Yang Immunity

Schizophrenia-related psychosis is associated with disturbances in mesolimbic dopamine (DA) transmission, characterized by hyperdopaminergic activity in the mesolimbic pathway. Currently, the only clinically effective treatment for schizophrenia involves the use of antipsychotic medications that block DA receptor transmission. However, these medications produce serious side effects leading to poor compliance and treatment outcomes. Emerging evidence points to the involvement of a specific phytochemical component of marijuana called cannabidiol (CBD), which possesses promising therapeutic properties for the treatment of schizophrenia-related psychoses. However, the neuronal and molecular mechanisms through which CBD may exert these effects are entirely unknown. We used amphetamine (AMPH)-induced sensitization and sensorimotor gating in rats, two preclinical procedures relevant to schizophrenia-related psychopathology, combined with in vivo single-unit neuronal electrophysiology recordings in the ventral tegmental area, and molecular analyses to characterize the actions of CBD directly in the nucleus accumbens shell (NASh), a brain region that is the current target of most effective antipsychotics. We demonstrate that Intra-NASh CBD attenuates AMPH-induced sensitization, both in terms of DAergic neuronal activity measured in the ventral tegmental area and psychotomimetic behavioral analyses. We further report that CBD controls downstream phosphorylation of the mTOR/p70S6 kinase signaling pathways directly within the NASh. Our findings demonstrate a novel mechanism for the putative antipsychotic-like properties of CBD in the mesolimbic circuitry. We identify the molecular signaling pathways through which CBD may functionally reduce schizophrenia-like neuropsychopathology. SIGNIFICANCE STATEMENT The cannabis-derived phytochemical, cannabidiol (CBD), has been shown to have pharmacotherapeutic efficacy for the treatment of schizophrenia. However, the mechanisms by which CBD may produce antipsychotic effects are entirely unknown. Using preclinical behavioral procedures combined with molecular analyses and in vivo neuronal electrophysiology, our findings identify a functional role for the nucleus accumbens as a critical brain region whereby CBD can produce effects similar to antipsychotic medications by triggering molecular signaling pathways associated with the effects of classic antipsychotic medications. Specifically, we report that CBD can attenuate both behavioral and dopaminergic neuronal correlates of mesolimbic dopaminergic sensitization, via a direct interaction with mTOR/p70S6 kinase signaling within the mesolimbic pathway.

The Pharmacogenomics Journal - Distinct proteomic profiles of amphetamine self-administration...

This study on serotonin transporters shows that amphetamine-induced monoamine release requires cooperative substrate and cosubstrate binding. A kinetic model is

The psychostimulant amphetamine can be prescribed to ameliorate the symptoms of narcolepsy, attention-deficit hyperactivity disorder and to facilitate weight lo...

In this study, we evaluated the application of the diffusive gradient in the thin films (DGT) technique to predict the bioavailability of methamphetamine (METH) and its metabolite, amphetamine (AMP), in zebrafish (Danio rerio). We simultaneously exposed zebrafish and DGT devices to water spiked with different concentrations of METH. Subsequently, METH and its major metabolite, AMP, were quantified in DGTs and in zebrafish in vivo, the latter of which tended to bioaccumulate and biotransform METH to AMP. After a two-week duration of METH exposure, concentrations were up to 4.49 ± 0.17, 6.42 ± 0.06, and 132 ± 0.48 ng/g wet weight for METH and 4.25 ± 0.62, 8.46 ± 0.58, and 419 ± 45.0 ng/g wet weight for AMP in zebrafish when exposed to 0.01, 1.00, and 100.00 μg/L of METH solution, respectively. Although the in vivo bioaccumulation and biotransformation of METH in zebrafish are likely complex, we found a strong positive correlation (R2 = 0.97–1.00, p < 0.001) between the mass of METH uptake by the DGT and the METH concentrations in vivo in zebrafish. Similarly, there was also a significant correlation (R2 = 0.95, p < 0.001) between the AMP concentration in zebrafish and the mass of AMP uptake by the DGT at a METH exposure concentration of 1.00 μg/L. The correlation in the other two exposure concentrations was not strong, probably due to the fact that AMP accumulated in fish did not increase in a concentration-dependent manner. Taken together, these findings suggest that the DGT may act as a useful tool for estimating the bioavailability of METH and its metabolite, AMP, in aquatic organisms.

Background The dopaminergic pathways have previously been reported to be involved in drug dependence. The candidate gene involved in the dopaminergic function has been associated with substance abuse. Objective The objective of the study is to investigate the possible association between dopaminergic system gene polymorphisms with mixed amphetamine-type stimulants and opioid dependence in Malaysian Malays. The study has never been done anywhere else, due to its unique population of study subjects. Subjects and methods In this study, genetic polymorphisms of dopamine D2 receptor (DRD2) dopamine transporter (SLC6A3), dopamine beta-hydroxylase (DβH), and norepinephrine transporter (SLC6A2) in Malay males (n = 70) having mixed amphetamine-type stimulant (ATS) and opioid dependence were compared with those in control subjects (n = 87). DNA was extracted from leucocytes followed by single nucleotide polymorphism (SNP) determination using PCR-RFLP. The association of the gene with drug dependency was analyzed using chi-squared tests. Results There was a significant difference between the genotype (χ2 = 10.048, p < 0.01) and allele frequency (χ2 = 14.039, p = 0.000) of the DRD2 rs1800497 gene in the drug dependence group as compared to the control. There was also a significant difference in DβH rs1611115 at the allelic (χ2 = 4.483, p = 0.034) but not at genotypic levels (χ2 = 7.572, p = 0.23) in both control and drug dependence groups. There was an association for SLC6A3 rs27072 with drug dependence at the genotypic level (χ2 = 7.006, p = 0.030) although no significant difference exist at the allelic level (χ2 = 2.091, p = 0.148). No significant difference was observed in SLC6A2 rs3785157 genes polymorphism at both genotype and allelic level in control and drug dependence group respectively (χ2 = 0.94, p = 0.954) (χ2 = 0.29, p = 0.865) indicating that these polymorphisms do not affect drug dependence. Conclusion Our study suggests that DRD2 rs1800497, DβH rs1611115, and SLC6A3 rs27072 but not SLC6A2 rs3785157 are associated with drug-dependent behavior among Malaysian Malays.

Researchers have investigated the actions of the drug in rats. Using dopamine cell recordings, electrochemical monitoring and computer modeling, they discovered a type of feedback loop that modulates dopamine levels in the rats' brains in response to the drug. This regulatory process may shed light on methylphenidate's therapeutic properties in ADHD.

At present, therapeutic options available for treating schizophrenia are limited to monoamine-based antipsychotic drugs. Recent genome wide association study (GWAS) indicated a close relationship between immune system and schizophrenia. To leverage the ...