Selective D2 Research Articles

Discovery of highly potent and selective D4 ligands by interactive SAR study

A series of thienylmethylphenylpiperazins was synthesized and tested for affinity towards the five subtypes of dopaminergic receptors. Compound 5f showed more than 1000 folds selectivity to D4 receptors; analogue 5e showed the highest affinity to D4 receptors with Ki 3.9nM. An interactive SAR approach was adopted and lead to compound 14a with Ki (D4) as low as 0.03nM. Molecular docking studies showed a potential, first to report arene cation interaction between the D4 unique residue Arg-186 and the ligands’ arene moiety, explaining the importance of having a strong negative electrostatic potential at this area of the compound structure.

Combined effects of modafinil and d-amphetamine in male Sprague–Dawley rats trained to discriminate d-amphetamine

Modafinil is a novel wake-promoting drug with FDA approval for the treatment of sleep-related disorders that has recently been investigated as a potential agonist replacement therapy for psychostimulant dependence. Previous research in animals and humans indicates modafinil has a lower abuse liability than traditional psychostimulants, although few studies have carefully assessed modafinil's stimulus properties in combination with other psychostimulants. The current study trained male Sprague–Dawley rats to discriminate subcutaneous injections of 0.3mg/kg (n=8) or 1.0mg/kg d-amphetamine (n=8) from saline under an FR 20 schedule of food reinforcement and substitution tests were administered with d-amphetamine (0.03–1.0mg/kg, s.c.), modafinil (32–256mg/kg, i.g.), and a low modafinil dose (32mg/kg, i.g.) in combination with d-amphetamine (0.03–1.0mg/kg, s.c.) to determine if these drugs have additive effects. The selective D2 dopamine agonist, PNU-91356A, was also tested as a positive control and ethanol and morphine were tested as negative controls. Results indicate that modafinil produced dose-dependent and statistically significant d-amphetamine-lever responding in both groups and nearly complete substitution in animals trained to discriminate 1.0mg/kg d-amphetamine. Modafinil pretreatment slightly increased the discrimination of low d-amphetamine doses in animals trained to discriminate 0.3mg/kg d-amphetamine. These results support previous findings that modafinil and d-amphetamine may have additive effects. In consideration of recent interests in modafinil as an agonist treatment for psychostimulant dependence, additional preclinical investigations utilizing other methodologies to examine modafinil in combination with other stimulants, such as behavioral sensitization paradigms or drug self-administration, may be of interest.

3,4-Dihydroxy- and 3,4-methylenedioxy- phenanthrene-type alkaloids with high selectivity for D2 dopamine receptor

Dopamine-mediated neurotransmission plays an important role in relevant psychiatric and neurological disorders. Nowadays, there is an enormous interest in the development of new drugs acting at the dopamine receptors (DR) as potential new targets for the treatment of schizophrenia or Parkinson’s disease. Previous studies have revealed that isoquinoline compounds such as tetrahydroisoquinolines (THIQs) can behave as selective D2 dopaminergic alkaloids. In the present study we have synthesized five aporphine compounds and five phenanthrene alkaloids and evaluated their potential dopaminergic activity. Binding studies on rat striatal membranes were used to evaluate their affinity and selectivity towards D1 and D2 DR. Phenanthrene type alkaloids, in particular the 3,4-dihydroxy- and 3,4-methylenedioxy derivatives, displayed high selectivity towards D2 DR. Therefore, they are potential candidates to be used in the treatment of schizophrenia (antagonists) or Parkinson’s disease (agonists) due to their scarce D1 DR-associated side effects.

Mesocortical dopamine system modulates mechanical nociceptive responses recorded in the rat prefrontal cortex

BackgroundPsychological conditions affect pain responses in the human anterior cingulate cortex (ACC) according to brain imaging analysis. The rodent prefrontal cortex (PFC) including cingulate areas is also related to the affective dimension of pain. We previously reported PFC nociceptive responses inhibited by inputs from the amygdala, such as with dopamine (DA) D2 receptor (D2R) blockers, to show decreased effect on amygdala projections. In this study, we examined whether direct projections from the ventral tegmental area (VTA) to the PFC affect nociceptive responses in the PFC.ResultsHigh frequency stimulation (HFS, 50 Hz, 30 s) delivered to the VTA produced long-lasting suppression (LLS) of nociceptive responses in the rat PFC including cingulate and prelimbic areas. Nociceptive responses evoked by mechanical pressure stimulation (2 s duration at 500 g constant force) applied to the tails of urethane-anesthetized rats were recorded using extracellular unit recording methods in the PFC. HFS delivered to the VTA, which has been reported to increase DA concentrations in the PFC, significantly suppressed nociceptive responses. The LLS of nociceptive responses persisted for about 30 minutes and recovered to the control level within 60 min after HFS. We also demonstrated local microinjection of a selective D2 agonist of DA receptors to induce LLS of mechanical nociceptive responses, while a D2 but not a D1 antagonist impaired the LLS evoked by HFS. In contrast, DA depletion by a 6-hydroxydopamine injection or a low concentration of DA induced by a κ-opiate receptor agonist injected into the VTA had minimal effect on nociceptive responses in the PFC.ConclusionHFS delivered to VTA inhibited nociceptive responses for a long period in PFC. DA D2R activation mediated by local D2 agonist injection also induced LLS of mechanical nociceptive responses. The mesocortical DA system may modify PFC nociceptive responses via D2 activity.

Dopamine D1 and D2 receptor antagonism effects on rat ultrasonic vocalizations

Voice disorders manifest in the early stages of Parkinson disease (PD), suggesting the vulnerability of the laryngeal sensorimotor system to mild alterations in dopamine signaling. Previous research has demonstrated that manipulations of central dopamine result in acoustic changes in rat ultrasonic vocalization (USV) and selective manipulation of receptor subtypes results in dose dependent changes in call rate and complexity. However, no study has specifically focused on the influence of dopamine receptor subtypes on acoustic features of USV production. This study examined the influence of D1 and D2 receptor subtypes on voluntary laryngeal sensorimotor control (USV) and gross whole-body involvement. Rat USV acoustics and catalepsy descent time were analyzed following the administration of selective D1 and D2 receptor antagonists in isolation and in combination, and a vehicle control. Results support the hypothesis that degradations of the acoustic signal would be most severe following combined receptor antagonism (D1+D2) compared with D1 or D2 receptor antagonism alone, and the vehicle (saline) condition. In addition, results indicate that selective D1 receptor antagonism alters acoustic parameters to a greater extent than D2 receptor antagonism. Thus, dopamine receptor subtypes appear to influence acoustic parameters to different degrees. Catalepsy descent time was longest following combined dopamine receptor antagonism but was also significantly increased with selective D1 or D2 antagonism. Together, these results support the potentially different contributions receptor subtypes play in cranial and limb sensorimotor control.

Presynaptic CaMKIIα modulates dopamine D3 receptor activation in striatonigral terminals of the rat brain in a Ca2+ dependent manner

CaMKIIα is expressed at high density in the nucleus accumbens where it binds to postsynaptic D3 receptors inhibiting their effects. In striatonigral projections, activation of presynaptic D3 receptors potentiates D1 receptor-induced stimulation of cAMP production and GABA release. In this study we examined whether the presynaptic effects of D3 receptor stimulation in the substantia nigra reticulata (SNr) are modulated by Ca2+ activation of CaMKIIα. In SNr synaptosomes two procedures that increase cytoplasmic Ca2+, ionomycin and K+-depolarization, blocked the additional stimulation of cAMP accumulation produced by coactivating D3 and D1 dopamine receptors. The selective CaMKIIα inhibitor KN-62 reversed the blockade produced by ionomycin and K+-depolarization. Incubation in either Ca2 -free solutions or with the selective Ca2+ blocker nifedipine, also reversed the blocking effects of K+-depolarization. Immunoblot studies showed that K+-depolarization increased CaMKIIα phosphorylation in a KN-62 sensitive manner and promoted CaMKIIα binding to D3 receptors. In K+-depolarized tissues, D3 receptors potentiated D1 receptor-induced stimulation of [3H]GABA release only when CaMKIIα was blocked with KN-62. In the presence of this inhibitor, the selective D3 agonist PD 128,907 reduced the ED50 for the D1 agonist SKF 38393 from 56 to 4 nM. KN-62 also enhanced the effects of dopamine on depolarization induced [3H]GABA release. KN-62 changed ED50 for dopamine from 584 to 56 nM. KN-62 did not affect D1 and D4 receptor responses. These experiments show that in striatonigral projections, CaMKIIα inhibits the action of D3 receptors in a Ca2+ dependent manner blocking their modulatory effects on GABA release. These findings suggest a mechanism through which the frequency of action potential discharge in presynaptic terminals regulates dopamine effects.

Quantum analysis/improvement of antipsychotic's docking results

Research support: CNPq‐BrazilHuman dopamine receptors are important targets in treatment of Parkinson's disease and Schizophrenia. Thus, the understanding of the binding mechanisms involving selective ligand agents and dopamine receptors D2 and D3 may contribute to pharmacologic strategies. Recently, we have applied quantum mechanics methods to calculate the contribution of each amino acid residue in the binding pocket of D3 receptor in complex with eticlopride (Zanatta, G et al, 2012). In this study, to understand the mechanism of haloperidol interaction, we employed the Molecular Fractionation with Conjugated Caps (MFCC) followed by quantum calculations to analyze the structure of haloperidol docked in D3 receptor using Autodock 4.0 (Fig 1).It was not possible to obtain the stabilization in total binding energy for a radius of 16 Å (Fig. 2), suggesting that this pose is not yet in the best binding conformation. In order to improve the results, we are performing a series of energy minimization steps using quantum mechanics/molecular mechanics (QM/MM). The establishment of a protocol to improve docking results is important to obtain representative structures of selective ligands to D2 and D3 receptors.

Histopathologic evaluation of anti-ulcerogenic effect of montelukast in indomethacin-induced experimental ulcer model

The effects of anti-ulcerogenic drugs are dependent on the increase in prostaglandin production and reduction in leukotriene production in the gastric mucosa. Montelukast is an anti-asthmatic drug, a selective reversible cysteinyl leukotriene D4 receptor antagonist. In this study, we aimed to evaluate the anti-ulcerogenic effect of montelukast and to investigate the relationship between its anti-ulcerogenic effect and polymorphonuclear leukocyte infiltration in the gastric tissues. Male Sprague-Dawley rats were separated into five groups. Distilled water (control group), famotidine (40 mg/kg), and montelukast (5, 10 and 20 mg/kg) were given orally (gavage). Thirty minutes later, indomethacin (25 mg/kg) was administered to all the groups. Six hours later, the animals were sacrificed by decapitation. The ulcer indexes for each stomach and the ulcer inhibition rates for each group were calculated, and the stomachs were later evaluated histopathologically (polymorphonuclear leukocyte infiltration). Ulcer inhibition rates were as follows: famotidine 96.14% and montelukast 59.96%, 72.65% and 76.97% (5, 10 and 20 mg/kg, respectively). Montelukast (10 and 20 mg/kg) showed effects similar to those of famotidine histopathologically. In this study, it was observed that there was a relationship between the anti-ulcerogenic effect of montelukast and polymorphonuclear leukocyte infiltration in the gastric mucosa, and montelukast behaved as an anti-ulcerogenic drug both macroscopically and microscopically.

SKF83959 is a partial agonist, not a functionally selective dopamine D1 receptor ligand as commonly believed

Full dopamine D1 agonists have shown promise in treating several central nervous system disorders. D1‐mediated adenylate cyclase (AC) activation reflects canonical signaling, but some reports have suggested that some D1 ligands also signal via phospholipase C (PLC) activation. It has been proposed and accepted that SKF83959 is a functionally selective D1 agonist that has high intrinsic activity at D1‐mediated PLC activation, but antagonism of D1‐mediated AC activation. Because of anomalies in the pharmacological evidence, we rigorously characterized the pharmacology of SKF83959 in vitro. Contrary to what is commonly assumed, SKF83959 has partial agonist activity at AC activation similar to the prototypical D1 partial agonist, SKF38393. Both SKF83959 and SKF38393 also have partial agonist activity for D1‐mediated β‐arrestin recruitment. Most importantly, no activation of PLC activation was found for either SKF83959 or SKF38393 even at very high pharmacological concentrations (≤300 μM). Thus, these data clearly demonstrate that SKF83959 is a potent low intrinsic activity D1 agonist at AC and β‐arrestin recruitment (consistent with its affinity for the D1 receptor), yet fails to activate PLC. These data show that SKF83959 is not a functionally selective ligand, that its behavioral effects can be explained by known mechanisms, and that its use as a novel probe of D1 receptors is ill‐founded.

Aripiprazole Treatment for Choreoathetoid and Psychotic Symptoms of Huntington’s Disease

Back to table of contents Previous article Next article LettersFull AccessAripiprazole Treatment for Choreoathetoid and Psychotic Symptoms of Huntington’s DiseaseK.F. Yavuz, M.D., S. Ulusoy, M.D., and İ. Alnıak, M.D.K.F. YavuzSearch for more papers by this author, M.D., S. UlusoySearch for more papers by this author, M.D., and İ. AlnıakSearch for more papers by this author, M.D.Published Online:1 Apr 2013https://doi.org/10.1176/appi.neuropsych.12040097AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: In this case report, we are presenting a 50-year-old man who has Huntington’s disease with choreoathetoid and psychotic symptoms. After 16 months of initial aripiprazole treatment, our patient showed significant progress with chorea and psychosis.Huntington's disease (HD), caused by CAG trinucleotide repeat expansion in the IT15 gene located on the short arm of chromosome 4; is an autosomal dominant, progressive, neurodegenerative disorder, characterized by motor, cognitive, and psychopathological symptoms.1 In this letter, we report a case of a male patient with HD with psychotic symptoms in whom aripiprazole effectively controlled these psychotic symptoms and involuntary movements.Case ReportThe patient, a 50-year-old man diagnosed 20 years previously with HD, first complained about tremor in the extremities and, in time, involuntary movements of the extremities and the body; gait difficulties and dysphagia added to his clinical presentation. He partially benefited from quetiapine 300 mg/day and clonazepam 2 mg/day during the last 1.5-year period. For the last 2 months, he has had insomnia, aggression, self-destructive behaviors, suicidal thoughts, and persecutory delusions, and his relatives took him to our outpatient clinic. On admission to our department, he scored 56 point on Unified Huntington’s Disease Rating Scale (UHDRS) motor section (oculomotor function, 12; hyperkinesias, 22; fine motor tasks, 9; parkinsonism, 4; gait, 9). We started aripiprazole treatment and gradually titrated up to 30 mg/day. In the first month of the treatment, we confirmed that irritability and persecutory delusions were markedly improved; his choreiform movements decreased significantly; and he finally became able to satisfy his own daily needs. At the end of the 16-month follow-up, we evaluated that his personal hygiene was significantly improved; dysarthria and dysphagia were completely ameliorated; and the intension and amplitude of choreiform movements were decreased. The patient still had no psychotic symptoms. We assessed that the last UHDRS total motor score was 20 (oculomotor function, 4; hyperkinesias, 6; fine motor tasks, 2; parkinsonism, 2; gait, 6).DiscussionHD is explained by the loss of the striatal cells, caused by degeneration and apoptosis2 and their dysfunction,3 which are made sensitive to glutamate and dopamine by mutant huntingtin protein. In this respect, the dopamine receptor-antagonist drugs may purport to be useful in treatment of HD. Aripiprazole, as an antipsychotic agent, acts as a partial agonist and affects psychotic symptoms by blocking mesolimbic dopaminergic neurotransmission, while rarely inducing extrapyramidal side effects, by reducing the antagonist load at the nigrostriatal pathway with selective D2 ligand and 5HT2A receptor antagonism.4 Our case report supports the idea that aripiprazole is an effective and safe agent in HD, especially HD with psychotic symptoms.Bakirkoy Mazhar Osman Psychiatry and Neurology Education and Research Hospital, 5th Psychiatry Clinic, Istanbul, TurkeyCorrespondence: Dr. Fatih Yavuz; e-mail: [email protected]comThis work was a Poster Presentation at the 4th International Congress on Psychopharmacology, Antalya, Turkey, November 23–27, 2011.References1 Walker FO: Huntington’s disease. Lancet 2007; 369:218–228Crossref, Medline, Google Scholar2 Paoletti P, Vila I, Rifé M, et al.: Dopaminergic and glutamatergic signaling crosstalk in Huntington’s disease neurodegeneration: the role of p25/cyclin-dependent kinase 5. J Neurosci 2008; 28:10090–10101Crossref, Medline, Google Scholar3 Cepeda C, Wu N, André VM, et al.: The corticostriatal pathway in Huntington’s disease. Prog Neurobiol 2007; 81:253–271Crossref, Medline, Google Scholar4 Naber D, Lambert M: Aripiprazole: a new atypical antipsychotic with a different pharmacological mechanism. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28:1213–1219Crossref, Medline, Google Scholar FiguresReferencesCited byDetailsCited byPsychopharmacotherapy in Patients with Tics and Other Motor Disorders5 November 2022State-of-the-art pharmacological approaches to reduce chorea in Huntington’s disease8 February 2021 | Expert Opinion on Pharmacotherapy, Vol. 22, No. 8Psychopharmacotherapy in Patients with Tics and Other Motor Disorders28 December 2019Frontiers in Neurology, Vol. 10Psychiatric Management of Huntington's DiseasePsychiatric Annals, Vol. 47, No. 5Medical management of motor manifestations of Huntington diseaseExpert Review of Neurotherapeutics, Vol. 17, No. 3Movement Disorders, Vol. 29, No. 11 Volume 25Issue 2 Spring 2013Pages E31-E31 Metrics This work was a Poster Presentation at the 4th International Congress on Psychopharmacology, Antalya, Turkey, November 23–27, 2011.PDF download History Published online 1 April 2013 Published in print 1 April 2013

Discovery, characterization, and optimization of highly selective D2 dopaminergic antagonists

The D2 dopamine receptor (DAR) is central in the etiology and/or therapy of many neuropsychiatric disorders. Unfortunately, truly specific drugs for this receptor have been difficult to obtain, primarily due to high conservation of the orthosteric binding site within DAR subtypes and other G protein‐coupled receptors (GPCRs). In order to develop novel molecular scaffolds for the D2 DAR, we used high throughput screening to interrogate a small molecule library and identify hit ligands with distinct functional characteristics, mechanisms of action, and selectivity among DAR subtypes. Here we present the discovery of a novel series of small molecule selective D2 DAR antagonists found in this campaign. One such hit was optimized via medicinal chemistry efforts, and a lead compound was identified with high D2 selectivity versus D1, D3, D4 and D5 DARs. Interestingly the binding of this compound to the D2 DAR demonstrated near complete dependence on Na+. Furthermore, the lead compound showed favorable ADME and in vivo pharmacokinetic (PK) properties. In a profiling screen of a large panel of GPCRs the compound showed relatively low cross reactivity. This probe could be a useful pharmacological tool for studying structure activity relationships with the help of computational docking and simulations, as well as an ideal scaffold for the further development of even more highly selective D2 DAR compounds.

Blonanserin reverses the phencyclidine (PCP)-induced impairment in novel object recognition (NOR) in rats: Role of indirect 5-HT1A partial agonism

Blonanserin is an atypical antipsychotic drug (APD) which, compared to other atypical APDs, is a relatively selective serotonin (5-HT)2A and dopamine D2 antagonist. Comparing blonanserin with more broadly acting atypical APDs could be useful to test the contributions of actions at other monoamine receptors, e.g. 5-HT1A receptors, to the reversal of PCP-induced novel object recognition (NOR) deficit. In this study, we tested the effect of blonanserin alone, and in combination with 5-HT1A agents, on NOR deficit induced by subchronic treatment with the N-methyl-D-aspartate (NMDA) receptor antagonist, phencyclidine (PCP; 2mg/kg), b.i.d., for 7 days. Blonanserin, 1mg/kg, but not 0.3mg/kg, improved the PCP-induced NOR deficit. However, at 1mg/kg, object exploration was diminished. Co-administration of sub-effective doses of blonanserin (0.3mg/kg) and the 5-HT1A partial agonist, tandospirone (0.2mg/kg), significantly reversed the NOR deficit without diminishing activity during the acquisition or retention periods. The combination of WAY100635 (0.6mg/kg), a 5-HT1A antagonist, and blonanserin (1mg/kg), also diminished object exploration which prevented assessment of the effect of this combination on NOR. WAY100635 (0.6mg/kg) blocked the ameliorating effect of risperidone (0.1mg/kg), another atypical APD with low affinity for 5-HT1A receptors, but did not impair exploration. These results suggest that blonansein and risperidone, atypical APDs which lack a direct action on 5-HT1A receptors require 5-HT1A receptor stimulation to reverse the subchronic PCP-induced NOR deficit and provide a support for clinical trial of blonanserin in combination with tandospirone to ameliorate cognitive impairment in schizophrenia and to have fewer side effects.

The selective D3receptor antagonist SB-277011A attenuates morphine-triggered reactivation of expression of cocaine-induced conditioned place preference

We examined the effect of acute administration of the selective D3 receptor antagonist SB-277011A on morphine-triggered reactivation of cocaine-induced conditioned place preference (CPP) in adult male Sprague-Dawley rats. Repeated pairing of animals with 15 mg/kg i.p. of cocaine HCl or vehicle to cue-specific CPP chambers produced a significant CPP response compared to animals paired only with vehicle in both chambers. Expression of the CPP response to cocaine was then extinguished by repeatedly giving the animals vehicle injections in the cocaine-paired chambers. The magnitude of the CPP response after extinction was not significantly different from that of animals paired only with vehicle. Expression of the extinguished CPP response was reactivated by acute administration of 5 mg/kg i.p. of morphine but not by vehicle. Acute administration of 6 or 12 mg/kg i.p. (but not 3 mg/kg) of SB-277011A significantly attenuated morphine-triggered reactivation of the cocaine-induced CPP. SB-277011A itself (12 mg/kg i.p.) did not reactivate the extinguished CPP response. Overall, SB-277011A decreases the incentive motivational actions of morphine. The present findings suggest that central D₃ dopamine receptors are involved in relapse to cocaine-seeking behavior, that a final common neural mechanism exists to mediate the incentive motivational effects of psychostimulants and opiates, and that selective dopamine D₃ receptor antagonists constitute promising compounds for treating addiction.

A single in vivo cocaine administration impairs 5‐HT1B receptor‐induced long‐term depression in the nucleus accumbens

The nucleus accumbens (NAc) is a crucial forebrain nucleus implicated in reward-based decision-making. While NAc neurons are richly innervated by serotonergic fibers, information on the functional role of serotonin 5-hydroxytryptamine (5-HT) in the NAc is still sparse. Here, we demonstrate that brief application of 5-HT or 5-HT1B receptor agonist CP 93129 induced a long-term depression (LTD) of glutamatergic transmission in NAc neurons. This LTD was presynaptically mediated and inducible by endogenous 5-HT. Remarkably, a single cocaine exposure impaired the induction of LTD by 5-HT or CP 93129. The inhibition was blocked when a selective dopamine D1 receptor antagonist SCH23390 was coadministered with cocaine. Cocaine treatment resulted in increased phosphorylation of presynaptic proteins, rabphilin 3A and synapsin 1, and significantly attenuated CP 93129-induced decrease in rabphilin 3A and synapsin 1 phosphorylation. Application of cAMP-dependent protein kinase inhibitor KT5720 caused a prominent synaptic depression in NAc neurons of mice with a history of cocaine exposure. Our results reveal a novel 5-HT1B receptor-mediated LTD in the NAc and suggest that cocaine exposure may result in elevated phosphorylation of presynaptic proteins involved in regulating glutamate release, which counteracts the presynaptic depressant effects of 5-HT1B receptors and thereby impairs the induction of LTD by 5-HT.

Dopamine D3 receptors regulate reconsolidation of cocaine memory

Memories of learned associations between the rewarding properties of drugs of abuse and environmental cues contribute to craving and relapse in humans. Disruption of reconsolidation dampens or even erases previous memories. Dopamine (DA) mediates the acquisition of reward memory and drugs of abuse can pathologically change related neuronal circuits in the mesolimbic DA system. Previous studies showed that DA D3 receptors are involved in cocaine-conditioned place preference (CPP) and reinstatement of cocaine-seeking behavior. However, the role of D3 receptors in reconsolidation of cocaine-induced reward memory remains unclear. In the present study, we combined genetic and pharmacological approaches to investigate the role of D3 receptors in reconsolidation of cocaine-induced CPP. We found that the mutation of the D3 receptor gene weakened reconsolidation of cocaine-induced CPP in mice triggered by a 3-min (min) retrieval. Furthermore, treatment of a selective D3 receptor antagonist PG01037 immediately following the 3-min retrieval disrupted reconsolidation of cocaine-induced CPP in wild-type mice and such disruption remained at least 1week after the 3-min retrieval. These results suggest that D3 receptors play a key role in reconsolidation of cocaine-induced CPP in mice, and that pharmacological blockade of these receptors may be therapeutic for the treatment of cocaine craving and relapse in clinical settings.

The dopaminergic stabilizer pridopidine increases neuronal activity of pyramidal neurons in the prefrontal cortex

The dopaminergic stabilizer pridopidine demonstrates state-dependent effects on locomotor activity, counteracting both hypo- and hyperactivity in rats. Pridopidine has been shown to display both functional dopamine D2 receptor antagonist properties and increase in biomarkers associated with NMDA-mediated glutamate transmission in the frontal cortex. To further characterise the effects of pridopidine on prefrontal cortex (PFC) neurons, a series of in vivo electrophysiological studies were performed in urethane-anaesthetised rats. Pridopidine, administered at doses from 10 to 60 mg/kg (i.v.), dose dependently increased pyramidal cell firing in the majority of the neurons tested. Pridopidine induced a significant increase of 162 % in mean firing activity of PFC neurons, versus initial basal firing activity as the cumulative dose of 30 mg/kg, i.v., was administered. This enhancement of activity was due to increased firing frequency of already spontaneously active neurons, rather than an increase in population activity. The increase was partially reversed or prevented by a sub-threshold dose of the dopamine D1 receptor antagonist SCH23390 (0.5 mg/kg, i.v.). Microiontophoretic application of pridopidine had only moderate activating effects. The selective dopamine D1 receptor agonist A-68930 also had limited effects when administered by microiontophoretic application, but exerted a dose dependent (0.2-3 mg/kg, i.v.) activation of firing in the majority of neurons tested (10/16). However, inhibition of firing by systemic administration of A-68930 was also observed in a subgroup of neurons (6/16). Both activation and inhibition of firing induced by systemic administration of A-68930 were reversed by the systemic administration of SCH23390. The present data suggests that pridopidine enhances pyramidal cell firing via an indirect dopamine D1 receptor-mediated mechanism. These effects of pridopidine may serve to strengthen the cortico-striatal communication and to improve motor control in Huntington's disease for which pridopidine is currently in development.

Preclinical pharmacokinetic and toxicological evaluation of MIF-1 peptidomimetic, PAOPA: Examining the pharmacology of a selective dopamine D2 receptor allosteric modulator for the treatment of schizophrenia

Schizophrenia is a mental illness characterized by a breakdown in cognition and emotion. Over the years, drug treatment for this disorder has mainly been compromised of orthosteric ligands that antagonize the active site of the dopamine D2 receptor. However, these drugs are limited in their use and often lead to the development of adverse movement and metabolic side effects. Allosteric modulators are an emerging class of therapeutics with significant advantages over orthosteric ligands, including an improved therapeutic and safety profile. This study investigates our newly developed allosteric modulator, PAOPA, which is a specific modulator of the dopamine D2 receptor. Previous studies have shown PAOPA to attenuate schizophrenia-like behavioral abnormalities in preclinical models. To advance this newly developed allosteric drug from the preclinical to clinical stage, this study examines the pharmacokinetic behavior and toxicological profile of PAOPA. Results from this study prove the effectiveness of PAOPA in reaching the implicated regions of the brain for therapeutic action, particularly the striatum. Pharmacokinetic parameters of PAOPA were found to be comparable to current market antipsychotic drugs. Necropsy and histopathological analyses showed no abnormalities in all examined organs. Acute and chronic treatment of PAOPA indicated no movement abnormalities commonly found with the use of current typical antipsychotic drugs. Moreover, acute and chronic PAOPA treatment revealed no hematological or metabolic abnormalities classically found with the use of atypical antipsychotic drugs. Findings from this study demonstrate a better safety profile of PAOPA, and necessitates the progression of this newly developed therapeutic for the treatment of schizophrenia.

Correction to Structure–Activity Relationship Study of N6-(2-(4-(1H-Indol-5-yl)piperazin-1-yl)ethyl)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine Analogues: Development of Highly Selective D3 Dopamine Receptor Agonists along with a Highly Potent D2/D3 Agonist and Their Pharmacological Characterization

ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionNEXTORIGINAL ARTICLEThis notice is a correctionCorrection to Structure–Activity Relationship Study of N6-(2-(4-(1H-Indol-5-yl)piperazin-1-yl)ethyl)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine Analogues: Development of Highly Selective D3 Dopamine Receptor Agonists along with a Highly Potent D2/D3 Agonist and Their Pharmacological CharacterizationMark Johnson, Tamara Antonio, Maarten E. A. Reith, and Aloke K. Dutta*Cite this: J. Med. Chem. 2013, 56, 2, 589–590Publication Date (Web):January 4, 2013Publication History Published online4 January 2013Published inissue 24 January 2013https://doi.org/10.1021/jm301634cCopyright © 2013 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views700Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (197 KB) Get e-Alerts Get e-Alerts

Comodulation of dopamine and serotonin on prefrontal cortical rhythms: a theoretical study

The prefrontal cortex (PFC) is implicated to play an important role in cognitive control. Abnormal PFC activities and rhythms have been observed in some neurological and neuropsychiatric disorders, and evidences suggest influences from the neuromodulators dopamine (DA) and serotonin (5-HT). Despite the high level of interest in these brain systems, the combined effects of DA and 5-HT modulation on PFC dynamics remain unknown. In this work, we build a mathematical model that incorporates available experimental findings to systematically study the comodulation of DA and 5-HT on the network behavior, focusing on beta and gamma band oscillations. Single neuronal model shows pyramidal cells with 5-HT1A and 2A receptors can be non-monotonically modulated by 5-HT. Two-population excitatory-inhibitory type network consisting of pyramidal cells with D1 receptors can provide rich repertoires of oscillatory behavior. In particular, 5-HT and DA can modulate the amplitude and frequency of the oscillations, which can emerge or cease, depending on receptor types. Certain receptor combinations are conducive for the robustness of the oscillatory regime, or the existence of multiple discrete oscillatory regimes. In a multi-population heterogeneous model that takes into account possible combination of receptors, we demonstrate that robust network oscillations require high DA concentration. We also show that selective D1 receptor antagonists (agonists) tend to suppress (enhance) network oscillations, increase the frequency from beta toward gamma band, while selective 5-HT1A antagonists (agonists) act in opposite ways. Selective D2 or 5-HT2A receptor antagonists (agonists) can lead to decrease (increase) in oscillation amplitude, but only 5-HT2A antagonists (agonists) can increase (decrease) the frequency. These results are comparable to some pharmacological effects. Our work illustrates the complex mechanisms of DA and 5-HT when operating simultaneously through multiple receptors.

Paradoxical dopaminergic drug effects in extraversion: dose- and time-dependent effects of sulpiride on EEG theta activity

Dopaminergic drugs frequently produce paradoxical effects depending on baseline performance levels, genotype, or personality traits. The present study for the first time aimed to specify the mechanisms underlying such opposite effects using the following recently reported scenario as an example: depending on the personality trait agentic extraversion (agentic facet, aE; i.e., assertiveness, dominance, ambition, positive emotionality) the selective dopamine D2 receptor antagonist sulpiride (200 mg) had opposite effects on resting posterior vs. anterior theta activity in the electroencephalogram (EEG). In order to better describe these opposite pharmaco-EEG effects and to generate hypotheses regarding the underlying mechanisms, we measured the EEG intermittently over 5 h in 80 healthy male volunteers extremely high or low in aE who had received either placebo or one of three doses of sulpiride (50, 200, or 400 mg). The findings suggest a model postulating stronger pre- vs. postsynaptic subreceptor effects in high aE individuals compared to low aE individuals. Future studies may now systematically apply the model to other examples of paradoxical dopaminergic drug effects and examine the molecular basis of individual differences in pre- vs. postsynaptic dopamine D2 subreceptor sensitivities and densities.