Number Of D2 Receptors Research Articles

Translational findings linking poor inhibitory control and heightened drug reward sensitivity.

Poor inhibitory control and heightened sensitivity to drug reward are two well-established risk factors for substance use disorders. Although these risk factors have traditionally been studied independently, there is reason to expect they may be related at the neurobiological level. Here, translational studies investigating the association between poor inhibition and greater drug reward sensitivity in both laboratory animals and humans are reviewed. Findings show that in animals, inhibitory deficits are associated with greater self-administration of cocaine, nicotine, 3,4-methylenedioxy-methamphetamine (MDMA), and alcohol, but not heroin. Likewise, in healthy human volunteers, poor inhibitory control and less brain engagement in right frontal regions during inhibition are associated with greater and more positive subjective responses to amphetamine and alcohol. The potential neurobiological mechanisms underlying this association are discussed, including the number or function of striatal dopamine D₂ receptors, as well as the implications of the findings and directions for future research. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Participation of Brain Receptors in the Mechanism of Anticonvulsant Action of a New 4-Benzoylpyridine Oxime Derivative GIZH-298

The aim of the work was to study the involvement of glutamate, dopamine and serotonin receptors in the mechanism of the anticonvulsant action of the 4-benzoylpyridine oxime derivative (GIZh-298). After a single exposure to the cornea with maximum electric shock (MES) and subsequent tonic-clonic seizures, an increase in the density (Bmax) of NMDA receptors in the hippocampus by 27% and a decrease in the number of mGluII receptors (mGluR2/3) by 25% in the prefrontal cortex of the brain of rats are noted. At the same time, the number of 5-HT2A receptors in the prefrontal cortex did not change. GIZh-298 (60 mg/kg) with a single application inhibits convulsive reactions, but does not affect the quantitative changes induced by MES in glutamate receptors and does not affect them under normal conditions, without MES. In tests on mice, subchronic (5 days) corneal exposure to MES reduced the density (Bmax) of D2 receptors in the striatum by 17% and did not change this parameter in the prefrontal cortex. GIZh-298 (60 mg/kg/5 days) eliminates clonic-tonic convulsions in mice and prevents a decrease in the number of D2 receptors from striatal membranes, and also increases their number by 13% in mice without MES in the same structure. The data obtained indicate significant changes in the functional activity of NMDA, mGluII and D2 receptors in the brains of animals that suffered seizures. The anticonvulsant effects of GIZH-298 are accompanied by the restoration of the number of D2 receptors in the striatum..

Dopaminylation in Psychostimulant Use Disorder Protects Against Psychostimulant Seeking Behavior by Normalizing Nucleus Accumbens (NAc) Dopamine Expression.

Repeated cocaine administration changes histone acetylation and methylation on Lys residues and Deoxyribonucleic acid (DNA) within the nucleus accumbens (NAc). Recently Nestler's group explored histone Arg (R) methylation in reward processing models. Damez-Werno et al. (2016) reported that during human investigations and animal self-administration experiments, the histone mark protein-R-methyltransferase-6 (PRMT6) and asymmetric dimethylation of R2 on histone H3 (H3R2me2a) decreased in the rodent and cocaine-dependent human NAc. Overexpression of PRMT6 in D2-MSNs in all NAc neurons increased cocaine seeking, whereas PRMT6 overexpression in D1-MSNs protects against cocaine-seeking. The hypothesis is that dopaminylation (H3R2me2a binding) occurs in psychostimulant use disorder (PSU), and the binding inhibitor Srcin1, like the major DRD2 A2 allelic polymorphism, protects against psychostimulant seeking behavior by normalizing nucleus accumbens (NAc) dopamine expression. Numerous publications confirmed the association between the DRD2 Taq A1 allele (30-40 lower D2 receptor numbers) and severe cocaine dependence. Lepack et al. (2020) found that acute cocaine increases dopamine in NAc synapses, and results in histone H3 glutamine 5 dopaminylation (H3Q5dop) and consequent inhibition of D2 expression. The inhibition increases with chronic cocaine use and accompanies cocaine withdrawal. They also found that the Src kinase signaling inhibitor 1 (Srcin1 or p140CAP) during cocaine withdrawal reduced H3R2me2a binding. Consequently, this inhibited dopaminylation induced a "homeostatic brake." The decrease in Src signaling in NAc D2-MSNs, (like the DRD2 Taq A2 allele, a well-known genetic mechanism protective against SUD) normalizes the NAc dopamine expression and decreases cocaine reward and motivation to self-administer cocaine. The Srcin1 may be an important therapeutic target.

ERK1/2 kinases and dopamine D2 receptors participate in the anticonvulsant effects of a new derivative of benzoylpyridine oxime and valproic acid

Inhibition of the activity of extracellular signal-regulated kinases (ERK1/2) induced by the activation of the dopamine D2 receptor signalling cascade may be a promising pharmacological target. The aim of this work was to study the involvement of ERK1/2 and dopamine D2 receptor in the mechanism of the anticonvulsant action of valproic acid (VA) and a new benzoylpyridine oxime derivative (GIZH-298), which showed antiepileptic activity in different models of epilepsy. We showed that subchronic exposure to maximal electroshock seizures (MES) for 5 days reduced the density of dopamine D2 receptors in the striatum of mice. GIZH-298 counteracted the decrease in the number of dopamine D2 receptors associated with MES and increased the number of ligand binding sites of dopamine D2 receptors in mice without MES. The affinity of dopamine D2 receptors to the ligand was not changed by GIZH-298. MES caused an increase in ERK1/2 and synapsin I phosphorylation in the striatum while GIZH-298, similar to VA, reduced the levels of both phospho-ERK1/2 and phosphosynapsin I after MES, which correlated with the decrease in the intensity of seizure in mice. In addition, GIZH-298 suppressed ERK1/2 phosphorylation in SH-SY5Y human neuroblastoma cells at therapeutic concentrations, while VA inhibited ERK1/2 phosphorylation in vivo but not in vitro. The data obtained expand the understanding of the mechanisms of action of VA and GIZH-298, which involve regulating the activity of ERK1/2 kinases, probably by modulating dopamine D2 receptors in limbic structures, as well as (in the case of GIZH-298) directly inhibiting of the ERK1/2 cascade.

Comparative assessment of effect of malt with different bud length on prolactin in hyperprolactinemia rat

Malt is the mature fruit of Hordeum vulgare L. after germination and drying and has been applied for treatment female abnormal galactorrhea. Previous studies have showed total alkaloids in malt have anti-HPRL effect. However, total alkaloids of malt change with the growth cycle, and the specified levels of total alkaloids in different bud length of malt have not been decided. To determine the definitive level of total alkaloids in different buds of malt and the most suitable bud length for clinical application by comparing effects on hyperprolactinemia rat. During the budding of malt, the content of total alkaloids first increased and then decreased, and it peaked at a bud length of 0.75 cm. Treated the HPRL model rats with different buds of malt, the PRL level was decreased, the number of PRLpositive cells and the mRNA expression level in the pituitary were significantly declined, and the number of dopamine D1 and D2 receptors in the hypothalamus was increased. The above changes were most significant in 0.75 cm bud. These results suggest that in terms of the content of effective substance and the effects on HPRL model rats, a malt bud length of 0.75 cm is optimal for clinical application.

An evaluation of the genetic conditioning of evoking pain.

Pain is an integral element of the pathogenic process and sometimes determines its course. Disorders in pain sensation, as well as its lack, the pain threshold, and variability in sensation of the same pain stimuli as more or less intensive by different persons, may be genetically conditioned. The aim of the study is to examine genes in pathogenesis of chronic pain. The study was conducted in a specially selected group of 31 persons: study group - 20 patients with chronic pain, and control group - 11 healthy individuals who did not experience pain. The control group of 11 healthy persons, compared with the study group, was the catalyst for determining the relative quantification (RQ) of gene expression. Biological material in the form of venous blood was collected from the study participants into the tubes containing anticoagulant EDTA KE/2.7 ml (ethylenediaminetetraacetic acid), preventing extracorporeal blood clotting. Analysis of expression of the examined genes showed over-expression of the DRD1 gene in patients experiencing chronic pain, which means that in these patients an increased number of dopamine D1 receptors encoded by this gene should be expected. The dopamine D1 receptor is a G-protein-coupled receptor which regulates (stimulates or inhibits) adenyl cyclase - the enzyme responsible for synthesis of cyclic AMP (cAMP). An increase in the concentration of cAMP in neurons enhances the sensation of pain. The genes (DRD1, COMT, OPRK1, HCN2) have a significant role in the pathogenesis of chronic pain in various diseases; they can also influence the perception of pain. Knowledge of these genes can contribute to the development of effective methods of combating pain.

Olanzapin kullanımına bağlı gelişen bir kekemelik olgusu

Stuttering is defined as a disturbance in time patterning and fluency of speech inappropriate for an individual’s age. The pathophysiology of stuttering is not fully understood. Some studies show that stuttering is related with an increased number of D2 receptors in the basal ganglia. Otherwise, a 50-200% increase in the level of dopaminergic activity has been found in stuttering cases in comparison to the control group. Stuttering as a side-effect of psychotropic medication is rare. Only a few stuttering cases are reported in the literature as being due to effects of antipsychotics like chlorpromazine, clozapine, olanzapine, risperidone, or trifluoperazine. Olanzapine is also used to treat the symptoms of stuttering via D2 receptor antagonism, and in the literature there are cases treated with the administration of olanzapine. Here we present a case of olanzapine-induced stuttering. The importance of this case is to show that while olanzapine may be used in the treatment of stuttering, it may also be the cause of stuttering as an adverse effect.

Temporomandibular joint dislocation due to atypical antipsychotic-induced acute dystonia: a case report.

Dystonia is a movement disorder that causes sustained muscle contractions, repetitive twisting movements, and abnormal postures of the trunk, neck, face, arms or legs [Fahn et al. 1987]. It may be focal, segmental (multifocal), or generalized and may also be primary or secondary based on their etiology. It may manifest as oculogyric crisis, deviation of eyes in all directions, protrusion of tongue, trismus, lock jaw, torticolis, laryngeal spasm, difficulty in speaking, facial grimacing, opisthotonus, lordosis or scoliosis and tortipelvic crisis. Drug-induced dystonia are secondary dystonias which occur commonly with drugs with antidopaminergic effects such as antipsychotics and metoclopramide [Ropper and Samuels, 2009; Fadare and Owolabi, 2009]. They reportedly arise from a drug-induced alteration of dopaminergic–cholinergic balance in the nigrostriatum (i.e. basal ganglia). Most drugs produce dystonic reactions by nigrostriatal dopamine D2 receptor blockade, which leads to an excess of striatal cholinergic output. High-potency D2 receptor antagonists are most likely to produce an acute dystonic reaction [Marsden and Jenner, 1980]. Agents that balance dopamine blockade with muscarinic M1 receptor blockade, such as atypical antipsychotics, are less likely to cause dystonic reactions [Marsden and Jenner, 1980; Volkow et al. 1998]. The incidence of acute dystonic reactions varies according to individual susceptibility, drug identity and dose of the drug. Increased age may carry less risk for the development of dystonia because of diminished numbers of D2 receptors. It occurs commonly to young males who are naive to antidopaminergic drugs [Volkow et al. 1998]. Oromandibular dystonia is one of the focal dystonias, which can be presented as jaw clenching, jaw opening or jaw deviation and leads to impaired speech and swallowing [Eken et al. 2009]. At times, oromandibular dystonia is so severe that it can cause temporomandibular joint (TMJ) dislocation. So far, few case reports have been published about TMJ dislocation due to antipsychotic medications [Ibrahim and Brooks, 1996]. Among antipsychotic-induced TMJ dislocation, case reports were mainly for high-potency first-generation antipsychotics such as haloperidol [Eken et al. 2009; Ibrahim and Brooks, 1996; Zakariaei et al. 2012]. It has been proposed that drugs such as risperidone and amisulpride which block specific receptors of serotonin (the S-HT2 receptors) and dopamine (the D2 receptors) are less likely to cause these effects [Owens, 1994]. Therefore, the present paper reports a case of oromandibular dystonia with TMJ dislocation with atypical antipsychotics such as risperidone and amisulpride.

P‐Aminosalicylic acid prevents the loss of immunofluorescence emissions of postsynaptic dopamine D2 receptors due to manganese treatment (796.1)

Manganese (Mn) a neurotoxin causing Manganism, a Parkinsons‐like disease, disrupts dopamine (DA) neurons. The neurotoxic mechanism is not fully resolved. It’s postulated more related to dysfunction of DA D2 receptors than degeneration of DA neurons. Crassostrea virginica gill lateral cells are innervated by DA nerves and have D2 post‐synaptic receptors. Mn blocks cilio‐inhibition of DA. PAS (p‐aminosalicylic acid) blocks the effects of Mn. It’s questioned if Mn decreases the number of DA D2 receptors in brain. We used 1̊ antibodies against D2 receptors and FITC‐linked 2̊ antibodies to quantify DA D2 receptors to test if Mn decreases the number of receptors in gill of C. virginica and if PAS prevents the decrease. We treated animals with 500 µM of Mn for up to 6 days. Sections were viewed on a fluorescence microscope, intensity was quantified with ImageJ software. Control gills had bright fluorescence corresponding to lateral and other gill cells. Intensity from animals treated up to 6 days with Mn showed a decrease up to 36% of controls. Animals co‐treated with Mn and PAS did not show reduced fluorescence. The study shows negative correlation between fluorescence intensity of DA D2 receptors in Mn treated animals vs controls and PAS negates effects of Mn. Whether intensity loss is due to decrease in D2 receptor number or altering of protein conformation and ligand binding site of D2 receptors needs to be further explored.Grant Funding Source: NIH‐ 2R25GM06003, NSF‐ 0622197, NYSED‐ 0516041071

Is schizophrenia a dopamine supersensitivity psychotic reaction?

Adolf Meyer (1866-1950) did not see schizophrenia as a discrete disorder with a specific etiology but, rather, as a reaction to a wide variety of biopsychosocial factors. He may have been right. Today, we have evidence that gene mutations, brain injury, drug use (cocaine, amphetamine, marijuana, phencyclidine, and steroids), prenatal infection and malnutrition, social isolation and marginalization, can all result in the signs and symptoms of schizophrenia. This clinical picture is generally associated with supersensitivity to dopamine, and activates dopamine neurotransmission that is usually alleviated or blocked by drugs that block dopamine D2 receptors. While the dopamine neural pathway may be a final common route to many of the clinical symptoms, the components of this pathway, such as dopamine release and number of D2 receptors, are approximately normal in schizophrenia patients who are in remission. Postmortem findings, however, reveal more dimers of D1D2 and D2D2 receptors in both human schizophrenia brains and in animal models of schizophrenia. Another finding in animal models is an elevation of high-affinity state D2High receptors, but no radioactive ligand is yet available to selectively label D2High receptors in humans. It is suggested that synaptic dopamine supersensitivity in schizophrenia is an attempt at compensation for the original damage by heightening dopamine neurotransmission pathways (preparing the organism for fight or flight). The dopamine overactivity is experienced subjectively as overstimulation, which accounts for some of the clinical symptoms, with attempts at dampening down the stimulation leading to still other symptoms. Reaction and counter-reaction may explain the symptoms of schizophrenia.

Neuroprotective potential of Bacopa monnieri and Bacoside A against dopamine receptor dysfunction in the cerebral cortex of neonatal hypoglycaemic rats.

Neonatal hypoglycaemia initiates a series of events leading to neuronal death, even if glucose and glycogen stores return to normal. Disturbances in the cortical dopaminergic function affect memory and cognition. We recommend Bacopa monnieri extract or Bacoside A to treat neonatal hypoglycaemia. We investigated the alterations in dopaminergic functions by studying the Dopamine D1 and D2 receptor subtypes. Receptor-binding studies revealed a significant decrease (p < 0.001) in dopamine D1 receptor number in the hypoglycaemic condition, suggesting cognitive dysfunction. cAMP content was significantly (p < 0.001) downregulated in hypoglycaemic neonatal rats indicating the reduction in cell signalling of the dopamine D1 receptors. It is attributed to the deficits in spatial learning and memory. Hypoglycaemic neonatal rats treated with Bacopa extract alone and Bacoside A ameliorated the dopaminergic and cAMP imbalance as effectively as the glucose therapy. The upregulated Bax expression in the present study indicates the high cell death in hypoglycaemic neonatal rats. Enzyme assay of SOD confirmed cortical cell death due to free radical accumulation. The gene expression of SOD in the cortex was significantly downregulated (p < 0.001). Bacopa treatment showed a significant reversal in the altered gene expression parameters (p < 0.001) of Bax and SOD. Our results suggest that in the rat experimental model of neonatal hypoglycaemia, Bacopa extract improved alterations in D1, D2 receptor expression, cAMP signalling and cell death resulting from oxidative stress. This is an important area of study given the significant motor and cognitive impairment that may arise from neonatal hypoglycaemia if proper treatment is not implemented.

The Speed of Cocaine Delivery Determines the Subsequent Motivation to Self-Administer the Drug

The rapid delivery of drugs of abuse to the brain is associated with an increased likelihood and severity of addiction. Here we evaluated the hypothesis that rapidly delivered cocaine facilitates the addiction process by promoting the development of enhanced motivation for the drug. Rats lever-pressed for cocaine delivered intravenously over 5 or 90 s under fixed ratio (FR) during 6-h sessions. The motivation for cocaine was subsequently assessed using a progressive ratio (PR) schedule, where each successive drug injection cost an exponentially greater number of lever presses, until the cessation of responding. Throughout all self-administration sessions, all rats could only take one injection every 90 s. The 5-s groups self-administered more drug than the 90-s groups across the FR sessions. Under PR, animals that had chronically self-administered rapidly delivered cocaine took more cocaine across a range of doses and regardless of whether the drug was delivered over 5 or 90 s during PR testing. The speed of delivery also determined the long-term neurobiological impact of cocaine. Fourteen days following cocaine withdrawal, caudate-putamen D2 levels were decreased only in the 90-s rats, and quinpirole-mediated Gα(i/o)-protein activation was increased to a greater extent in the 90- vs 5-s rats. Thus, rapid delivery promotes the pursuit of cocaine in the face of rising costs and alters cocaine-induced changes in striatal D2 receptor number and function. As such, rapidly delivered cocaine might facilitate addiction because it more readily alters brain motivation circuits in ways that contribute to the compulsive pursuit of the drug.

Manganese treatments decrease immunofluorescence emissions of post‐synaptic dopamine D2 receptors

Manganese (Mn) a neurotoxin causing Manganism, a Parkinsons‐like disease, disrupts dopamine (DA) neurotransmission. Gill lateral cell cilia of Crassostrea virginica are controlled by DA innervations. DA is cilio‐inhibition. Our lab showed post‐synaptic DA receptors in gill cells are D2 type and Mn blocks cilio‐inhibitory effects of DA. Questions exist in the literature if Mn decreases the number of D2 receptors in brain. To test this we used histoimmunofluorescence techniques to visualize DA D2 receptors in gill and ganglia of C. virginica. Animals were treated with 500 FM of Mn for 5 days. Paraffin embedded sections were viewed with a phase contrast fluorescence microscope with a ProgRes C3 Peltier cooled camera. Antibody treated sections showed bright FITC fluorescence in lateral ciliated cells and other areas of gill and ganglia. Sections lacking 1E antibody treatment did not display similar fluorescence. We analyzed fluorescence intensity of the cells using ImageJ software. Intensity of Mn treated cells was 70% less than controls. The study identifies DA D2 receptors in gill cells and cerebral and visceral ganglia and shows a negative correlation between fluorescence intensity of the receptors in Mn treated animals. The question if the decrease in intensity is due to decrease in actual number of receptors or if Mn alters protein conformation of D2 receptor and D2‐ligand binding sites needs to be further explored.

Physostigmine and Restless Legs Syndrome

Restless legs syndrome (RLS) is a common neurologic disorder that uncommonly manifests in the perioperative period. Its anesthetic implications were recently discussed,1,2but the reviewers did not reference a 2005 case report that described rapid relief of symptoms with physostigmine.3Their perioperative recommendations for prevention and treatment were based on the current theory of causation involving dysfunctional central iron and dopamine metabolism and six case reports in which no patient experienced prompt resolution of symptoms. Oral administration of the dopamine D2/D3 receptor agonist, 0.125 mg pramipexole, produced relief after 30 min.4We report the second case of prompt relief of RLS symptoms with intravenous physostigmine.A 65-yr-old man presented for endoscopic ultrasound and fine needle aspiration of a submucosal gastric lesion. The patient met the international standard essential criteria for RLS: irresistible urge to move his legs, accompanied by unpleasant sensory complaints in his legs; increased agitation when the nursing staff insisted that he remain still; symptoms at home relieved by walking; and symptoms that are worse in the evening but reasonably controlled with dopamine D2/D3 receptor agonist therapy.1,5His daily dose of pramipexole, extended-release 1.5 mg after dinner, was twice the maximum daily dose usually recommended for RLS6and may reflect the severity of the syndrome. However, it is less than the average dose used to treat early Parkinson disease.7His other comorbidities (medications) included obesity, obstructive sleep apnea, diabetes mellitus type 2 (insulin, metformin, glipizide), hypertension (lisinopril), coronary artery disease (aspirin, lovastatin), gastroesophageal reflux (omeprazole), and osteoarthritis (oxaprozin).Anesthesia was provided with 2 mg midazolam, 440 mg propofol, and 10 mg ketamine intravenously (IV). He also received 4 mg ondansetron, 0.2 mg glycopyrrolate, and 20 mg IV esmolol and oxymetazoline intranasally before insertion of a nasopharyngeal airway. He was conversant on arrival in the recovery room. Within minutes he became agitated and tried to get off his stretcher to walk. He exhibited severe restlessness in both legs and complained of lower extremity tingling and tugging. The differential diagnoses in this setting included hypoxia (SpO298%), hypoglycemia (blood glucose 168 mg/dL), emergence delirium (conversant, oriented), neuroleptic-induced akathisia (no droperidol given), peripheral neuropathy, and a RLS flare (patient stated, “It’s my restless legs”). Administration of 1 mg IV physostigmine attenuated these symptoms within 3 min. Symptoms completely resolved with a second dose of 1 mg physostigmine. Five hours later, he was free of symptoms, despite not yet taking his usual evening dose of pramipexole.It is difficult to reconcile this apparent effectiveness of physostigmine with the current view of the pathophysiology of RLS – central iron insufficiency altering the dopaminergic system with a decrease in the number of D2 receptors in the putamen, increased activity of tyrosine hydroxylase, and increased dopamine transporter density in the caudate, putamen, and striatum.1,8,9But the cholinergic and dopaminergic systems do interact in certain brain regions, e.g. , striatal cholinergic output is dopamine D2 receptor-mediated.10In summary, two patients with acute manifestations of RLS syndrome obtained prompt sustained relief after administration of physostigmine. A clinical trial in the nonperioperative setting is needed to confirm this beneficial effect. A positive outcome could spur a different line of research into the mechanisms involved.Jeff Peacock, M.D., Girish Mishra, M.D., Raymond C. Roy, M.D., Ph.D.**Wake Forest School of Medicine, Winston-Salem, North Carolina. rroy@wakehealth.edu

Possible mechanisms for the effects of neuromodulators on the perception of time intervals

We propose possible mechanisms for the effects of neuromodulators on the perception of time on the basis of our hypothesis that estimation of intervals between sensory stimuli depends on the beat frequency of a “internal clock,” which is inversely proportional to the latency of reentering excitation of the neocortex. These effects are based on the modification of the efficacy of excitatory inputs to the cortical neurons, as well as inputs from the cortex to the striatum, which are necessary for the disinhibition of thalamic neurons by the basal ganglia and subsequent excitation of the cortex. The character of influence is determined by the concentration of neuromodulators, the types of receptors activated by them on neurons of the striatum and cortex, and the modulation rules. According to the proposed mechanism, an increase in the frequency of the “internal clock” and overestimation of the duration of intervals may result from treatment with dopaminergic drugs, agonists of dopamine D1 and D2 receptors, and opioids and cannabinoids, which promote an increase in the dopamine concentration, as well as antagonists of adenosine A1 and A2A and muscarinic M2 receptors, whose activation facilitates disinhibition of the thalamus by the basal ganglia. Antagonists of A1, M2, and D2 receptors, which prevent depression of excitatory inputs to neocortical pyramidal cells, also can increase the frequency of the “internal clock.” The activation of a large number of D2 receptors on the cortical pyramidal cells, which results from a considerable increase in dopamine concentration, like activation of cannabinoid CB1 receptors, should promote a decrease in the frequency of the “internal clock” and the underestimation of interval duration. The activation of D2 and M2 receptors on the GABAergic interneurons of the cortex under conditions of strong inhibition of pyramidal neurons may increase the beat frequency of the “internal clock.” The proposed mechanism helps to understand the causes of errors in time perception in neurological diseases and to explain the discrepancies in the results of studies on the effects of neuromodulators on the estimation of time. The hypothesis may be experimentally examined by treatment of the striatum or neocortex with agonists and antagonists of various types of receptors and measurement of the drug-induced changes in the interval between the first and second peaks in the distribution of latencies of responses of cortical neurons to sensory stimulus.

Aripiprazole may be free from tachyphylaxis: Preliminary findings

Loss of antipsychotic efficacy (tachyphylaxis), possibly linked to an increase in D₂ receptor number and sensitivity, is a significant impediment to treatment in chronic schizophrenia patients. Animal studies, however, suggest that aripiprazole may be free from tachyphylaxis. The aim of the present study was to investigate this hypothesis. In this preliminary study, aripiprazole-treated patients were retrospectively investigated for the presence or absence of tachyphylaxis. Clinical Global Impression-Improvement (CGI-I) scores did not significantly change and there was no significant association of CGI scores with fixed dose duration. This suggests that aripiprazole may be free from tachyphylaxis.

Rutin Protects Dopaminergic Neurons from Oxidative Stress in an Animal Model of Parkinson’s Disease

This study was undertaken to investigate the neuroprotective effects of rutin (vitamin P) on 6-hydroxydopamine (6-OHDA)-induced Parkinson's disease (PD) in rats. Oxidative stress and inflammation is an important event, play a crucial role in neurodegenerative diseases. Rutin has been shown to have antioxidant and anti-inflammatory actions, and thus was tested for its beneficial effects using 6-OHDA-induced PD rat model. Male Wistar rats were pre-treated with rutin (25mg/kg bwt, orally) for 3weeks and subjected to unilateral intrastriatal injection of 6-OHDA (10μg in 0.1% ascorbic acid in normal saline). Three weeks after 6-OHDA infusion, rats were tested for neurobehavioral activity, and were killed after 4weeks of 6-OHDA infusion for the estimation of thiobarbituric acid reactive substances, glutathione, and its dependent enzymes (glutathione peroxidase and glutathione reductase), dopamine (DA) and its metabolite 3,4-dihydroxyphenyl acetic acid. The increase in 6-OHDA-induced rotations and deficits in locomotor activity and motor coordination and decrease in antioxidant level, DA content and its metabolite and increase in the number of dopaminergic D2 receptors in striatum were protected significantly with lesioned group pre-treated with rutin. These findings were further supported by the histopathological and immunohistochemical findings in the substantia nigra that showed that rutin protected neurons from deleterious effects of 6-OHDA. These results suggest that the consumption of rutin, which is novel vitamin, may have the possibility of protective effect against the neurological disorder such as PD.

Inhibitory Effects of Antivascular Endothelial Growth Factor Strategies in Experimental Dopamine-Resistant Prolactinomas

Prolactin-secreting adenomas are the most frequent type among pituitary tumors, and pharmacological therapy with dopamine agonists remains the mainstay of treatment. But some adenomas are resistant, and a decrease in the number or function of dopamine D2 receptors (D2Rs) has been described in these cases. D2R knockout [Drd2(-/-)] mice have chronic hyperprolactinemia and pituitary hyperplasia and provide an experimental model for dopamine agonist-resistant prolactinomas. We described previously that disruption of D2Rs increases vascular endothelial growth factor (VEGF) expression. We therefore designed two strategies of antiangiogenesis using prolactinomas generated in Drd2(-/-) female mice: direct intra-adenoma mVEGF R1 (Flt-1)/Fc chimera (VEGF-TRAP) injection for 3 weeks [into subcutaneously transplanted pituitaries from Drd2(-/-) mice] and systemic VEGF neutralization with the specific monoclonal antibody G6-31. Both strategies resulted in substantial decrease of prolactin content and lactotrope area, and a reduction in tumor size was observed in in situ prolactinomas. There were significant decreases in vascularity, evaluated by cluster of differentiation molecule 31 vessel staining, and proliferation (proliferating cell nuclear antigen staining) in response to both anti-VEGF treatments. These data demonstrate that the antiangiogenic approach was effective in inhibiting the growth of in situ dopamine-resistant prolactinomas as well as in the transplanted adenomas. No differences in VEGF protein expression were observed after either anti-VEGF treatment, and, although serum VEGF was increased in G6-31-treated mice, pituitary activation of the VEGF receptor 2 signaling pathway was reduced. Our results indicate that, even though the role of angiogenesis in pituitary adenomas is contentious, VEGF might contribute to adequate vascular supply and represent a supplementary therapeutic target in dopamine agonist-resistant prolactinomas.

P02-207 - Genetic addiction risk score analysis: hypodopaminergic polymorphic risk alleles in polydrug addicted males and meso-limbic dopaminergic agonistic activation by neuroadaptagen amino-acid therapy

IntroductionThere is a need to classify patients at genetic risk for drug seeking behavior prior to or upon entry to chemical dependency programs.MethodsThe prevalence of seven risk alleles (DRD2 = A1; SLC6A3 (DAT) = 10R; DRD4 = 3R or 7R; 5HTTLPR = L or LA; MAO = 3R; COMT = G) and corresponding severity risk score (Low (LS) = 1–36%, moderate (MS) = 37–50%, and high (HS) = 51–100%) were calculated. Group 1 consisted of 16 Caucasian male psycho-stimulant addicts, and Group 2 consisted of 10 Chinese male heroin addicts (9 were genotyped). qEEG and fMRI visualized the impact of Neuroadaptagen Amino-Acid Therapy complex on mesolimbic system activation.Results[Findings by Group]74% of the combined groups had a moderate to high genetic addiction risk score (GARS). One acute dose of KB220-IV variant in heroin addicts having brain abnormalities was found to normalize qEEG. Additionally, a randomized double-blind placebo controlled study involving oral KB220-Z variant established qEEG normalization of reward circuitry in abstinent psycho-stimulant abusers (P &lt; 0.03).ConclusionsWe cautiously suggest that long-term activation of dopaminergic receptors will lead to D2 receptor proliferation and enhanced “dopamine sensitivity,” thus reducing aberrant craving behavior especially in carriers of the DRD2 A1 allele. Although supported by 20 clinical trials, KB220-Z awaits PET scanning to determine its chronic effects on D2 receptor numbers.

Acute Intravenous Synaptamine Complex Variant KB220™ “Normalizes” Neurological Dysregulation in Patients during Protracted Abstinence from Alcohol and Opiates as Observed Using Quantitative Electroencephalographic and Genetic Analysis for Reward Polymorphisms: Part 1, Pilot Study with 2 Case Reports

It is well established that in both food- and drug-addicted individuals, there is dopamine resistance due to an association with the DRD2 gene A1 allele. Evidence is emerging whereby the potential of utilizing a natural, nonaddicting, safe, putative D2 agonist may find its place in recovery from reward deficiency syndrome (RDS) in patients addicted to psychoactive chemicals. Utilizing quantitative electroencephalography (qEEG) as an imaging tool, we show the impact of Synaptamine Complex Variant KB220™ as a putative activator of the mesolimbic system. We demonstrate for the first time that its intravenous administration reduces or “normalizes” aberrant electrophysiological parameters of the reward circuitry site. For this pilot study, we report that the qEEGs of an alcoholic and a heroin abuser with existing abnormalities (ie, widespread theta and widespread alpha activity, respectively) during protracted abstinence are significantly normalized by the administration of 1 intravenous dose of Synaptamine Complex Variant KB220™. Both patients were genotyped for a number of neurotransmitter reward genes to determine to what extent they carry putative dopaminergic risk alleles that may predispose them for alcohol or heroin dependence, respectively. The genes tested included the dopamine transporter (DAT1, locus symbol SLC6A3), dopamine D4 receptor exon 3 VNTR (DRD4), DRD2 TaqIA (rs1800497), COMT val158 met SNP (rs4680), monoamine oxidase A upstream VNTR (MAOA-uVNTR), and serotonin transporter-linked polymorphic region (5HTTLPR locus symbol SLC6A4). We emphasize that these are case studies, and it would be unlikely for all individuals to carry all putative risk alleles. Based on previous research and our qEEG studies (parts 1 and 2 of this study), we cautiously suggest that long-term activation of dopaminergic receptors (ie, DRD2 receptors) will result in their proliferation and lead to enhanced “dopamine sensitivity” and an increased sense of happiness, particularly in carriers of the DRD2 A1 allele. This is supported by a clinical trial on Synaptamine Complex Variant KB220™ using intravenous administration in > 600 alcoholic patients, resulting in significant reductions in RDS behaviors. It is also confirmed by the expanded oral study on Synaptose Complex KB220Z™, published as part 2 of this study. Future studies must await both functional magnetic resonance imaging and positron emission tomography scanning to determine the acute and chronic effects of oral KB220™ on numbers of D2 receptors and direct interaction at the nucleus accumbens. Confirmation of these results in large, population-based, case-controlled experiments is necessary. These studies would provide important information that could ultimately lead to significant improvement in recovery for those with RDS and dopamine deficiency as a result of a multiple neurotransmitter signal transduction breakdown in the brain reward cascade.