D2 Receptor Research Articles

Virtual Screening Approaches to Identify Promising Multitarget-Directed Ligands for the Treatment of Autism Spectrum Disorder

Autism spectrum disorder is a complex neurodevelopmental disorder. The available medical treatment options for autism spectrum disorder are very limited. While the etiology and pathophysiology of autism spectrum disorder are still not fully understood, recent studies have suggested that wide alterations in the GABAergic, glutamatergic, cholinergic, and serotonergic systems play a key role in its development and progression. Histamine neurotransmission is known to have complex interactions with other neurotransmitters that fit perfectly into the complex etiology of this disease. Multitarget-directed compounds with an affinity for the histamine H3 receptor indicate an interesting profile of activity against autism spectrum disorder in animal models. Here, we present the results of our research on the properties of (4-piperazin-1-ylbutyl)guanidine derivatives acting on histamine H3 receptors as potential multitarget ligands. Through the virtual screening approach, we identified promising ligands among 32 non-imidazole histamine H3 receptor antagonists/inverse agonists with potential additional activity against the dopamine D2 receptor and/or cholinesterases. The virtual screening protocol integrated predictions from SwissTargetPrediction, SEA, and PPB2 tools, along with molecular docking simulations conducted using GOLD 5.3 and Glide 7.5 software. Among the selected ligands, compounds 25 and 30 blocked radioligand binding to the D2 receptor at over 50% at a screening concentration of 1 µM. Further experiments allowed us to determine the pKi value at the D2 receptor of 6.22 and 6.12 for compounds 25 and 30, respectively. Our findings suggest that some of the tested compounds could be promising multitarget-directed ligands for the further research and development of more effective treatments for autism spectrum disorder.

Exploring the role of Cdk5 on striatal synaptic plasticity in a 3-NP-induced model of early stages of Huntington’s disease

Impaired mitochondrial function has been associated with the onset of neurodegenerative diseases. Specifically, certain mitochondrial toxins, such as 3-nitropropionic acid (3-NP), initiate cellular changes within the striatum that closely resemble the pathology observed in Huntington’s disease (HD). Among the pivotal signaling molecules contributing to neurodegeneration, cyclin-dependent kinase 5 (Cdk5) stands out. In particular, Cdk5 has been implicated not only in cellular pathology but also in the modulation of synaptic plasticity. Given its widespread presence in the striatum, this study seeks to elucidate the potential role of Cdk5 in the induction of corticostriatal synaptic plasticity in murine striatal cells subjected to subchronic doses of 3-NP in vivo, aiming to mimic the early stages of HD. Immunostaining analyses revealed an increase in Cdk5 in tissues from animals treated with 3-NP, without a significant change in protein levels. Regarding striatal plasticity, long-term depression (LTD) was induced in both control and 3-NP cells when recorded in voltage clamp mode. The Cdk5 inhibitor roscovitine-reduced LTD in most cells. A minority subset of cells exhibited long-term potentiation (LTP) generation in the presence of roscovitine. The inhibitor of D1 receptors SCH23390 prevented LTP in three of nine cells, implying that MSN cells lacking D1/PKA activation were capable of LTP induction when Cdk5 was also blocked. Nevertheless, the co-administration of H89, a PKA inhibitor, along with roscovitine, prevented the generation of any type of plasticity in all recorded cells. These findings show the impact of 3-NP treatment on striatal plasticity and suggest that Cdk5 during early neurodegeneration may attenuate signaling pathways that lead neurons to increase their activity.

B2R-D2R interaction in prolactinomas and non-functional adenomas: impact on dopamine resistance.

Prolactinomas, the most common pituitary-secreting adenomas, can be effectively treated with dopamine D2 receptor (D2R) agonists. However, a subset of them (∼20%) are resistant to dopamine (DA)-based therapies and require extirpation. The molecular mechanisms underlying their escape from dopaminergic regulation are not fully elucidated and may include alterations in D2R signaling. D2R can heteromerize with other G protein-coupled receptors, resulting in modulation of dopaminergic signaling. Since the bradykinin receptor type 2 (B2R) is overexpressed in prolactinomas, we interrogated whether this dopaminergic dysregulation observed in some prolactinomas may depend on a physical and functional interaction between D2R and B2R. The formation of B2R-D2R complexes in cultured cells transiently expressing both receptors was validated using NanoBiT technology. Interestingly, while D2R stimulation did not alter B2R-induced intracellular calcium mobilization, B2R stimulation abolished D2R signaling through modulation of cAMP. The existence of B2R-D2R complexes in pituitary adenomas (PitNet) biopsies was evaluated using an ALPHALisa approach. Importantly, B2R-D2R complexes were detected in human prolactinomas and nonfunctioning pituitary adenomas (NFPA), but not in mixed (prolactin + growth hormone) secreting adenomas. These results suggest that overexpression of B2R in resistant prolactinomas may promote the formation of B2R-D2R complexes, with B2R precluding D2R signaling, thus generating resistance to D2R agonists.

Dopamine D4 receptors in the lateral habenula regulate anxiety-related behaviors in a rat model of Parkinson's disease

Although the output of the lateral habenula (LHb) controls the activity of midbrain dopamine (DA) and 5-hydroxytryptamine (5-HT) containing systems, which are implicated in the pathophysiology of anxiety, it is not clear how activation and blockade of LHb D4 receptors affects anxiety-like behaviors, particularly in Parkinson’s disease related anxiety. In this study, unilateral 6-hydroxydopamine lesions of the substantia nigra pars compacta (SNc) in rats induced anxiety-like behaviors, which attribute to hyperactivity of LHb neurons and decrease in the level of DA in the medial prefrontal cortex (mPFC), amygdala and ventral hippocampus (vHip) compared to sham-operated rats. Intra-LHb injection of D4 receptor agonist A412997 induced or increased the expression of anxiety-like behaviors, while injection of D4 receptor antagonist L741742 showed anxiolytic effects in sham-operated and the SNc-lesioned rats. However, the doses producing behavioral effects in the lesioned rats were higher than those of sham-operated rats. Intra-LHb injection of A412997 increased firing rate of LHb neurons, and decreased levels of DA and 5-HT in the mPFC, amygdala and vHip; conversely, L741742 decreased firing rate of LHb neurons, and increased levels of DA and 5-HT in two groups of rats. Compared to sham-operated rats, the duration of A412997 and L741742 action on the firing rate of neurons was markedly shortened in the lesioned rats. Collectively, these findings suggest that D4 receptors in the LHb are involved in the regulation of anxiety-like behaviors, and degeneration of the nigrostriatal pathway down-regulates function and/or expression of these receptors.

Investigation into the biomolecular bases of blunted cocaine-induced glutamate release within the nucleus accumbens elicited by adolescent exposure to phenylpropanolamine

Globally, phenylpropanolamine (PPA) is a prevalent primary active ingredient in over-the-counter cough and cold, as well as weight-loss medications. Previously, we showed that a sensitization of cocaine-induced glutamate release within the nucleus accumbens (NAC) and the expression of cocaine-conditioned reward is not apparent in adult mice with a prior history of repeated PPA exposure during adolescence. As NAC glutamate is a purported driver of cocaine reward and reinforcement, the present study employed in vivo microdialysis and immunoblotting approaches to inform as to the receptor and transporter anomalies that might underpin the disrupted glutamate response to cocaine in adolescent PPA-exposed mice. For this, male and female C57BL/6J mice were pretreated, once daily, with either 0 or 40mg/kg PPA during post-natal days 35-44. Adolescent PPA pretreatment significantly altered the expression of mGlu2/3 and α2 receptors in the NAC, with less robust changes detected for EAAT2, D2 receptors, DAT and NET. However, we detected no overt change in the capacity of these receptors or transporters to affect extracellular glutamate levels in adolescent PPA-pretreated mice. The present findings contrast with the pronounced changes in the capacity of mGlu2/3 receptors, EAAT, DAT and NET to regulate NAC extracellular glutamate reported previously for juvenile PPA-pretreated mice, indicating further that the long-term biochemical consequences of PPA depend on the critical period of neurodevelopment during which an individual is PPA-exposed, although the specific biomolecular changes underpinning the cocaine phenotype produced by adolescent PPA remain to be elucidated.

Brain drug delivery from the nasal olfactory region is enhanced using lauroylcholine chloride: An estimation using in vivo PET imaging

IntroductionIntranasal (IN) administration, often referred to as nose-to-brain (N2B) drug delivery, is an attractive approach for delivering drugs to the central nervous system. However, the efficacy of this method is limited because of the small size of the nasal olfactory region, which limits the drug dosage. Using permeation enhancers could improve drug delivery from this region to the brain, though their effects are not fully understood. We therefore investigated the effects of co-administration of permeation enhancers on N2B drug delivery of a model drug domperidone, a peripherally acting dopamine D2 receptor (D2R) blocker. MethodsWe conducted in vitro permeability assays to evaluate the effects of sodium lauryl sulfate (SLS), a classical permeation enhancer, and lauroylcholine chloride (LCC) on domperidone permeation in human nasal mucosa-derived cells. We also used the D2R ligand [11C]raclopride to assess the in vivo effects of LCC on domperidone delivery in the rat brain using a positron emission tomography (PET) competition paradigm. In comparative PET experiments, we tested the effects of intravenously administered domperidone without LCC co-administration. ResultsLCC effectively improved nasal mucosal permeation of domperidone in vitro compared to SLS. In rat IN administration experiments, striatal [11C]raclopride uptake was significantly decreased by the addition of LCC to domperidone. On the other hand, intravenously administered domperidone with or without intranasally administered LCC did not decrease [11C]raclopride brain uptake, suggesting a lesser influence of peripheral domperidone on [11C]raclopride brain uptake. PET studies showed that striatal D2R occupancy of domperidone was increased 2.4-fold by co-administration of LCC. ConclusionLCC effectively enhances the domperidone delivery from the rat olfactory region to the brain, probably not via a circulating blood. The combination of permeation enhancers and olfactory region-selective drug administration could be effective for N2B drug delivery.

Selective dopamine D3 receptor partial agonist (±)VK4-40 reduces the reinforcing strength of d-amphetamine but not cocaine in rhesus monkeys responding under a progressive-ratio schedule of reinforcement

Selective dopamine D3 receptor partial agonist (±)VK4-40 reduces the reinforcing strength of d-amphetamine but not cocaine in rhesus monkeys responding under a progressive-ratio schedule of reinforcement

Dopaminergic modulation of visual attention in the prefrontal cortex

An essential cognitive ability that enables creatures to interpret pertinent information from their surroundings only is visual attention. The prefrontal cortex (PFC) is involved in modulating visual attention, and this review focuses on the dopaminergic aspects of this process. The PFC is crucial for top-down attention management, improving visual responses, and coordinating neural activity. This is especially true of the frontal eye field (FEF). Dopamine is an important neuromodulator that directly influences the PFC's visual signal processing by adjusting sensory input and the variability of neuronal response. The substantia nigra (SN) and ventral tegmental area (VTA) send dopaminergic pathways to the prefrontal cortex, where D1 and D2 receptors have different functions in attention regulation. Dopamine receptor modification has been shown in studies involving rodents and primates to have a major effect on visual attention and cognitive task performance. The exact mechanisms underlying dopamine's involvement in executive control are still unknown despite a great deal of research, which calls for more study, especially in rodent models. The present review highlights the significance of dopamine in the domain of high-level cognitive regulation and advocates for more investigation to clarify its mechanisms in visual attention.

Cariprazine in Bipolar Disorder and Substance Use: A Dual Approach to Treatment?

Bipolar disorder (BD) is characterized by recurrent episodes of mania, hypomania, and depression and is often complicated by comorbid substance use disorders (SUDs). Up to 60% of individuals with BD experience SUDs, which exacerbate mood instability and increase the risk of rapid cycling, suicide, and poor clinical outcomes. Current treatment strategies, including lithium and valproate, show limited efficacy in treating both BD and SUD. Psychotherapeutic approaches such as cognitive behavioral therapy (CBT) offer benefits but lack a specific focus on substances such as cannabis and cocaine. Since there is still debate on how to treat this comorbidity, there is a need to find new therapeutic options; this mini-review examines the pharmacological properties of cariprazine and its emerging role in the treatment of comorbid BD and SUD. Cariprazine, an atypical antipsychotic with partial agonism at dopamine D2 and D3 receptors, has shown promise in treating both mood symptoms and cognitive dysfunction in BD. Its unique affinity for D3 receptors, which are involved in motivation and reward processing, may offer advantages in reducing drug craving. Clinical trials indicate that cariprazine effectively treats manic, depressive, and mixed episodes in BD with a favorable side effect profile, particularly at lower doses. Preliminary results suggest its potential to reduce craving and substance use in individuals with co-occurring BD and SUD. Therefore, cariprazine, with its unique pharmacodynamic mechanism, could be further studied for the treatment of BD in comorbidity with SUD. However, evidence on the role of cariprazine in the treatment of SUDs remains limited, based primarily on case reports and animal studies. Further research, including large-scale clinical trials, is needed to determine its full efficacy in this dual diagnosis.

Stimulation of Dopamine D4 Receptors in the Nucleus Accumbens Shell Increases Palatable Food Intake in Satiated Male Rats: Modulation by NMDA and AMPA Receptors

Background/Objectives: Palatability significantly influences food consumption, often leading to overeating and obesity by activating the brain’s reward systems. The nucleus accumbens (NAc) plays a central role in this process, modulating reward mechanisms primarily via dopamine through D2-like receptors (D2R, D3R, D4R). While the involvement of D2 receptors in feeding is well-documented, the role of D4 receptors (D4Rs) is less clear. Methods: Male Wistar rats received intra-NAc shell microinjections of the D4R agonist PD-168077 and the antagonist L-745870. This study also examined the modulation between D4R and glutamatergic transmission by administration of NMDA, NMDA receptor antagonist AP-5, AMPA, and AMPA receptor antagonist CNQX. Results: PD-168077 increased sweet solution intake by 46%, an effect that was reversed by L-745870. Pre-treatment with NMDA prevented the stimulatory effect of PD-168077, whereas the NMDA receptor antagonist AP-5 had no such effect. Additionally, AMPA administration reduced sweet solution intake by 63%, counteracting the effect of PD-168077, while the AMPA receptor antagonist CNQX, on its own, increased intake by 40%. Conclusions: These findings suggest that D4Rs promote hedonic feeding by modulating glutamatergic transmission in the NAc shell, highlighting the complexity of D4R involvement in food intake regulation. This study underscores the potential of targeting D4Rs for therapeutic interventions in eating disorders and obesity, though further research is essential to clarify the precise mechanisms through which D4R modulates AMPA and NMDA receptor activity in feeding behavior.

A drug repurposing screen reveals dopamine signaling as a critical pathway underlying potential therapeutics for the rare disease DPAGT1-CDG.

DPAGT1-CDG is a Congenital Disorder of Glycosylation (CDG) that lacks effective therapies. It is caused by mutations in the gene DPAGT1 which encodes the first enzyme in N-linked glycosylation. We used a Drosophila rough eye model of DPAGT1-CDG with an improperly developed, small eye phenotype. We performed a drug repurposing screen on this model using 1,520 small molecules that are 98% FDA/EMA-approved to find drugs that improved its eye. We identified 42 candidate drugs that improved the DPAGT1-CDG model. Notably from this screen, we found that pharmacological and genetic inhibition of the dopamine D2 receptor partially rescued the DPAGT1-CDG model. Loss of both dopamine synthesis and recycling partially rescued the model, suggesting that dopaminergic flux and subsequent binding to D2 receptors is detrimental under DPAGT1 deficiency. This links dopamine signaling to N-glycosylation and represents a new potential therapeutic target for treating DPAGT1-CDG. We also genetically validate other top drug categories including acetylcholine-related drugs, COX inhibitors, and an inhibitor of NKCC1. These drugs and subsequent analyses reveal novel biology in DPAGT1 mechanisms, and they may represent new therapeutic options for DPAGT1-CDG.

Temporal dynamics of nucleus accumbens neurons in male mice during reward seeking

The nucleus accumbens (NAc) regulates reward-motivated behavior, but the temporal dynamics of NAc neurons that enable “free-willed” animals to obtain rewards remain elusive. Here, we recorded Ca2+ activity from individual NAc neurons when mice performed self-paced lever-presses for sucrose. NAc neurons exhibited three temporally-sequenced clusters, defined by times at which they exhibited increased Ca2+ activity: approximately 0, −2.5 or −5 sec relative to the lever-pressing. Dopamine D1 receptor (D1)-expressing neurons and D2-neurons formed the majority of the −5-sec versus −2.5-sec clusters, respectively, while both neuronal subtypes were represented in the 0-sec cluster. We found that pre-press activity patterns of D1- or D2-neurons could predict subsequent lever-presses. Inhibiting D1-neurons at −5 sec or D2-neurons at −2.5 sec, but not at other timepoints, reduced sucrose-motivated lever-pressing. We propose that the time-specific activity of D1- and D2-neurons mediate key temporal features of the NAc through which reward motivation initiates reward-seeking behavior.

Vitex agnus castus Extract Ze 440: Diterpene and Triterpene’s Interactions with Dopamine D2 Receptor

Pre-clinical studies suggest that extracts prepared from the fruits of Vitex agnus castus (VAC) interact with dopamine D2 receptors, leading to reduced prolactin secretion. In previous experiments, dopaminergic activity was mostly evaluated using radioligand binding assays or via the inhibition of prolactin release from rat pituitary cells. Diterpenes featuring a clerodadienol scaffold were identified as major active compounds, but no conclusive data regarding their potency and intrinsic activity are available. Utilising advances in chromatography, we re-examined this topic using HPLC-based tracking of bioactivity via microfractionation of the VAC extract Ze 440. Using a cAMP-based assay, we measured dopaminergic activity in CHO-K1 cells that overexpress the human D2 receptor. Six diterpenes were isolated from two active HPLC microfractions. Viteagnusin I emerged as the most potent diterpene (EC50: 6.6 µM), followed by rotundifuran (EC50: 12.8 µM), whereas vitexilactone was inactive (EC50: >50 µM). Interestingly, triterpenes were also identified as active, with 3-epi-maslinic acid being the most active compound (EC50: 5.1 µM). To better understand these interactions at the molecular level, selected diterpenes and triterpenes were analysed through molecular docking against D2 receptor structures. Our data show that the dopaminergic activity of VAC diterpenes seems to depend on the configuration and on ring substitution in the side chain. This study also highlights for the first time the dopaminergic contribution of triterpenes such as 3-epi-maslinic acid.

Preexisting risk-avoidance and enhanced alcohol relief are driven by imbalance of the striatal dopamine receptors in mice

Alcohol use disorder (AUD) is frequently comorbid with anxiety disorders, yet whether alcohol abuse precedes or follows the expression of anxiety remains unclear. Rodents offer control over the first drink, an advantage when testing the causal link between anxiety and AUD. Here, we utilized a risk-avoidance task to determine anxiety-like behaviors before and after alcohol exposure. We found that alcohol’s anxiolytic efficacy varied among inbred mice and mice with high risk-avoidance showed heightened alcohol relief. While dopamine D1 receptors in the striatum are required for alcohol’s relief, their levels alone were not correlated with relief. Rather, the ratio between striatal D1 and D2 receptors was a determinant factor for risk-avoidance and alcohol relief. We show that increasing striatal D1 to D2 receptor ratio was sufficient to promote risk-avoidance and enhance alcohol relief, even at initial exposure. Mice with high D1 to D2 receptor ratio were more prone to continue drinking despite adverse effects, a hallmark of AUD. These findings suggest that an anxiety phenotype may be a predisposing factor for AUD.

The antipsychotic chlorpromazine reduces neuroinflammation by inhibiting microglial voltage-gated potassium channels.

Neuroinflammation, the result of microglial activation, is associated with the pathogenesis of a wide range of psychiatric and neurological disorders. Recently, chlorpromazine (CPZ), a dopaminergic D2 receptor antagonist and schizophrenia therapy, was proposed to exert antiinflammatory effects in the central nervous system. Here, we report that the expression of Kv1.3 channel, which is abundant in T cells, is upregulated in microglia upon infection, and that CPZ specifically inhibits these channels to reduce neuroinflammation. In the mouse medial prefrontal cortex, we show that CPZ lessens Kv1.3 channel activity and reduces proinflammatory cytokine production. In mice treated with LPS, we found that CPZ was capable of alleviating both neuroinflammation and depression-like behavior. Our findings suggest that CPZ acts as a microglial Kv1.3 channel inhibitor and neuroinflammation modulator, thereby exerting therapeutic effects in neuroinflammatory psychiatric/neurological disorders.

Design and Synthesis of Potential Multi-Target Antidepressants: Exploration of 1-(4-(7-Azaindole)-3,6-dihydropyridin-1-yl)alkyl-3-(1H-indol-3-yl)pyrrolidine-2,5-dione Derivatives with Affinity for the Serotonin Transporter

We describe the design, synthesis and structure–activity relationship of a novel series of 1-(4-(7-azaindole)-3,6-dihydropyridin-1-yl)alkyl-3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives with combined effects on the serotonin (5-HT1A) and dopamine (D2) receptors and the serotonin (5-HT), noradrenaline (NA), and dopamine (DA) transporters as multi-target directed ligands for the treatment of depression. All of the tested compounds demonstrated good affinity for the serotonin transporter (SERT). Among them, compounds 11 and 4 emerged as the lead candidates because of their promising pharmacological profile based on in vitro studies. Compound 11 displayed a high affinity for the 5-HT1A (Ki = 128.0 nM) and D2 (Ki = 51.0 nM) receptors, and the SERT (Ki = 9.2 nM) and DAT (Ki = 288.0 nM) transporters, whereas compound 4 exhibited the most desirable binding profile to SERT/NET/DAT among the series: Ki = 47.0 nM/167.0 nM/43% inhibition at 1 µM. These results suggest that compounds 4 and 11 represent templates for the future development of multi-target antidepressant drugs.

Simple and robust method for the synthesis of Metopimazine by utilising smile’s rearrangement. Elimination of genotoxic impurities via derivatization

A simple, efficient and scalable methodology has been developed for the synthesis of Metopimazine, a dopamine D2–receptor antagonist. Starting from nitrophenylthio substituted methylsulfonyl benzenamine subjected to simple N–formylation using formic acid followed by base–catalysed cyclization resulted the formation of 2–(methylsulfonyl)–10H–phenothiazine. This method does not involve the conventional peracid oxidation that exemplifies the formation of several oxidized species that are tedious to separate. The later derivative is proven effective in the synthesis of title active pharmaceutical ingredient via N–chloroproylation followed by treating piperidine–4–carboxamide resulted in the formation of Metopimazine in high yield. The potential genotoxic impurities such as nitroaromatic derivatives were effectively removed by reduction using simple zinc dust formic acid treatment, which effectually converts nitro derivatives into amine hydrochlorides that are water soluble. Similarly, the N–alkylation of phenothiazine derivative forms potential impurities such as the formation of N–allyl and propyl bridged dimer derivatives that are removed by effective recrystallization. This method has been scaled up and evidenced no compromise with the yield and hence can be considered as industry ready.

Real-World Data Mining for Signal Detection of Antipsychotics-Associated Adverse Events Using the Korea Adverse Event Reporting System (KAERS) Database.

Background and Objectives: Recent studies suggest that the binary categorization of first-generation antipsychotics (FGAs) as being primarily responsible for extrapyramidal symptoms (EPSs) and second-generation antipsychotics (SGAs) for cardiometabolic abnormalities is an oversimplification. SGAs also demonstrate antagonistic affinity for D2 receptors, indicating their potential to induce EPSs. This study utilized the Korea Adverse Event Reporting System (KAERS) database to explore adverse drug event (ADE) signals related to both FGAs and SGAs. Materials and Methods: Relevant ADE reports from January 2013 to December 2022 were extracted from the KAERS database and analyzed using disproportionality analysis, employing the proportional reporting ratio (PRR), reporting odds ratio (ROR), and information component (IC) with its 95% lower confidence interval (LCI) indices. Results: Of the initial dataset of 2,890,702 ADE reports, those with insufficient data and duplicates were removed, resulting in a final dataset of 5249 reports for analysis. Aripiprazole, an SGA, showed signals for movement disorders, including EPSs (PRR 4.7, ROR 4.8, IC 2.2), tremors (PRR 5.3, ROR 5.4, IC 2.4), and akathisia (PRR 18.6, ROR 19.3, IC 3.5). Notably, for quetiapine, cardiovascular signals were detected, including increased blood pressure (PRR 2.1, ROR 2.3, IC 0.5), and tachyarrhythmia (PRR 13.9, ROR 14.1, IC 1.8), along with peripheral edema (PRR 2.5, ROR 2.5, IC 0.2). Metabolic abnormalities, such as weight gain and increased appetite, were identified for four SGAs: aripiprazole, olanzapine, quetiapine, and risperidone. Safety signals related to movement disorders were not detectable for FGAs, likely due to the limited number of ADE reports available for analysis. Conclusions: Our study findings support that the distribution of ADEs between FGAs and SGAs is not strictly binary. Aripiprazole, despite being an SGA, showed signals for extrapyramidal movement disorders. Four SGAs (aripiprazole, olanzapine, quetiapine, and risperidone) were linked to metabolic side effects, while quetiapine was associated with cardiovascular safety signals.

Exposure-Efficacy Analysis and Dopamine D2 Receptor Occupancy in Adults with Schizophrenia after Treatment with the Monthly Intramuscular Injectable Risperidone ISM.

Dopamine D2 receptor occupancy (D2RO) significantly influences the clinical effectiveness and safety of many antipsychotic drugs. Maintaining a D2RO range of 65%-80% provides the best antipsychotic effects while minimizing adverse reactions. Data from a Phase III trial were used to establish an exposure-response relationship for monthly intramuscular Risperidone ISM (75 and 100 mg) or placebo administered to adults with schizophrenia. Pharmacodynamic analysis was based on an Emax model for Positive and Negative Syndrome Scale (PANSS) developed in NONMEM. Plasma concentrations of the active moiety were derived using a previously developed population pharmacokinetic model, which was used for D2RO simulations in conjunction with a published Emax model. The optimal D2RO range (65%-80%) was reached for the median within hours following the first injection of both Risperidone ISM doses. At steady state, median D2RO for both doses remained above 65% throughout the 28-day dosing period and demonstrated lower variability than oral risperidone. PANSS response did not differ significantly between dose groups, most likely because active moiety concentrations had already reached the plateau of the concentration-response relationship. The pharmacokinetic/pharmacodynamic analysis showed a profound placebo effect (-11.7%), and an additional maximal drug effect (-6.6%) resulting in a total PANSS improvement over time of -18.3%. Pharmacokinetic/pharmacodynamic modeling quantified a PANSS improvement over time after Risperidone ISM administration. The response was not significantly different in either dose group, likely because D2RO was already above the proposed efficacy threshold (65%) within 1 h after the first Risperidone ISM injection and remained above this level following repeated administrations.

Pramipexole, a D3 receptor agonist, increases cortical gamma power and biochemical correlates of cortical excitation; implications for mood disorders.

Major depressive disorder (MDD) has been associated with deficits in working memory as well as underlying gamma oscillation power. Consistent with this, overall reductions in cortical excitation have also been described with MDD. In previous work, we have demonstrated that the monoamine reuptake inhibitor venlafaxine increases gamma oscillation power in ex vivo hippocampal slices and that this is associated with concomitant increases in pyramidal arbour and reduced levels of plasticity-restricting perineuronal nets (PNNs). In the present study, we have examined the effects of chronic treatment with pramipexole (PPX), a D3 dopamine receptor agonist, for its effects on gamma oscillation power as measured by in vivo electroencephalography (EEG) recordings in female BALB/c and C57Bl6 mice. We observe a modest but significant increase in 20-50 Hz gamma power with PPX in both strains. Additionally, biochemical analysis of prefrontal cortex lysates from PPX-treated BALB/c mice shows a number of changes that could contribute to, or follow from, increased pyramidal excitability and/or gamma power. PPX-associated changes include reduced levels of specific PNN components as well as tissue inhibitor of matrix metalloproteases-1 (TIMP-1), which inhibits long-term potentiation of synaptic transmission. Consistent with its effects on gamma power, PNN proteins and TIMP-1, chronic PPX treatment also improves working memory and reduces anhedonia. Together these results add to an emerging literature linking extracellular matrix and/or gamma oscillation power to both mood and cognition.