Migraine and anxiety disorders are frequently co-morbid with balance disorders. Potential mechanisms for migrainous vertigo include sites of action of 5-HT (serotonin) 1B and 1D receptor agonists such as rizatriptan, which attenuate motion sickness in migraineurs. Selective serotonin reuptake inhibitors (SSRIs) are also known to be efficacious in the treatment of vertigo. Relative distribution of the 5-HT receptor subtypes and their functional roles in the vestibular nuclei and inner ear is still unknown. Using 5-HT1A, 1B, AND 1D receptors-specific antibody, we have demonstrated a differential distribution of these receptor subtypes within the rat vestibular nuclei and inner ear. For 5-HT receptor subtypes expression in the vestibular and auditory periphery, most ganglion cells in the vestibular ganglion showed immunoreactivity for 5-HT1A, 5-HT1B and 5-HT1D receptors. In addition, 5-HT1B and 1D receptors immunopositive reactivities were associated with endothelial cells of small blood vessels in the vestibular ganglion and nerve, endothelial cells in both the spiral ligament deep to the spiral prominence and stria vascularis and endothelial cells on blood vessels along the margins of the spiral ganglion. For 5-HT receptor subtypes expression in the vestibular nuclei (VN), the 5-HT1A, 1B and 1D receptors were expressed differentially in the VN. Fine varicose axons in the periventricular plexus showed intense 5-HT1A receptor expression in the medial VN (MVN) and extended into the superior VN (SVN). By contrast, 5-HT1B receptors were not expressed the ventricular plexus axons. Rather, 5-HT1B and 1D receptors immunopositive cell bodies and neuronal processes were dense in rostral MVN, dorsal SVN, lateral VN (LVN) and ventral aspect of nucleus prepositus hypoglossi (NPH). In the present study, inner ear and vestibular nuclei showed distinct distributions of 5- HT1A, 1B and 1D receptors expressions that are parallel to their distribution in peripheral and central nociceptive pathways. These differentially distributed 5-HT receptor subtypes are potential targets to explain the efficacy of SSRIs and triptans in treating migraine and migrainous vertigo.
Animals ; Anxiety Disorders ; Axons ; Blood Vessels ; Ear, Inner ; Endothelial Cells ; Ganglion Cysts ; Migraine Disorders ; Motion Sickness ; Neurons ; Rats ; Receptor, Serotonin, 5-HT1A ; Receptor, Serotonin, 5-HT1B ; Receptor, Serotonin, 5-HT1D ; Serotonin ; Serotonin Uptake Inhibitors ; Spiral Ganglion ; Spiral Ligament of Cochlea ; Stria Vascularis ; Triazoles ; Tryptamines ; Vertigo ; Vestibular Nuclei

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'.
Affective Symptoms ; Antipsychotic Agents ; Autoreceptors ; Dopamine ; Humans ; Limbic System ; Meta-Analysis as Topic ; Schizophrenia

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.
Autoreceptors ; Diabetes Mellitus ; Dizziness ; Female ; Glucose ; Humans ; Hyperglycemia* ; Middle Aged ; Norepinephrine ; Serotonin ; Weight Gain

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.
Autoreceptors ; Dopamine Plasma Membrane Transport Proteins ; Dopamine* ; Dopaminergic Neurons ; Endocytosis ; Hand

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.
Autoreceptors ; Bipolar Disorder* ; Bupropion ; Depression ; Depressive Disorder, Major ; Dopamine ; Female ; Humans ; Mood Disorders ; Norepinephrine ; Prevalence ; Risk Factors ; Risk Management

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.
Administration, Oral ; Animals ; Attention Deficit Disorder with Hyperactivity* ; Autoreceptors ; Catecholamines ; Diffusion ; Dopamine ; Dopamine Agents ; Executive Function ; Ganglia ; Humans ; Molecular Biology ; Neuroimaging ; Signal-To-Noise Ratio ; Synaptic Transmission

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.
Acetylcholine ; Asthma ; Autoreceptors ; Humans ; Inhalation ; Korea ; Methacholine Chloride ; Models, Animal ; Muscle, Smooth ; Neurons* ; Pilocarpine ; Pulmonary Medicine ; Receptors, Muscarinic* ; Respiratory Tract Infections ; Vagus Nerve

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.
Alzheimer Disease ; Antipsychotic Agents ; Anxiety ; Autoreceptors ; Brain ; Depression ; Drug Therapy* ; Felodipine ; Hippocampus ; Neurogenesis ; Prefrontal Cortex ; Psychopharmacology ; Receptor, Serotonin, 5-HT1A* ; Schizophrenia ; Serotonin ; Serotonin Uptake Inhibitors ; Stroke

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.
Adenosine ; Autoreceptors ; Brain Stem ; Epinephrine ; Glutamic Acid ; GTP-Binding Proteins* ; Patch-Clamp Techniques ; Presynaptic Terminals ; Receptor, Adenosine A1 ; Receptors, G-Protein-Coupled* ; Receptors, Metabotropic Glutamate ; Rodentia ; Synapses

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.
Antidepressive Agents* ; Autoreceptors ; Axis, Cervical Vertebra ; Brain-Derived Neurotrophic Factor ; Corticotropin-Releasing Hormone ; Cytokines ; Depression ; Dopamine ; Drug Therapy ; Monoamine Oxidase ; Neurobiology ; Neuropeptides ; Norepinephrine ; Plastics ; Serotonin ; Substance P