Functional Regulation of Dopamine D₃ Receptor through Interaction with PICK1

PICK1, a PDZ domain-containing protein, is known to increase the reuptake activities of dopamine transporters by increasing their expressions on the cell surface. Here, we report a direct and functional interaction between PICK1 and dopamine D₃ receptors (D₃R), which act as autoreceptors to negatively regulate dopaminergic neurons. PICK1 colocalized with both dopamine D₂ receptor (D₂R) and D₃R in clusters but exerted different functional influences on them. The cell surface expression, agonist affinity, endocytosis, and signaling of D₂R were unaffected by the coexpression of PICK1. On the other hand, the surface expression and tolerance of D₃R were inhibited by the coexpression of PICK1. These findings show that PICK1 exerts multiple effects on D₃R functions.

Ginger facilitates cholinergic activity possibly due to blockade of muscarinic autoreceptors in rat stomach fundus

Ginger [Zingiber officinale] is universally known food plant reputed for its medicinal use in gastrointestinal disorders as a prokinetic and laxative. We recently showed that 70% aqueous-methanolic extract of ginger [Zo.Cr] exhibits prokinetic activity in rats via activation of post-synaptic muscarinic M[3] receptor in rat stomach fundus. In view of the physiological significance of pre-synaptic muscarinic M[1] and M[2] autoreceptors, this study was undertaken to further look into the possible mode of action of the prokinetic effect of ginger through inhibition of pre-synaptic muscarinic receptors. Isolated tissue bath experiments were performed with Sprague-Dawley rat stomach fundus strip preparations immersed in Kreb's solution at 37 degree C. Carbachol [CCh] maximum responses [1 microM] were obtained in rat stomach fundus. Zo.Cr, given in multiple increasing bolus concentrations [0.01-0.1 mg/ml] 10 min prior to administration of CCh, potentiated the CCh peak responses showing that it is possibly inhibiting the pre-synaptic muscarinic receptors. Like wise, increasing bolus concentrations of pirenzepine [0.03-0.3 micro M] and himbacine [0.01-0.03 micro M], standard muscarinic M[1] and M[2] antagonists respectively, also potentiated the CCh responses. These results show that ginger, in addition to having a direct cholinergic effect on the post-synaptic M[3] receptors, also has a possible inhibitory effect on pre-synaptic muscarinic autoreceptors, similar to standard muscarinic antagonists, thus reiterating the gastric stimulant effect of this age-old plant

The Function of 5-HT(1A) Receptor and Pharmacotherapy / 대한정신약물학회지

5-HT(1A) receptor is implicated in the pathogenesis and the therapeutic mechanism of various psychiatric disorders. Especially, the mechanism of action of selective serotonin reuptake inhibitors (SSRIs) was hypothesized that 5-HT(1A) autoreceptor desensitization plays an important role in the treatment of depression and anxiety. 5-HT(1A) receptor stimulation may also mediate the neurogenesis of prefrontal cortex and hippocampus. The 5-HT(1A) agonism has an important meaning in the treatment of schizophrenia. Most atyptical antipsychotics have the property of 5-HT(2A) antagonist, and some have that of 5-HT(1A) agonist. In the various regions of brain, 5-HT(1A) and 5-HT(2A) have the functionally antagonistic properties. Recently, 5-HT(1A) receptor-related agents have been investigated in the treatment of acute ischemic stroke and Alzheimer's disease. Therefore, the further understanding about the 5-HT(1A) receptors in the brain functions will provide the development of future drugs and the advancement of psychopharmacology.

Lack of association between the G681C polimorphism in the 5-HT1Dâ autoreceptor gene and schizophrenia

O sistema serotonérgico tem sido implicado na fisiopatologia da esquizofrenia, principalmente por conta dos mecanismos de ação dos antipsicóticos atípicos. Alterações nas vias cerebrais serotonérgicas têm sido relacionadas com a etiologia desse transtorno psiquiátrico. Assim, o objetivo do presente estudo foi investigar uma possível associação entre esquizofrenia e o polimorfismo G861C no gene do auto-receptor serotonérgico 5-HT1Db. Para tanto, conduziu-se estudo do tipo caso-controle em amostra de 196 pacientes com esquizofrenia e 143 indivíduos pareados para sexo, idade e etnia. Não se evidenciaram diferenças estatísticas nas distribuições alélicas e genotípicas entre as populações de pacientes e controles. Desse modo, os resultados dessa investigação não correlacionaram o polimorfismo G861C no gene do auto-receptor serotonérgico 5-HT1Db como fator de susceptibilidade genética para o desenvolvimento de esquizofrenia na amostra estudada.

Recent Development on Future Antidepressants

The current understanding of the mechanisms of pharmacotherapy for depression is characterized by an emphasis on increasing synaptic availability of serotonin, noradrenaline, and possibly dopamine, while minimizing side effects. The acute effects of current available effective antidepressants include blocking selective serotonin or noradrenaline reuptake, alpha2 autoreceptors or monoamine oxidase. Although efficacious, current treatments often produce partial or limited symptomatic improvement rather than remission. While current pharmacotherapies target monoaminergic systems, distinct neurobiological underpinnings and other systems are likely involved in the pathogenesis of depression. Recently, several promising hypotheses of depression and antidepressant action have been formulated. These hypotheses are largely based on dsyregulation of neural plasticity, CREB, BDNF, corticotropin-releasing factor, glucocorticoid, hypothalamic-pituitary adrenal axis and cytokines. Based on these new theories and hypotheses of depression, a number of new and novel agents, including corticotropin-releasing factor antagonists, antiglucocorticoids, and substance P antagonists show a considerable promise for refining treatment options for depression. In this article, the current available pharmacotherapies, current understanding of neurobiology and pathogenesis of depression and new and promising directions in pharmacological research on depression will be discussed.

Presynaptic Mechanism Underlying Regulation of Transmitter Release by G Protein Coupled Receptors

A variety of G protein coupled receptors (GPCRs) are expressed in the presynaptic terminals of central and peripheral synapses and play regulatory roles in transmitter release. The patch-clamp whole-cell recording technique, applied to the calyx of Held presynaptic terminal in brainstem slices of rodents, has made it possible to directly examine intracellular mechanisms underlying the GPCR-mediated presynaptic inhibition. At the calyx of Held, bath-application of agonists for GPCRs such as GABAB receptors, group III metabotropic glutamate receptors (mGluRs), adenosine A1 receptors, or adrenaline alpha2 receptors, attenuate evoked transmitter release via inhibiting voltage-activated Ca2+ currents without affecting voltage-activated K+ currents or inwardly rectifying K+ currents. Furthermore, inhibition of voltage-activated Ca2+ currents fully explains the magnitude of GPCR-mediated presynaptic inhibition, indicating no essential involvement of exocytotic mechanisms in the downstream of Ca2+ influx. Direct loadings of G protein beta gamma subunit (G beta gamma) into the calyceal terminal mimic and occlude the inhibitory effect of a GPCR agonist on presynaptic Ca2+ currents (IpCa), suggesting that G beta gammamediates presynaptic inhibition by GPCRs. Among presynaptic GPCRs glutamate and adenosine autoreceptors play regulatory roles in transmitter release during early postnatal period when the release probability (p) is high, but these functions are lost concomitantly with a decrease in p during postnatal development.

A Review of Meta-analysis Studies with Amisulpride / 대한정신약물학회지

Amisulpride, a substituted benzamide derivative, is a newer atypical antipsychotics. It mainly blocks presynaptic dopamine D2/D3 autoreceptors which is preferentially located in prefrontal area and blocks postsynaptic dopamine D2/D3 receptors in the limbic system. By these mechanism, amisulpride can improve both negative and positive symptoms. In addition to these action, its property of fast dissociation (Koff) and selectivity to D2/D3 receptors can explain more favorable side effects profiles. A lot of studies showed that amisulpride has equivalent or better efficacy and safety to other atypical antipsychotics. Meta-analysis studies is very informative because it contains many cases of previous studies. So we reviewed some meta-analysis studies which compared amisulpride with placebo or other antipsychotics. On positive symptoms of acute schizophrenia, the most pooled analyses of amisulpride have shown to be equally effective with conventional antispychotics. One meta-analysis study have shown that amisulpride is more effective than conventional drugs. On primary negative symptoms, amisulpride is only agents which is investigated for the efficacy in patients with predominantly negative symptoms. as a results of meta-analysis, amisulpride was shown to be more effective than placebo in primary negative symptoms and have a trend of superiority to conventional agents. The safety and tolerability of amisulpride was equal to or better than other atypical drugs on pooled analysis. The drop out rate was also more favorable than conventional antipsychotics. In Summary, amisulpride showed efficacy similar to that of other atypical antipsychotics in reducing positive symptoms. Moreover, its better properties for negative and affective symptoms, and favorable side effects profiles provides another alternative for treatment of schizophrenia. These results show that amisulpride is a favorable `atypical' antipsychotics, and that 5-HT2/D2 antagonism is not only mechanism of `atypicality'.

A Neurodegenerative Hypothesis of Cytokine-Serotonin Interaction in Major Depression / 신경정신의학

A growing body of evidence suggests that major depression is associated with increased productions of pro-inflammatory cytokines such as IL-1, IL-6, IL-12 or TNF-alpha and increased concentrations of prostaglandin E2 and negative-regulatory cytokines such as IL-4 or IL-10. In major depression, interactions among brain 5-HT levels, the activity of its autoreceptors, and that of postsynaptic receptors play a critical role in mood changes and depression. Recently, the link between cytokines and serotonergic turnover has been explored. Cytokines such as IL-1, IL-2 and IFN-gamma reduce the production of 5-HT by stimulating the activity of indoleamine-2,3 dioxygenase (IDO), an enzyme which convert tryptophan, the precursor of 5-HT to kynurenine. The kynurenine is metabolized into quinolinic acid (quinolinate) and kynurenic acid (kynurenate), an excitotoxic NMDA receptor agonist and the antagonist of three ionotropic excitotatory aminoacid receptors, respectively. The cytokineserotonin interaction through IDO that leads to the challenge between quinolinate and kynurenate in the brain may finally induce the neurodegeneration in depression. The neurodegeneration hypothesis of depression can explain how people cope with psychological or physical stress at different stages according to severity and duration of stress and why major depression develops.

Hyperglycemia Associated with Mirtazapine: A Case Report / 신경정신의학

Mirtazapine-a newly developed drug with reduce adverse effects and toxicity of original antidepre-ssants-has been known to have antidepressant effect by enhancing the transmission of norepinephrine and serotonin via blockade of alpha2-noradrenergic autoreceptor and heteroreceptor and to have common side effects such as sedation, weight gain, and dizziness. We report a case of 50 years old female depressive patient who developed mirtazapine-associated hyperglycemia during treatment with mirtazapine and returned to normal glucose level after stopping the usage of mirtazapine. In patients who receive drugs with the risk of hyperglycemia and diabetes mellitus, we should consider the evaluation for diabetes mellitus and follow it up carefully in the future.

Neurobiological Pathophysiology of Attention Deficit Hyperactivity Disorder / 영남의대학술지

BACKGROUND: Models of attention deficit hyperactivity disorder(ADHD) that have proposed a hypodopaminergic state resulting in hypofunction of the prefrontal circuitry have assumed a unitary dopamine system, which largely ignores the distinct functional differences between mesocortical dopamine system and nigrostriatal dopamine system. PURPOSE: The author's goal was to develop a pathophysiological model for ADHD with greater explanotory power than dopaminergic hypofunction hypothesis in prefronal circuitry. MATERIALS AND METHODS: Published clinical findings on ADHD were integrated with data from genetic, pharmacological, neuroimaging studies in human and animals. RESULTS: Molecular genetic studies suggest that three genes may increase the susceptibility to ADHD. The three candidate genes associated with ADHD are each involved in dopaminergic function, and this consistent with the neurobiologic studies implicating catecholamines in the etiology of ADHD. Pharmacological data also provide compelling support for dopamine and noradrenergic hypothesis of ADHD. Neuroimaging studies lend substantial support for the hypothesis that right-sided abnormalities of prefrontal-basal ganglia circuit would be found in ADHD. CONCLUSIONS: The present hypothesis takes advantage of the major differences between the two pertinent dopamine systems. Mesocortical dopamine system, which largely lacks inhibitory autoreceptors, is ideally positioned to regulate cortical inputs, thus improving the signal-to-noise ratio for biologically valued signals. In this circuit, therapeutic doses of stimulants are hypothesized to increase postsynaptic dopamine effects and enhance executive functions. By contrast, symptoms of hyperactivity/impulsivity in ADHD are hypothesized to be associated with relative overactivity of nigrostriatal circuit. This nigrostriatal circuit is tightly regulated by inhibitory autoreceptoors as well as by long distance feedback from the cortex, and slow diffusion of therapeutic doses of stimulant via oral administration is hypothesized to produce a net inhibition of dopaminergic neurotransmission and improves hyperactivity.

Function of the neuronal M2 muscarinic receptor in asthmatic patients / 결핵

BACKGROUND: The dominant innervation of airway smooth muscle is parasympathetic fibers which are carried in the vagus nerve. Activation of these cholinergic nerves releases acetylcholine which binds to M3 muscarinic receptors on the smooth muscle causing bronchocontraction. Acetylcholine also feeds back onto neuronal M2 muscarinic receptors located on the postganglionic cholinergic nerves. Stimulation of these receptors further inhibits acetylcholine release, so these M2 muscarinic receptors act as autoreceptors. Loss of function of these M2 receptors, as it occres in animal models of hyperresponsiveness, leads to an increase in vagally mediated hyperresponsiveness. However, there are limited data pertaining to whether there are dysfunctions of these receptors in patients with asthma. The aim of this study is to determine whether there are dysfunction of M2 muscarinic receptors in asthmatic patients and difference of function of these receptors according to severity of asthma. METHODS: We studied twenty-seven patients with asthma who were registered at Pulmonology Division of Korea University Hospital. They all met asthma criteria of ATS. Of these patients, eleven patients were categorized as having mild asthma, eight patients moderate asthma and eight patients severe asthma according to severity by NAEPP Expert Panel Report 2(1997). All subjects were free of recent upper respiratory tract infection within 2 weeks and showed positive methacholine challenge test(PC 20<16mg/ml). Methacholine provocation tests performed twice on separate days allowing for an interval of one week. In the second test, pre-treatment with the M2 muscarinic receptor agonist pilocarpine(180µg) through inhalation was performed before the routine procedures. RESULTS: Eleven subjects with mild asthma and eight aubjects with moderate asthma showed significant increase of PC20 from 5.30±5.23mg/ml(mean±SD) to 20.82±22.56mg/ml(p=0.004) and from 2.79±1.5mg/ml to 4.67±3.53mg/ml(p=0.012) after pilocarpine inhalation, respectively. However, in the eight subjects with severe asthma significant increase of PC20 from 1.76±1.50mg/ml to 3.18±4.03mg/ml(p=0.161) after pilocarpine inhalation was not found. CONCLUSION: In subjects with mild and moderate asthma, function of M2 muscarinic receptors was normal, but there was a dysfunction of these receptors in subjects with severe asthma. These results suggest that function of M2 muscarinic receptors is different according to severity of asthma.

The effect of typical and atypical antipsychotic drugs on the mRNA expression of rat mesencephalic D2 receptor

Recently various types of dopamine receptors have been proved to exist in human central nervous system. And the understanding of the of specific function is expected to improve therapeutic effect as well as to reduce undesirable side-effect of current antipsychotic and antiparkinson treatment. Since the dopamine autoreceptor is known to be more sensitive to dopaminergic drugs, there is a growing concern about its functional role in neuropsyhiatric disease. Besides ligand binding studies, recent advances in molecular biology make it possible to quantitate mRNA coding for specific receptors which gives more direct information about its rate of synthesis at the gene level. It is documented that chronic antipsychotics treatment enhances the sensitivity of dopamine autoreceptor, but changes in its mRNA expression have never been investigated yet. Using male Sprague-Dawley rats, 6-hydroxydopamine was injected into left median forebrain bumdle to test whether D2 receptoe mRNA found in midbrain is coding for autoreceptors. And antipsychotic drugs, haloperidol, sulpiride, and clozapine, were administered daily for 2 weeks in order to evaluate their effect on dopamine autoreceptor mRNA, expression. The quantitation of mRNA expression was performed using ribonuclease protection assay. After 6-hydroxydopamine injection, significant reduction in D2, both D2L and D2S, receptor mRNA expression was observed in left midbrain compared with right side. The ratios of D2L/beta-actin and D2S/beta-actin- mRNA in left midbrain were 23.3% and 21.6% of that in right side respectively. Significant expression was demonstrated after repetitive haloperidol and sulpiride, but not after clozapine treatment ; D2S mRNA was increased after haloperidol treatment, while sulpiride enhanced D2L mRNA expression. However, the relative ratio of D2L and D2S mRNA expression in rat midbrain was not changed after repetitive administration of antipsychotic drugs used in this study. These result suggest ; first, the major proportion of mesencephalic D2 receptor mRNA is coding for autoreceptor ; second, the D2 receptor mRNA expression is increases after chronic haloperidol and sulpiride, ut not after clozapine treatment, which may be related to development of extrapyramidal side to alter the relative ratio of D2L and D2S mRNA expression in rat midbrain.

Antiepressant-Associated Mania / 신경정신의학

To examine the causative agents, clinical characteristics, management, risk factors, and neurochemical mechanism of the antidepressant-associated mania, MEDLINE searches were conducted. Mania can occur by chance during antideressant treatment or withdrawal, particularly in patients predisposed to mood disorder. Antidepressant-associated mania, especially withdrawal mania, appears to be milder and a more time-limited syndrome than a spontaneous mania and may represent a distinct clinical entity. MAOI, especially RIMA or bupropion may be associated with milder and less manic inductions than either TCA or SSRI. The possible risk factors for antidepressant-induced mania are female, mood disorder, especially bipolar type I, past and family history of mood disorder, especially bipolar type I, long-term treatment, high dose, and combined therapy in treatment-resistant depression, the possible for withdrawal mania are female, mood disorder, especially major depressive disorder, past and family history of mood disorder, especially major depressive disorder, long-term treatment, high dose, abrupt discontinuation or dose reduction, TCA or MAO(except RIMA?). Antidepressant-induced mania can result from dysfunction of mechanisms that maintain noradrenaline/acetylcholine balance associated with the antidepressant-induced activation of noradrenaline system. The mechanism of withdrawal mania with TCA is cholinergic-monoaminergic interaction theory, and with MAOI is related a hyperdopaminergic state due to loss of drug-induced subsensitivity of dopamine autoreceptors. The prevention of these side effects will require further well-designed study on risk factors.