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Attention-deficit hyperactivity disorder (ADHD) is a neurocognitive disorder characterized by hyperactivity, inattention, working memory deficits and impulsivity. Its worldwide prevalence is estimated to be 3-5% in children and adolescents. The mainstay treatment for ADHD is stimulant medications (e.g. methylphenidate), which increase synaptic dopamine by directly blocking dopamine transporter (DAT). Although these pharmacological agents are effective, they are often associated with various side effects including risks for future substance use disorders in ADHD patients. Here, we investigated an interaction between DAT and dopamine D2 receptor (D2R) as a novel target to develop potential therapeutics for the treatment of ADHD by using an interfering peptide (TAT-DATNT) to dissociate this protein complex. We found that TAT-DATNT promotes locomotor behavior in Sprague-Dawley rats. Furthermore, using in vivo microdialysis and high-performance liquid chromatography, we found that the disruption of D2R-DAT elevates extracellular dopamine level. More importantly, the interfering peptide, TAT-DATNT, attenuates hyperactivity and improves spontaneous alternation behavior in spontaneously hypertensive rats (SHR) ------ a common animal model of ADHD. This work presents a different means (i.e. other than direct blockade by a DAT inhibitor) to regulate the activity of DAT and dopaminergic neurotransmission, and a potential target site for future development of ADHD treatments. [ABSTRACT FROM AUTHOR]

Posttraumatic stress disorder (PTSD) can develop after exposure to severe psychological trauma, leaving patients with disabling anxiety, nightmares, and flashbacks. Current treatments are only partially effective, and development of better treatments is hampered by limited knowledge of molecular mechanisms underlying PTSD. We have discovered that the glucocorticoid receptor (GR) and FK506 binding protein 51 (FKBP51) form a protein complex that is elevated in PTSD patients compared with unaffected control subjects, subjects exposed to trauma without PTSD, and patients with major depressive disorder (MDD). The GR-FKBP51 complex is also elevated in fear-conditioned mice, an aversive learning paradigm that models some aspects of PTSD. Both PTSD patients and fear-conditioned mice had decreased GR phosphorylation, decreased nuclear GR, and lower expression of 14-3-3ε, a gene regulated by GR. We created a peptide that disrupts GR-FKBP51 binding and reverses behavioral and molecular changes induced by fear conditioning. This peptide reduces freezing time and increases GR phosphorylation, GR-FKBP52 binding, GR nuclear translocation, and 14-3-3ε expression in fear-conditioned mice. These experiments demonstrate a molecular mechanism contributing to PTSD and suggest that the GR-FKBP51 complex may be a diagnostic biomarker and a potential therapeutic target for preventing or treating PTSD. [ABSTRACT FROM AUTHOR]

γ-aminobutyric acid (GABA)-ergic interneurons are essential for the physiological function of the mammalian central nervous system. Dysregulated GABAergic interneuron function has been implicated in the pathophysiology of a number of neurodevelopmental disorders including schizophrenia and autism spectrum disorder. Tangential migration is an important process to ensure the proper localization of GABAergic interneurons. Previously we found that disrupting the interaction between dopamine D1 receptor (D1R) and synaptic Ras GTPase- activating protein (SynGAP) using an interfering peptide (TAT-D 1 R pep ) during embryonic development impaired tangential migration. Here, we assessed the effects of prenatal disruption of D1R-SynGAP complex with the TAT-D 1 R pep on the expression of several behaviours during adulthood. Mice with prenatal D1R-SynGAP disruption exhibited transiently reduced locomotor activity, abnormal sensorimotor gating, impaired sociability and deficits in visual discrimination associative learning compared to their control counterparts. Our findings reinforce the importance of GABAergic interneuron migration in the manifestation of normal motor, sensory, and cognitive behaviours of animals during adulthood., (Copyright © 2020. Published by Elsevier Inc.)

Striatal dopamine D2R homodimerization is increased in the dorsal striatum after acute amphetamine challenge and in the amphetamine-induced sensitized state, a well-known animal model of schizophrenia. Therefore, it was tested if the increase in D2R homoreceptor complexes found after acute amphetamine challenge in the saline or the amphetamine sensitized state leads to changes in the antagonistic adenosine A2AR-D2R interactions in the striatum. [ 3 H]-raclopride binding was performed in membrane preparations from the ventral and dorsal striatum involving competition with the D2R like agonist quinpirole. In the ventral striatum CGS 21680 produced a significant increase of the K iH values (p<0.05) in the amphetamine sensitized group when expressed in percent versus the corresponding values in saline sensitized rats after amphetamine challenge. However, in the dorsal striatum a significant change did not develop in the K iH values when expressed in percent of the corresponding values in saline sensitized rats after amphetamine challenge. In fact, the non-significant change was in the opposite direction towards a reduction of the K iH values. Taken together, a reduced affinity of the high affinity D2 agonist binding site (K iH value) developed in the ventral but not in the dorsal striatum as a result of increased antagonistic allosteric A2AR-D2R interactions in the amphetamine-induced sensitized state versus the saline sensitized state after an acute amphetamine challenge. The selective reappearance of antagonistic A2AR-D2R receptor-receptor interactions in the ventral striatum after amphetamine challenge in the amphetamine sensitized rat may give one possible mechanism for the atypical antipsychotic-like actions of A2AR receptor agonists., (Copyright © 2016. Published by Elsevier Inc.)

Current antipsychotic drugs primarily target dopamine D2 receptors (D2Rs), in conjunction with other receptors such as those for serotonin. However, these drugs have serious side effects such as extrapyramidal symptoms (EPS) and diabetes. Identifying a specific D2R signaling pathway that could be targeted for antipsychotic effects, without inducing EPS, would be a significant improvement in the treatment of schizophrenia. We report here that the D2R forms a protein complex with Disrupted in Schizophrenia 1 (DISC1) that facilitates D2R-mediated glycogen synthase kinase (GSK)-3 signaling and inhibits agonist-induced D2R internalization. D2R-DISC1 complex levels are increased in conjunction with decreased GSK-3α/β (Ser21/9) phosphorylation in both postmortem brain tissue from schizophrenia patients and in Disc1-L100P mutant mice, an animal model with behavioral abnormalities related to schizophrenia. Administration of an interfering peptide that disrupts the D2R-DISC1 complex successfully reverses behaviors relevant to schizophrenia but does not induce catalepsy, a strong predictor of EPS in humans., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Docosahexaenoic acid (DHA) is an omega-3 polyunsaturated fatty acid (n-3 PUFA) which has been shown to raise seizure thresholds following acute administration in rats. The aims of the present experiment were the following: 1) to test whether subchronic DHA administration raises seizure threshold in the maximal pentylenetetrazol (PTZ) model 24h following the last injection and 2) to determine whether the increase in seizure threshold is correlated with an increase in serum and/or brain DHA. Animals received daily intraperitoneal (i.p.) injections of 50mg/kg of DHA, DHA ethyl ester (DHA EE), or volume-matched vehicle (albumin/saline) for 14days. On day 15, one subset of animals was seizure tested in the maximal PTZ model (Experiment 1). In a separate (non-seizure tested) subset of animals, blood was collected, and brains were excised following high-energy, head-focused microwave fixation. Lipid analysis was performed on serum and brain (Experiment 2). For data analysis, the DHA and DHA EE groups were combined since they did not differ significantly from each other. In the maximal PTZ model, DHA significantly increased seizure latency by approximately 3-fold as compared to vehicle-injected animals. This increase in seizure latency was associated with an increase in serum unesterified DHA. Total brain DHA and brain unesterified DHA concentrations, however, did not differ significantly in the treatment and control groups. An increase in serum unesterified DHA concentration reflecting increased flux of DHA to the brain appears to explain changes in seizure threshold, independent of changes in brain DHA concentrations., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The long-term use of many antipsychotic medications carries a risk of tardive dyskinesia in a small proportion of patients. Although metoclopramide is an antipsychotic at high doses, this drug is more commonly used at low daily doses to accelerate stomach movement of food. Because prolonged use of metoclopramide has also been associated with tardive dyskinesia, this drug is convenient to study to examine the possible basis of tardive dyskinesia. Previous work proposed that antipsychotics accumulated in the melanin granules of the human substantia nigra, ultimately building up to high concentrations that could disrupt cell membranes of nigral neurons. While previous work demonstrated the accumulation of metoclopramide in postmortem human nigral tissue, it remained to be tested whether high concentrations of metoclopramide would actually disrupt cell membranes. Therefore, the present work examined whether metoclopramide could disrupt cell membranes, using human erythrocytes directly exposed to various concentrations of metoclopramide in vitro. It was found that metoclopramide caused disruption of the red cells starting at a threshold of 1 mM, which would result in ~280 μmoles of metoclopramide per kilogram of dry red cell membranes. However, the nonspecific adsorption of metoclopramide to human substantia nigra is ~23 μmol/kg of dry solids (measured at the clinical spinal fluid concentration of metoclopramide). Therefore, the membrane-lytic concentration of metoclopramide is only about 12 times higher than that after a single exposure of the drug to the nigral tissue. Hence, metoclopramide accumulation in the substantia nigra over a matter of months may lead to nigral neuron damage., (Copyright © 2011 Wiley Periodicals, Inc.)