Dynamic dichotomy of accumbal population activity underlies cocaine sensitization

Locomotor sensitization (LS) is an early behavioral adaptation to addictive drugs, driven by the increase of dopamine in the Nucleus Accumbens (NAc). However, the effect on accumbal population activity remains elusive. Here we used single cell calcium imaging in mice to record the activity of dopamine-1-receptor (D1R) and dopamine-2-receptor (D2R) expressing spiny projection neurons (SPNs) during cocaine LS. Acute exposure to cocaine elevated D1R SPN activity and reduced D2R SPN activity, albeit with high variability between neurons. During LS, the number of D1R and D2R neurons responding in opposite directions increased. Moreover, preventing LS by inhibition of the ERK signaling pathway decreased the number of cocaine responsive D1R SPNs, but had little effect on D2R SPNs. These results indicate that accumbal population dichotomy is dynamic and contains a subgroup of D1R SPNs that eventually drives LS. Insights into the drug-related activity dynamics provides a foundation for understanding the circuit-level addiction pathogenesis.

LEAP2 Impairs the Capability of the Growth Hormone Secretagogue Receptor to Regulate the Dopamine 2 Receptor Signaling

The growth hormone secretagogue receptor (GHSR) signals in response to ghrelin, but also acts via ligand-independent mechanisms that include either constitutive activation or interaction with other G protein-coupled receptors, such as the dopamine 2 receptor (D2R). A key target of GHSR in neurons is voltage-gated calcium channels type 2.2 (CaV2.2). Recently, the liver-expressed antimicrobial peptide 2 (LEAP2) was recognized as a novel GHSR ligand, but the mechanism of action of LEAP2 on GHSR is not well understood. Here, we investigated the role of LEAP2 on the canonical and non-canonical modes of action of GHSR on CaV2.2 function. Using a heterologous expression system and patch-clamp recordings, we found that LEAP2 impairs the reduction of CaV2.2 currents induced by ghrelin-evoked and constitutive GHSR activities, acting as a GHSR antagonist and inverse agonist, respectively. We also found that LEAP2 prevents GHSR from modulating the effects of D2R signaling on CaV2.2 currents, and that the GHSR-binding N-terminal region LEAP2 underlies these effects. Using purified labeled receptors assembled into lipid nanodiscs and Forster Resonance Energy Transfer (FRET) assessments, we found that the N-terminal region of LEAP2 stabilizes an inactive conformation of GHSR that is dissociated from Gq protein and, consequently, reverses the effect of GHSR on D2R-dependent Gi activation. Thus, our results provide critical molecular insights into the mechanism mediating LEAP2 modulation of GHSR.

Recognition and Management of Antipsychotic-Induced Parkinsonism in Older Adults: A Narrative Review

Background: Parkinsonism is a common side-effect of antipsychotic drugs especially in older adults, who also present with a higher frequency of neurodegenerative disorders like Idiopathic Parkinson’s disease (IPD). Distinguishing between antipsychotic-induced parkinsonism (AIP) and IPD is challenging due to clinical similarities. Up to 20% of older adults may suffer from persisting parkinsonism months after discontinuation of antipsychotics, suggesting underlying neurodegeneration. A review of the literature on AIP in older adults is presented, focusing on epidemiology, clinical aspects, and management. Methods: A literature search was undertaken on EMBASE, MEDLINE and PsycINFO, for articles on parkinsonism induced by antipsychotic drugs or other dopamine 2 receptor antagonists in subjects aged 65 or older. Results: AIP in older adults is the second most common cause of parkinsonism after IPD. Older age, female gender, exposure to high-potency first generation antipsychotics, and antipsychotic dosage are the main risk factors. The clinical presentation of AIP resembles that of IPD, but is more symmetrical, affects upper limbs more, and tends to have associated motor phenomena such as orofacial dyskinesias and akathisia. Presence of olfactory dysfunction in AIP suggests neurodegeneration. Imaging of striatal dopamine transporters is widely used in IPD diagnosis and could help to distinguish it from AIP. There is little evidence base for recommending pharmacological interventions for AIP, the best options being dose-reduction/withdrawal, or switching to a second-generation drug. Conclusions: AIP is a common occurrence in older adults and it is possible to differentiate it from IPD. Further research is needed into its pathophysiology and on its treatment.

Repurposing the Antiemetic Metoclopramide as an Antiviral Against Dengue Virus Infection in Neuronal Cells

Dengue virus (DENV) is transmitted by Aedes mosquitoes to humans and is a threat worldwide. No effective new drugs have been used for anti-dengue treatment, and repurposing drugs is an alternative approach to treat this condition. Dopamine 2 receptor (D2R) is a host receptor positively associated with DENV infection. Metoclopramide (MCP), a D2R antagonist clinically used to control vomiting and nausea in patients with DENV infection, was putatively examined for inhibition of DENV infection by targeting D2R. In the mouse neural cell line Neuro-2a with D2R expression, a plaque assay demonstrated the antiviral efficacy of MCP treatment. However, in the cell line BHK-21, which did not express D2R, MCP treatment caused no further inhibition of DENV infection. Either MCP treatment or exogenous administration of a neutralizing D2R antibody blocked DENV binding. Treatment with MCP also reduced DENV dsRNA replication and DENV-induced neuronal cell cytotoxicity in vitro. An in vivo study demonstrated the antiviral effect of MCP against DENV-induced CNS neuropathy and mortality. These results showed that repurposing the D2R-targeting antiemetic MCP is a potential therapeutic strategy against DENV infection.

Dynamic dichotomy of accumbal population activity underlies cocaine sensitization

Locomotor sensitization (LS) is an early behavioral adaptation to addictive drugs, driven by the increase of dopamine in the Nucleus Accumbens (NAc). However, the effect on accumbal population activity remains elusive. Here we used single cell calcium imaging to record the activity of dopamine-1-receptor (D1R) and dopamine-2-receptor (D2R) expressing spiny projection neurons (SPNs) during cocaine LS. Acute exposure to cocaine elevated D1R SPN activity and reduced D2R SPN activity, albeit with high variability between neurons. During LS, the number of D1R and D2R neurons responding in opposite directions increased. Moreover, preventing LS by inhibition of the ERK signalling pathway decreased the number of cocaine-responsive D1R SPNs, but had little effect on D2R SPNs. These results indicate that accumbal population dichotomy is dynamic and contains a subgroup of D1R SPNs that eventually drives LS. Insights into the drug-related activity dynamics provides a foundation for understanding the circuit-level addiction pathogenesis.

Ascorbic acid improves extrapyramidal syndromes and corpus striatal degeneration induced by dopamine-2 receptor inhibition in Wistar rats

ObjectivesThe prolonged uses of fourth-generation antipsychotics have been implicated in inducing extrapyramidal syndromes characterized by the motor deficit. This was attributed to the loss of dopamine-2 receptor (D2R) signaling. However, ascorbic acid (SVCT2R stimulation) in the brain is proposed to modulate D2R activity. We, therefore, investigated the beneficial roles of ascorbic acid in improving the extrapyramidal symptoms seen in D2R loss.MethodsTwenty adult male Wistar rats of average weight 200 g were distributed randomly into four groups. The control (NS) received normal saline for 28 days, Untreated D2R inhibition group (−D2R) received normal saline for seven days and then subsequently received chlorpromazine for 21 days, D2R inhibition group treated with ascorbic acid (−D2R+SVCT2R) received chlorpromazine for 21 days and was subsequently treated with ascorbate for seven days while the withdrawal group (WG) received chlorpromazine for 21 days and subsequently received normal saline for seven days. Motor deficits were assessed using a rotarod and cylinder test. The corpus striatum was harvested, processed, and stained using H&E and Nissl stains. Cellular density was analyzed using Image J software 1.8.0.ResultsMotor deficit was observed in −D2R animals administered chlorpromazine with less improvement in WG compared to control (p<0.05) in both rotarod and cylinder test. Ascorbic acid (SVCT2R stimulation) significantly (p<0.001) improved the latency of fall and climbing attempts observed in −D2R animals. The density of basophilic trigoid bodies was significantly (p<0.001) restored in −D2R+SVCT2R group, suggesting recovery of neural activity in the corpus striatum. Moreover, the hallmarks of neuronal degeneration were less expressed in the ascorbic acid treatment groups.ConclusionsAscorbic acid putatively ameliorates extrapyramidal symptoms observed in D2R blockage by chlorpromazine in Wistar rats.

The mammalian target of rapamycin (mTOR) kinase mediates haloperidol-induced cataleptic behavior

The mammalian target of rapamycin (mTOR) is a ubiquitously expressed serine/threonine kinase protein complex (mTORC1 or mTORC2) that orchestrates diverse functions ranging from embryonic development to aging. However, its brain tissue-specific roles remain less explored. Here, we have identified that the depletion of the mTOR gene in the mice striatum completely prevented the extrapyramidal motor side effects (catalepsy) induced by the dopamine 2 receptor (D2R) antagonist haloperidol, which is the most widely used typical antipsychotic drug. Conversely, a lack of striatal mTOR in mice did not affect catalepsy triggered by the dopamine 1 receptor (D1R) antagonist SCH23390. Along with the lack of cataleptic effects, the administration of haloperidol in mTOR mutants failed to increase striatal phosphorylation levels of ribosomal protein pS6 (S235/236) as seen in control animals. To confirm the observations of the genetic approach, we used a pharmacological method and determined that the mTORC1 inhibitor rapamycin has a profound influence upon post-synaptic D2R-dependent functions. We consistently found that pretreatment with rapamycin entirely prevented (in a time-dependent manner) the haloperidol-induced catalepsy, and pS6K (T389) and pS6 (S235/236) signaling upregulation, in wild-type mice. Collectively, our data indicate that striatal mTORC1 blockade may offer therapeutic benefits with regard to the prevention of D2R-dependent extrapyramidal motor side effects of haloperidol in psychiatric illness.

An Effective Method to Facilitate Personalized and Precise Medicine for Schizophrenia Treatment Based on Pharmacogenomics

Background: Schizophrenia is a serious mental illness affecting 0.3% - 0.7% of people in the whole world. It is a classic quantitative genetic disease and is affected by a variety of common and rare genetic variants. Methods: To facilitate personalized and precise medicine for schizophrenia treatment, we designed a program by genotyping a panel of related genes, including cytochrome P450 genes CYP1A2, CYP2D6, CYP3A4, dopamine 2 receptor gene (DRD2), 5-Hydroxytryptamine Receptor 1A and 2C genes (HTR1A and HTR2C) as well as melanocortin4 receptor (MC4R) gene, for the schizophrenia patients using MassArray time-of-flight mass spectrometry. Results: The program is tested in an observational clinical study conducted at the Hulunbuir Mental Health Center of China. In the study, a total of 254 patients diagnosed with schizophrenia were recruited and genotyped. The genotyping results were used to generate reports listing where the 16 included antipsychotics should be placed: 'Use as directed', 'Use with caution' or 'Use with caution and with frequent blood concentration monitoring' columns. However, the medication would not change regardless. 72 of the patients completed the 24-week follow-up observation, during which their PANSS scores were assessed at eight time points. For all of them, the PANSS scores dropped significantly, showing the effectiveness of the treatments. The treatments for those cohorts initially in the 'Use with caution' or 'Use with caution and with frequent blood concentration monitoring' categories were more effective than those in the 'Use as directed' category in a shorter term sense, up to three months. However, in the longer term, it was still those who were initially in the 'Use as directed' column fared better, whose PANSS scores dropped more significantly. Conclusions: This research indicated that our pharmacogenomic-based program could be a suitable and effective tool to facilitate precise medicine in schizophrenia treatment.