Serotonin Antagonist Mianserin Research Articles

Ritualistic Chewing Behavior induced by mCPP in the rat is an animal model of Obsessive Compulsive Disorder

Obsessive Compulsive Disorder (OCD) is characterized by recurrent, anxiety-producing thoughts accompanied by unwanted, overwhelming urges to perform ritualistic behaviors. Pharmacological treatments for this disorder (serotonin uptake inhibitors) are problematic because there is a 6–8week delayed onset and half of the patients do not adequately respond. The present study evaluated whether Ritualistic Chewing Behaviors (RCBs) induced by the serotonin agonist mCPP in the rat is a behavioral model for OCD. The effects upon the RCBs induced by mCPP (1mg/kg) were evaluated following treatments with either the serotonin antagonist mianserin (3mg/kg), the dopamine antagonist haloperidol (1mg/kg), the GABA modulator diazepam (10mg/kg), or the serotonin uptake inhibitors clomipramine and fluvoxamine (15mg/kg). The response to mCPP was blocked by acute treatment with mianserin, but not with acute haloperidol or diazepam. Further experiments revealed that the effects of mCPP were blocked by chronic, but not acute, treatment with clomipramine and fluvoxamine. A time-course demonstrated that 14days of chronic treatment were required for blockade of the mCPP-evoked response.The current study demonstrates that mCPP-evoked RCBs may be a rodent model for OCD that can be used to predict the clinical efficacy and time course of novel OCD treatment. Future investigations may be able to use the current model as a tool for bench-marking corresponding changes in other measures of neurological activity that may provide insight into the mechanisms underlying OCD.

Serotonergic cerebral cells control activity of cilia in the foregut of the pteropod mollusk Clione limacina

Bilaterally symmetrical pair of serotonergic cells, named C1 in Clione, has been described in the cerebral ganglia of all gastropod species. Here we describe a new role of C1 cells in gastropod mollusks: control of activity of ciliated epithelium in the foregut. Detailed morphological investigation of C1 neurons in the pteropod mollusk Clione limacina revealed that these cells among other destinations send their neurites into foregut where they produce intense arborization with large varicosities along the processes. Intracellular stimulation of a single C1 induced pronounced activation (often followed by inhibition) of cilia lining the foregut. This activation was substantially reduced by serotonin antagonist mianserin. Bath application of serotonin also induced transient increase in ciliary transport rate, followed by inhibition of ciliary activity up to its full cessation in some areas of isolated foregut. These data suggest that C1 in Clione may use serotonin to influence cilia in the foregut. Taking into account high homology of serotonergic cerebral cells across studied species we can speculate that these cells may be involved in the neural control of cilia in the foregut in other gastropod mollusks.

Behavioral choice by presynaptic inhibition of tactile sensory terminals

When presented with multiple stimuli, animals generally choose to respond only to one input. The neuronal mechanisms determining such behavioral choices are poorly understood. We found that the medicinal leech had greatly diminished responses to moderate mechanosensory input as it fed. Feeding dominated other responses by suppressing transmitter release from mechanosensory neurons onto all of their neuronal targets. The effects of feeding on synaptic transmission could be mimicked by serotonin. Furthermore, the serotonin antagonist mianserin blocked feeding-induced decreases in synaptic transmission. These results indicate that feeding predominates behaviors by using serotonin at an early stage of sensory processing, namely on presynaptic terminals of mechanosensory neurons.

Effect of treatment at weaning with the serotonin antagonist mianserin on the brain serotonin and cerebrospinal fluid nocistatin level of adult female rats: a case of late imprinting

Four weeks old (weanling) female rats were treated with the tricyclic antidepressant and histamine/serotonin receptor blocker mianserin for studying its faulty hormonal imprinting effect. Measurements were done four months later. Brain serotonin levels significantly decreased in four regions (hippocampus, hypothalamus, striatum and brainstem), without any change in the cortex. Sexual activity of the treated and control rats was similar. Cerebrospinal fluid nocistatin level was one magnitude higher in the treated rats, than in the controls. The density of uterine estrogen receptors was significantly reduced, while binding capacity of glucocorticoid receptors of liver and thymus remained at control level. The results call attention to the possibility of 1. a broad spectrum imprinting at the time of weaning by a receptor level acting non-hormone molecule 2. imprinting of the brain in a non-neonatal period of life and 3. a very durable (lifelong?) effect of the late imprinting with an antidepressant.

Effect of treatment at weaning with the serotonin antagonist mianserin on the brain serotonin and cerebrospinal fluid nocistatin level of adult female rats: a case of late imprinting

Four weeks old (weanling) female rats were treated with the tricyclic antidepressant and histamine/serotonin receptor blocker mianserin for studying its faulty hormonal imprinting effect. Measurements were done four months later. Brain serotonin levels significantly decreased in four regions (hippocampus, hypothalamus, striatum and brainstem), without any change in the cortex. Sexual activity of the treated and control rats was similar. Cerebrospinal fluid nocistatin level was one magnitude higher in the treated rats, than in the controls. The density of uterine estrogen receptors was significantly reduced, while binding capacity of glucocorticoid receptors of liver and thymus remained at control level. The results call attention to the possibility of 1. a broad spectrum imprinting at the time of weaning by a receptor level acting non-hormone molecule 2. imprinting of the brain in a non-neonatal period of life and 3. a very durable (lifelong?) effect of the late imprinting with an antidepressant.

Local injections of the 5-hydroxytryptamine antagonist mianserin into substantia nigra pars reticulata block tremulous jaw movements in rats: studies with a putative model of Parkinsonian tremor

Atypical antipsychotics such as clozapine and olanzapine have a low liability for producing motor side effects. In addition to being D2 antagonists, these drugs have a complex binding profile that includes affinity for muscarinic, alpha, H1, and various serotonin receptors. Previous work in rats has shown that atypical antipsychotics suppress tremulous jaw movements induced by the anticholinesterase tacrine in rats. Cholinomimetic-induced jaw movements are a putative model of parkinsonian tremor, and the ability of antipsychotic drugs to suppress these movements in rats is correlated with motor side-effect liability in humans. The present work was undertaken to study the role of central serotonin receptors in the generation of cholinomimetic-induced jaw movements. Systemic injections of the serotonin antagonist mianserin suppressed tacrine-induced jaw movements, with an ED(50) of 2.77 mg/kg. Local injections of mianserin directly into substantia nigra pars reticulata (SNr) also suppressed tacrine-induced jaw movements. Injections into ventrolateral neostriatum, or a control site dorsal to SNr, failed to have any effects on jaw movement activity. These studies suggest that atypical antipsychotics may act both on striatal muscarinic receptors and nigral serotonin receptors to suppress jaw movement activity. It is possible that the unique motor properties of atypical antipsychotics result from actions on multiple receptors in several brain areas. The precise serotonin receptor subtype involved in these effects is unknown, and future work will examine the effects of drugs that act selectively on 5-HT(2A) and 5-HT(2C) receptors.

Possible Participation of Serotonin in the Peripheral Link of the Defensive Reflex in the Mollusc Lymnaea stagnalis

The contractions of the dorsal longitudinal muscle of the mollusc Lymnaea stagnalis L., which are evoked by electric stimulation of n. cervicalis inferior were studied. It has been shown that an increase of magnesium ion concentration in saline to 10–15 mM decreases reversibly amplitude of the evoked contractions. Application of serotonin produced a dual effect: at concentrations of 2 × 10−5–10−6 M, it enhanced muscle contractions, whereas at concentrations above 10-5 M, on the contrary, decreased them. The inhibitory effect of the serotonin antagonist mianserin on the evoked contraction amplitude increased with elevation of its concentrations in the studied range (from 10−5 to 10−3 M). The enhancing effect of serotonin on muscle contractions was blocked either by previous mianserin application or its application on the background of the already acting serotonin. A participation of serotoninergic mechanisms in the control of the contractile function of the studied muscle is suggested.

Differential effects of serotonergic and peptidergic cardioexcitatory neurons on the heart activity in the pteropod mollusc, Clione limacina.

A group of four cardioexcitatory neurons has been identified in the intestinal ganglia of the mollusc Clione limacina. Relatively weak stimulation of the intestinal neurons induced auricle contractions only, while strong stimulation produced initial auricle contractions followed by full-cycle auricle-ventricle contractions. Intestinal cardioexcitatory neurons probably utilized as their transmitter a peptide similar to Tritonia pedal peptide--they showed pedal peptide-like immunoreactivity, and their effects were mimicked by application of the exogenous pedal peptide. The pedal cardioexcitatory neuron was found to produce strong excitatory effects only on the ventricle contractions. Its stimulation induced ventricle contractions in the quiescent heart or significantly accelerated the rate of ventricle contractions in the rhythmically active heart. The pedal cardioexcitatory neuron apparently utilized serotonin as a neurotransmitter, based upon serotonin immunoreactivity, blocking effect of serotonin antagonists mianserin and methysergide, and the observation that exogenous serotonin mimicked its effect. A dense network of pedal peptide-like immunoreactivity was found both in the auricle and ventricle tissue. Serotonin immunoreactivity was densely present in the ventricle, while the auricle contained only a separate serotonin-immunoreactive unbranched axon. Thus, there are two separate groups of central cardioexcitatory neurons with different effects on heart activity, which together might provide a complex cardio-regulatory function in Clione.

Cerebral serotonergic neurons reciprocally modulate swim and withdrawal neural networks in the mollusk Clione limacina

1. A pair of serotonin-immunoreactive neurons has been identified in the cerebral ganglia of the pteropod mollusk Clione limacina, which produce coordinated, excitatory/inhibitory effects on neurons controlling two incompatible behaviors, swimming and whole body withdrawal. These cells were designated cerebral serotonergic ventral (Cr-SV) neurons. 2. Activation of Cr-SV neurons produces a prominent inhibition of the pleural withdrawal neurons, which have been previously shown to induce whole body withdrawal in Clione. In addition, the cerebral neurons produce weak excitatory inputs to swim motor neurons, pedal serotonergic neurons involved in the peripheral modulation of swimming, and to the serotonergic heart excitor neuron. 3. Inhibitory and excitatory effects appear to be produced by serotonin because they are mimicked by exogenous serotonin and are blocked by the serotonin antagonist mianserin. 4. All serotonergic neurons identified thus far in the CNS of Clione appear to function in a coordinated manner, altering a variety of neural centers all directed toward the activation of swimming behavior.

Serotonergic modulation of swimming speed in the pteropod mollusc Clione limacina. II. Peripheral modulatory neurons.

A symmetrical cluster of serotonin-immunoreactive neurons in the pedal ganglia of Clione limacina has been described morphologically and physiologically. At least five of the cluster neurons send axons to the ipsilateral wing that branch throughout the entire wing area. Activation of these cells did not produce a motor effect in non-swimming preparations, but did enhance contractility in swimming preparations. Activity in the pedal neurons did not produce detectable central effects as neither swim interneuron nor swim motor neuron activities were altered. Most notable was a lack of a change in swim frequency, a characteristic of swim acceleration. Activity in the pedal neurons did enhance the size of muscle junctional potentials and spike-like responses, but only in slow-twitch muscles. The peripheral modulatory effect was blocked by the serotonin antagonist mianserin.

The serotonin antagonist mianserin improves functional recovery following experimental spinal trauma

The ability of the serotonin antagonist mianserin to improve neurological recovery after graded impact trauma to the thoracic region of the spinal cord was compared to that of cyproheptadine and ketanserin in pentobarbital-anesthetized rats. Spinal cord injury was produced at T-10 by the weight-drop method and confirmed by the disappearance of the somatosensory-evoked response during the subsequent 15 minutes. In all experiments, drug or vehicle treatments were randomly administered as a single intravenous bolus 15 minutes after injury. Functional outcome was blindly assessed for 2 weeks after injury using a modified Tarlov scale, and in some cases, the Rivlin-Tator angleboard test. The survival of descending raphe-spinal axons was determined by the measurement of serotonin in postmortem spinal tissues located above and below the site of injury. In separate acute experiments, the physiological and hemodynamic correlates of a 50 gm cm injury and either mianserin or vehicle injection were examined, as were the effects on serotonin content and metabolism in spinal tissues harvested 30 minutes after injury. All doses of mianserin were associated with some index of improved recovery following a 50 gm cm injury, with a 1-mg/kg dose being clearly superior. Both ketanserin (0.1 mg/kg) and cyproheptadine (2 mg/kg) displayed marginal therapeutic actions for 50 gm cm injuries. In acute studies, mianserin at 1 mg/kg was associated with the preservation of posttraumatic spinal cord blood flow at T-12 as well as a pronounced alteration in postmortem spinal serotonin content and metabolism, in contrast to vehicle control treatments.(ABSTRACT TRUNCATED AT 250 WORDS)

Participation of serotonin and substance P in the action of cholecystokinin on colonic motility

Cholecystokinin (CCK) has a potent stimulatory effect on gastrointestinal motility. The mechanism of CCK-generated contractions in the colon is unknown. We explored the possibility that CCK-mediated contractions in the guinea pig colon occur via a serotonin and/or substance P pathway. In the circular layer, octapeptide of CCK (CCK-8) had no effect under basal conditions, but after treatment with tetrodotoxin the peptide generated dose-dependent contractions (ED50 6 X 10(-8) M). In the longitudinal layer, CCK-8 produced dose-related contractions (ED50 6 X 10(-9) M) blocked by tetrodotoxin and markedly inhibited by the substance P antagonist, Spantide. The effect of substance P was not significantly antagonized by tetrodotoxin but was markedly attenuated by Spantide. Serotonin produced dose-dependent contractions in the longitudinal layer (ED50 4 X 10(-8) M). Desensitization to serotonin antagonized the action of CCK-8 but had no effect on substance P-mediated contractions. Pretreatment with the serotonin antagonist mianserin inhibited CCK-8- but not substance P-generated contractions. In contrast, the stimulatory effect of serotonin was antagonized by Spantide. These studies suggest that in the circular layer of the guinea pig colon CCK-8 has no effect under basal conditions, but after removal of tonic inhibition, the peptide produced a direct stimulatory effect. In contrast, CCK-8 generated contractions in guinea pig colon longitudinal layer, mediated by a pathway involving serotonin and substance P.

Neuronal protein phosphorylation: Recent studies concerning protein I, A synapse-specific phosphoprotein

Recent studies are described concerning the physiological role and tissue distribution of Protein I, a synapse-specific phosphoprotein. This protein is present in both the central and the peripheral nervous system and appears to be enriched in synaptic vesicles. It is a major substrate for both Ca2(-)- and cyclic AMP-dependent phosphorylation in the brain. In slices of the facial motor nucleus from rat brainstem, serotonin (5-HT) added to the incubation medium stimulates the phosphorylation of Protein I. This effect is potentiated by low concentrations of isobutylmethylxanthine and is prevented by the serotonin antagonist mianserin.