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Previous evidence suggests that α 2 -adrenoceptors (α 2 -AR) may be involved in the pathophysiology of schizophrenia. However, postmortem brain studies on α 2 -AR expression and functionality in schizophrenia are scarce. The aim of our work was to evaluate α 2A -AR and α 2C -AR expression in different subcellular fractions of prefrontal cortex postmortem tissue from antipsychotic-free (absence of antipsychotics in blood at the time of death) (n = 12) and antipsychotic-treated (n = 12) subjects with schizophrenia, and matched controls (n = 24). Functional coupling of α 2 -AR to G α proteins induced by the agonist UK14304 was also tested. Additionally, G α protein expression was also evaluated. In antipsychotic-free schizophrenia subjects, α 2A -AR and α 2C -AR protein expression was similar to controls in all the subcellular fractions. Conversely, in antipsychotic-treated schizophrenia subjects, increased α 2A -AR expression was found in synaptosomal plasma membrane and postsynaptic density (PSD) fractions (+60% and +79% vs controls, respectively) with no significant changes in α 2C -AR. [ 35 S]GTPγS SPA experiments showed a significant lower stimulation of G αi2 and G αi3 proteins by UK14304 in antipsychotic-treated schizophrenia subjects, whereas stimulation in antipsychotic-free schizophrenia subjects remained unchanged. G αo protein stimulation was significantly decreased in both antipsychotic-free and antipsychotic-treated schizophrenia subjects compared to controls. Expression of G αi3 protein did not differ between groups, whereas G αi2 levels were increased in PSD of schizophrenia subjects, both antipsychotic-free and antipsychotic-treated. G αo protein expression was increased in PSD of antipsychotic-treated subjects and in the presynaptic fraction of antipsychotic-free schizophrenia subjects. The present results suggest that antipsychotic treatment is able to modify in opposite directions both the protein expression and the functionality of α 2A -AR in the cortex of schizophrenia patients., (Copyright © 2021. Published by Elsevier B.V.)

Schizophrenia has been associated with alterations in neurotransmission and synaptic dysfunction. Spinophilin is a multifunctional scaffold protein that modulates excitatory synaptic transmission and dendritic spine morphology. Spinophilin can also directly interact with and regulate several receptors for neurotransmitters, such as dopamine D 2 receptors, which play a role in the pathophysiology of schizophrenia and are targets of antipsychotics. Several studies have thus suggested an implication of spinophilin in schizophrenia. In the present study spinophilin protein expression was determined by western blot in the postmortem dorsolateral prefrontal cortex of 24 subjects with schizophrenia (12 antipsychotic-free and 12 antipsychotic-treated subjects) and 24 matched controls. Experiments were performed in synaptosomal membranes (SPM) and in postsynaptic density fractions (PSD). As previously reported, two specific bands for this protein were observed: an upper 120-130 kDa band and a lower 80-95 kDa band. The spinophilin lower band showed a significant decrease in schizophrenia subjects compared to matched controls, both in SPM and PSD fractions (-15%, p = 0.007 and -15%, p = 0.039, respectively). When schizophrenia subjects were divided by the presence or absence of antipsychotics in blood at death, the lower band showed a significant decrease in antipsychotic-treated schizophrenia subjects (-24%, p = 0.003 for SPM and -26%, p = 0.014 for PSD), but not in antipsychotic-free subjects, compared to their matched controls. These results suggest that antipsychotics could produce alterations in spinophilin expression that do not seem to be related to schizophrenia per se. These changes may underlie some of the side effects of antipsychotics., Competing Interests: Conflict of interest Authors declare that they have no conflicts of interest., (Copyright © 2020. Published by Elsevier B.V.)

We had previously shown that alcohol consumption can induce cellular isoaspartate protein damage via an impairment of the activity of protein isoaspartyl methyltransferase (PIMT), an enzyme that triggers repair of isoaspartate protein damage. To further investigate the mechanism of isoaspartate accumulation, hepatocytes cultured from control or 4-week ethanol-fed rats were incubated in vitro with tubercidin or adenosine. Both these agents, known to elevate intracellular S-adenosylhomocysteine levels, increased cellular isoaspartate damage over that recorded following ethanol consumption in vivo. Increased isoaspartate damage was attenuated by treatment with betaine. To characterize isoaspartate-damaged proteins that accumulate after ethanol administration, rat liver cytosolic proteins were methylated using exogenous PIMT and (3)H-S-adenosylmethionine and proteins resolved by gel electrophoresis. Three major protein bands of ∼ 75-80 kDa, ∼ 95-100 kDa, and ∼ 155-160 kDa were identified by autoradiography. Column chromatography used to enrich isoaspartate-damaged proteins indicated that damaged proteins from ethanol-fed rats were similar to those that accrued in the livers of PIMT knockout (KO) mice. Carbamoyl phosphate synthase-1 (CPS-1) was partially purified and identified as the ∼ 160 kDa protein target of PIMT in ethanol-fed rats and in PIMT KO mice. Analysis of the liver proteome of 4-week ethanol-fed rats and PIMT KO mice demonstrated elevated cytosolic CPS-1 and betaine homocysteine S-methyltransferase-1 when compared to their respective controls, and a significant reduction of carbonic anhydrase-III (CA-III) evident only in ethanol-fed rats. Ethanol feeding of rats for 8 weeks resulted in a larger (∼ 2.3-fold) increase in CPS-1 levels compared to 4-week ethanol feeding indicating that CPS-1 accumulation correlated with the duration of ethanol consumption. Collectively, our results suggest that elevated isoaspartate and CPS-1, and reduced CA-III levels could serve as biomarkers of hepatocellular injury., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Recent advances in the understanding of alcohol dependence suggest that the endocannabinoid system (ECS) plays a key role in the neurobiological mechanisms underlying this pathology., Methods: The aim of the present review is to show the currently available biochemical, behavioral and genetic evidence on the involvement of the ECS in alcohol dependence., Discussion: Firstly, biochemical studies have shown that both chronic and acute administration of ethanol produce alterations in different elements of this neurotransmission system. Secondly, the pharmacological and genetic manipulation of the ECS in rodents result in altered ethanol-related behavior. Furthermore, rodent strains with different preference for ethanol differ in their ECS state. Also, genetic studies have described that particular polymorphisms in the genes coding for some elements of this system are associated with some phenotypes of alcohol dependence. Finally, the possible efficacy of cannabinoid receptor blockers in the prevention of relapse to alcohol has been tested in clinical trials., Conclusion: Altogether, these multiple lines of evidence suggest that the ECS is implicated in the development of alcohol abuse and dependence., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)