caused by the withdrawal of buprenorphine. In this way, we have selected those scientific papers filed in the database PubMed looking for the key words: “Tramadol; Oxycodone” AND “psychosis, psychotic symptoms; schizophrenia”. Results and conclusions: In current literature, there are three publications dealing with clinic cases where patients suffered from psychotic symptoms after the removal of tramadol or oxycodone. Two of them are case reports about patients who presented psychotic symptoms after stopping these opioids. It is necessary to continue observing and reporting all cases of psychotic symptoms after an opioid withdrawal, as well as the potential antipsychotic effect of the drugs

Design, Synthesis and Biological Profiling of Novel Phenothiazine Derivatives as Potent Antitubercular Agents

Background: Neuroleptic phenothiazines have been reported for antitubercular activity, but the unwanted side effect (antipsychotic activity) restricted their use as antitubercular drugs. Objective: The study aimed to carry out development of phenothiazine based antitubercular agents by modifying/removing the chemical group(s)/ linker(s) of chlorpromazine essential for exerting an antipsychotic effect. Methods: The designed molecules were filtered with a cut-off of docking score < 2.0 Kcal/mol against dopamine receptors, so that their binding with the receptor would be reduced to produce no/ less antipsychotic effect. The molecules were then synthesized and screened against M. tuberculosis H37Rv. They were further screened against a gram-positive (S. aureus) and a gram-negative (E. coli) bacterial strains to evaluate the spectrum of activity. The ability of the compounds to cross the blood-brain barrier (BBB) was also analyzed. The compounds were further examined for cytotoxicity (CC50) against mammalian VERO cells. Results: Compounds 14p, 15p and 16p were found to be the most effective against all the strains viz. M. tuberculosis H37Rv, S. aureus and E. coli with MIC of 1.56µg/ml, 0.98µg/ml and 3.91µg/ml, respectively. Further, BBB permeability was found to be diminished in comparison to chlorpromazine, which would ultimately reduce the unwanted antipsychotic activity. They were also found to be free from toxicity against VERO cells. Conclusion: The designed strategy, to enhance the antitubercular activity with concomitant reduction of dopamine receptor binding and BBB permeability was proved to be fruitful.