Serotonergic Hypothesis Research Articles

Potentiation of DOM-induced stimulus control by non-competitive NMDA antagonists: A link between the glutamatergic and serotonergic hypotheses of schizophrenia

The present investigation examined the interaction between 2,5-dimethoxy-4-methylamphetamine [DOM] and non-competitive NMDA antagonists in rats trained with DOM [0.6 mg/kg; 75 min pretreatment time] as a discriminative stimulus. Pretreatment with phencyclidine [PCP] at a dose of 3 mg/kg shifted the DOM dose-response relationship to the left. When a fixed dose of DOM [0.1 mg/kg] which by itself yielded 32% DOM-appropriate responding was combined with a range of doses of PCP, dizocilpine, and ketamine, DOM-appropriate percentages increased to maxima of 73%, 84%, and 79%, respectively. When given alone, PCP, dizocilpine, and ketamine were followed by maxima of 36%, 15%, and 13%, respectively. It is concluded that the effects of DOM as a discriminative stimulus are potentiated by pretreatment with non-competitive antagonists of glutamate receptors of the NMDA subtype. These data suggest that the application of the technique of drug-induced stimulus control may prove useful in the reconciliation and integration of current hypotheses as to the etiology of psychotic disorders.

Molecular Abnormalities in Brains of Depressed Patients

Studies on the molecular pharmacology of antidepressants have lead to a reinterpretation of earlier models of the neuropathology of depression. Noradrenergic and serotonergic hypotheses of depression have been expanded to include postsynaptic intracellular signal transduction pathways and regulation of gene expression. Because much of this evidence was obtained from postmortem brain, there has been increased interest in the use of this tissue to study depression. In the following pages, we will review the postmortem brain studies in depressed individuals focusing on neurotransmitter systems, signal transduction, and structural abnormalities.

Evidence for the serotonin HTR2A receptor gene as a susceptibility factor in attention deficit hyperactivity disorder (ADHD).

A recent study demonstrated that treatment of hyperactive mice with psychostimulants and serotonergic agents produced a calming effect that was dependent on serotonergic neurotransmission and was not associated with any changes in extracellular dopamine levels. The complex interaction between the serotonergic and dopaminergic neurotransmitter systems suggests that a balance between the two systems may be necessary for mediating hyperactive behaviour. Defects in serotonin system genes, therefore, may disrupt normal brain serotonin function causing an imbalance between these neurotransmitter systems leading to the development of attention deficit hyperactivity disorder (ADHD). Using the transmission disequilibrium test (TDT), the current study assesses for linkage disequilibrium between polymorphisms in the serotonin HTR2A receptor gene and ADHD. One hundred and fifteen families with a total of 143 children diagnosed with ADHD (DSM-IV) were genotyped for the His452 Tyr and the T102C polymorphisms in the serotonin HTR2A receptor gene. TDT analysis revealed a preferential transmission of the 452Tyr allele to the affected offspring (P = 0.03), suggesting linkage disequilibrium of this polymorphism with ADHD. This may open a new door in ADHD molecular genetics research, expanding the existing view of a catecholaminergic hypothesis to include a serotonergic hypothesis and should help elucidate the complex interplay among the neurotransmitter systems in the etiology of ADHD.

Obsessive Compulsive Disorder: Serotonin and Beyond

Summary: OCD was considered a rare, treatment refractory disorder of psychological origin, up until 20 years ago. Research in the last two decades has altered the perspectives regarding OCD. It is now clear that OCD is a prevalent disorder—about 2% of the population suffer from OCD—and that it is amenable both to psychological (cognitive-behavioural approach) and pharmacological intervention (with serotonergic medication). The biochemical and neuroanatomical (the frontal basal-thalamo cortical circuit) pathophysiology of OCD is also beginning to emerge.OCD is unique with regards to its specific response to serotonergic medication that blocks reuptake. Clomiprimine, fluoxetine, fluvoxemine, paroxetine, sertraline and citalopram were all found to be effective treatments for OCD based on large, multicentre, double-blind, placebo-controlled studies. As only serotonergic medications appear to be effective in OCD, the serotonergic hypothesis has been formulated and tested. Indeed, pharmacological challenges with specific serotonin agonists such as mCPP and sumatriptan, which were associated with transient exacerbation of OCD symptoms, are in line with the specific role of 5HT in the pathogenesis of OCD. However, this serotonergic hypothesis, while necessary, is not sufficient. It is clear that the dopaminergic and autoimmune mechanism are also implicated in the pathogenesis of OCD.Further studies are required to understand the relevance of the serotonergic and non-serotonergic systems in OCD, and to highlight the various possible subtypes of this intriguing disorder.

Is Sleeping Sickness a Orcadian Disorder? The Serotonergic Hypothesis

Patients with human African trypanosomiasis (HAT, sleeping sickness), due to the inoculation of Trypanosoma brucei gambiense or rhodesiense by the tsetse fly, are “sleepy by day and restless by night.” The first 24h poly-somnographic recording (electroencephalogram [EEG], electromyogram [EMG], electrooculogram [EOG]), showing a disappearance of the 24h rhyth-micity of sleep and wakefulness, was performed in 1988. Thereafter, our team recorded 18 patients and 6 control volunteers at bed rest during 24h sessions. Blood samples were taken hourly from 8 of the patients through a venous catheter and every 10 minutes from the remaining 10 patients. Plasma Cortisol, prolactin, growth hormone (GH), melatonin, and plasma renin activity were analyzed. No disruptions of the circadian rhythms of sleep and wakefulness were described in the 6 healthy African subjects, and there also were no disturbances of 24h hormone profiles. The patients experienced a dysregulation of the circadian rhythmicity of sleep and wakefulness that was proportional to the severity of the disease. Sleep onset rapid eye movement (REM) episodes were more frequent in the most severely sick patients, who also showed major disruptions in the 24h plasma hormonal profiles, with intermediate profiles being observed at earlier stages of the sickness. However, the relationship between hormonal secretions and the states of vigilance persisted. Contrary to the other hormones, melatonin secretion remained undisturbed. These findings indicate that, at the stage of meningoencephalitis, HAT represents a dysregulation of the sleep-wake cycle and sleep structure, rather than a hypersomnia; this dysregulation is proportional to the degree of severity of the clinical and biological symptoms. It is accompanied by a circadian dysrhythmia of hormonal secretions, although the relationship between hormone pulses and sleep states is preserved. We therefore favor the involvement of the serotonergic raphé nuclei-suprachiasmatic nuclei liaison in the reversible disturbance of the circadian rhythms of the sleep-wake cycle and of hormonal secretions.

A noradrenergic and serotonergic hypothesis of the linkage between epilepsy and affective disorders.

Noradrenergic and/or serotonergic deficits, as well as other abnormalities, may contribute to predisposition to some epilepsies and depressions. Evidence for this hypothesis stems from several sources. Epidemiological investigations are intriguing but incomplete. Pharmacological studies show that noradrenergic and/or serotonergic transmission are both anticonvulsant and antidepressant. Therapeutically pertinent investigations show that antidepressant drugs have anticonvulsant properties, whereas antiepileptic drugs are effective in the management of affective disorders. Additional investigations demonstrate that seizures, whether spontaneously occurring or therapeutically induced, protect against depression. Through studies of innate pathophysiology, noradrenergic and serotonergic deficits have been identified in individuals with depression and in animal models of epilepsy, as well as in some humans with epilepsy. Vagal nerve stimulation, a treatment already known to be effective in the epilepsies, is presently under investigation for effectiveness in affective disorder. New evidence suggests that vagal nerve stimulation exerts at least some of its therapeutic effects through its capacity to increase noradrenergic and serotonergic transmission. Finally, emerging evidence supports the concept that some genetic mammalian models of the human epilepsies exhibit analogous manifestations of depression.

Obsessive compulsive disorder: Opportunities within and beyond the serotonergic domain.

Abnormality of the serotonin (5-hydroxytryptamine - 5-HT) system and particularly hypersensitivity of postsynaptic 5-HT receptors remained the leading hypothesis for the underlying pathophysiology of obsessive compulsive disorder (OCD) during the 1980s. A number of lines of evidence supported this serotonergic hypothesis, not least the treatment studies which demonstrated clearly and consistently that anti-obsessional efficacy was a function of serotonin re-uptake inhibition. Studies of markers and biological probes provided further evidence: platelet studies, for example, linked reductions in 5-HT activity with clinical response, and treatment response was correlated with decreased 5-hydroxyindolacetic acid (5-HIAA) levels within the cerebrospinal fluid of OCD patients. Added to this was the evidence from the behavioral or physiological responses observed following serotonergic challenge with the serotonin agonists meta-chlorophenylpiperazine, a compound with high affinity for 5-HT1A-, 5-HT1D- and 5-HT2C-receptors.

Serotonin function in panic disorder: intravenous administration of meta-chlorophenylpiperazine

A placebo-controlled study of the direct serotonin receptor agonist meta-chlorophenylpiperazine (MCPP), intravenously infused over 90 s in a 0.06 mg/kg dose, was conducted in 10 patients with panic disorder and 9 normal control subjects. Cortisol, MCPP serum levels, and behavioral responses were measured over a 180-min period. MCPP induced equivalent cortisol release and behavioral responses in both groups. Differences between intravenous and oral administration of MCPP are discussed, and the present findings are related to the serotonergic hypothesis of panic disorder.

The pathogenesis and treatment of obsessive-compulsive disorder.

The outlook for patients with obsessive-compulsive disorder (OCD) began to change in the early 1980s with the introduction of clomipramine (CMI), a serotonergic antidepressant. The observation that only drugs with a serotonergic profile are effective in OCD has been the basis for the serotonergic hypothesis of OCD. The serotonin-selective reuptake inhibitors are effective alternatives for CMI and can be used when the patient cannot use or tolerate CMI. In this review, we examine the pathophysiology of OCD, based on drug response profile, peripheral markers of serotonergic function, pharmacologic challenge studies, and neuroimaging. We also consider the medications found to be effective in OCD, the length of treatment, with special regard for maintenance therapy, and such issues as the approach for the treatment-resistant patient, augmentation strategies, and nonpharmacological treatments.

Treatment duration of obsessive compulsive disorder

The first breakthrough in the treatment of obsessive-compulsive disorder (OCD) came in 1967, when Fernandez and Lopez-Ibor reported on the efficacy of clomipramine (CMI) in the treatment of 16 patients with OCD (Fernandez and Lopez-Ibor, 1967). However, controlled studies with CMI were not published until 1980 (Montgomery, 1980; Thoren et al, 1980), and only in the last 5 years have large well-controlled studies been published (Clomipramine Collaborative Study, 1991). Several studies demonstrated that among the tricyclics (TCA), only CMI is effective in OCD, while effective antidepressants with a noradrenergic profile, such as desipramine (DMI), appear to be totally ineffective (Zohar and Insel, 1987; Goodman et al, 1990; Leonard et al, 1989). This selective response to TCA with a serotonergic profile led to the formulation of the serotonergic hypothesis of OCD and to the development and use of other serotonergic agents in the treatment of this disorder. Several drugs, possessing a serotonergic profile are currently being studied worldwide, among them CMI, fluoxetine, fluvoxamine, sertraline, paroxetine and citalopram. Currently, as the knowledge regarding the pharmacological approach to OCD is only beginning to accumulate, very little is known regarding treatment duration in OCD. In this review we shall attempt to examine the existing data regarding treatment duration in OCD.

Pharmacologic Therapy of Obsessive Compulsive Disorder

OCD is an anxiety disorder that was once viewed as rare and very difficult to treat. Although the first evidence that a serotonergic drug, clomipramine, might be effective in treating symptoms of OCD was published by Fernandez-Cordoba and Lopez-Ibor Alino in 1967, controlled trials demonstrating the efficacy of pharmacologic treatments in OCD did not appear until the 1980s. The availability of potentially effective treatments, combined with the awareness of prevalence rates for the disorder that are higher than previously believed, led to considerable interest in OCD. Numerous studies have been undertaken to investigate the biology of OCD. The observation that drugs that act by inhibiting serotonin uptake, such as clomipramine, fluvoxamine, sertraline, and fluoxetine, are effective in treating symptoms of OCD has resulted in intense interest in the relationship between serotonin and this disorder. Several lines of investigation support a serotonergic hypothesis for the pathophysiology and treatment of this disorder. Clomipramine, a tricyclic antidepressant that is a potent serotonin uptake inhibitor, was the first pharmacologic treatment for OCD to be studied in large multicenter trials. The successful outcome of these studies resulted in marketing approval by the United States Food and Drug Administration in 1989. Subsequently, similar multicenter trials have been undertaken with the selective serotonin uptake inhibitors fluvoxamine, sertraline, and fluoxetine. Results from these multicenter trials indicate that all these drugs are more effective than placebo in treating OCD. However, meta-analytic techniques applied to the data from controlled trials of these drugs suggest that the effect size for clomipramine is somewhat larger than that of the selective serotonin uptake inhibitors. A number of other drugs that affect serotonin through mechanisms other than uptake inhibition have been tried as treatments for OCD. Because of the small size of many of these studies, it is difficult to evaluate them in the context of the multicenter trials that studied hundreds of patients. Nevertheless, there may be a role for other serotonergic drugs in the treatment of OCD, particularly as adjunctive treatments used to enhance the effect of the serotonin uptake inhibitors. The data supporting the use of adjunctive treatment are limited and cannot be considered to demonstrate definitively the value of augmentation strategies with adjunctive treatment. Nevertheless, the serotonin uptake inhibitors, although effective in a large number of patients, do not appear to provide adequate symptom relief for some patients. Furthermore, among the patients who do respond to serotonin uptake inhibitors, complete remission in uncommon, which leaves a need for improvement of therapies.(ABSTRACT TRUNCATED AT 400 WORDS)

Serotonergic hypothesis of OCD supported

Serotonergic hypothesis of OCD supported

The link between smoking and P: A serotonergic hypothesis

Research indicates that regular cigarette smokers score higher on the P scale of the Eysenck Personality Questionnaire than do nonsmokers. The relation between smoking and P appears to be constitutional in nature in that it predates the onset of smoking. P has been found to be related to attenuated functioning of the serotonergic system of the brain, as has behavior analogous to P in animals. Evidence also indicates that nicotine affects serotonergic function in animals as well as diminishing behavior analogous to P. There is also evidence that smoking may attenuate constitutionally higher levels of P-related impulsive behavior in humans. On this basis, it is hypothesized that the link between P and human smoking may represent a situationally-employed effect on the part of high-P individuals to prevent themselves from acting impulsively, a notion that fits within a “psychological resource” model of human smoking.

High-affinity platelet [ 3H]LSD binding is decreased in panic disorder

Platelet [ 3H]LSD binding was measured in 15 patients with panic attacks and 15 control. The mean (±SD) B max values of the patients (14.1 ±6.3 fmol/mg protein) and of the controls (18.5 ±4.7 fmol/mg protein) were significantly different ( P < 0.05, Mann-Whitney U-test). Mean (±SD) values of K d for the patients (0.55 ± 0.34 nM) and for the controls (0.51 ± 0.12 nM) were not significantly different ( P > 0.1, Mann-Whitney U-test). The results are discussed in terms of a serotonergic hypothesis of the aetiology of panic disorders.

Neuroendocrine aspects of the serotonergic hypothesis of depression

This review examines the role of serotonin (5-HT) in depression. Dysfunction of serotonergic neurons has been implicated as one of the causes of endogenous depression. Since serotonergic neurons innervate the hypothalamus and these neurons send collaterals to several other brain areas, it is possible that hypothalamic sites which control hormone secretion receive the same serotonergic afferents that innervate other limbic areas in the brain. Several investigators have devised neuroendocrine challenge tests measuring the effect of 5-HT agonists on plasma cortisol and prolactin in depressed patients. These tests help to identify dysfunctional 5-HT neurons, and are a "window into the brain." The secretion of cortisol and prolactin is increased predominantly by 5-HT1 receptors. However, changes in 5-HT2 receptors have also been implicated in depression. Results from our laboratory and by others suggest that brain serotonergic neurons stimulate renin and vasopressin secretion by activation of 5-HT2 receptors. Therefore, the renin and vasopressin response to 5-HT agonists should be included in neuroendocrine tests of serotonergic function in affective disorders. Since antidepressants produce a decrease in the density of 5-HT2 receptors, renin and vasopressin could be used to evaluate the antidepressant potential of new drugs.

Decreased platelet 3H-imipramine binding in parkinson's disease

Defects of the serotonergic neurotransmitter system have been identified consistently in both Parkinson’s disease (PD) and depression, including decreased 5hydroxyindole acetic acid (5HIAA) in cerebrospinal fluid (CSF) (e.g., Asberg et al. 1976; Mayeux et al. 1984). Depression, the most common mental disturbance in PD, occurs in nearly one-half of patients and is not related to the severity of motor symptoms or changes in dopamine metabolism (Mayeux et al. 1984). The decrease in CSF 5-HIAA seems to be more marked in PD patients who also are clinically depressed, supporting a serotonergic hypothesis for depression in PD (Mayeux et al. 1984). Recently, decreased ‘H-imipramine binding density was reported in both putamen (Raisman et al. 1986) and cerebral cortex (Cash et al. 1985) from PD patients. 3H-Imipramine binds to a site associated with serotonin uptake, and its distribution parallels brain serotonergic innervation (Langer et al. 1987). Therefore, decreased binding density may rep-

Monoaminergic responses to spinal trauma

The monoamines norepinephrine (NE), dopamine (DA), and serotonin (5-HT) and their major metabolites were measured in the spinal cord of rabbits following laminectomy or impact injury to the thoracic cord. Samples were taken 30 minutes, 60 minutes, 4 hours, and 6 weeks after injury. Utilization ratios (metabolite/transmitter) were calculated from the data. Turnover rates for NE and DA were also calculated at 30 minutes using the alpha-methylparatyrosine method. Trauma resulted in rapid and sustained elevations in 5-HT concentration at and around the injury site. The catecholamines were depleted slightly at the injury site. Levels of 5-hydroxyindole-3-acetic acid were elevated at 30 minutes but fell to baseline by 4 hours, resulting in a decrease in the 5-HT utilization ratio. The utilization and turnover of NE was increased at the injury site, while DA function was not affected. The large short-term increase in 5-HT levels may have been due to extravasation of platelet 5-HT stores into spinal tissue, rather than due to changes in neuronal 5-HT metabolism. At 6 weeks after injury, each monoamine and metabolite appeared to accumulate in spinal cord tissue proximal to the insult. Distal to the injury, depleted amine stores displayed augmented utilization. The data are discussed in terms of a serotonergic hypothesis of the progression of neural damage after trauma, with the interaction of 5-HT with raphe-spinal nerve terminals as a principal event.

Raphe unit activity in freely moving cats: Effects of benzodiazepines

Benzodiazepines (chlordiazepoxide and diazepam) produced a dose-dependent decrease in the discharge rate of serotonin-containing neurons in the dorsal raphe nucleus of freely moving cats. This ranged from no significant change at doses of 0.5 and 1.0mg/kg (i.p.), to greater than 90% reductions in unit activity at 10 mg/kg. The effects of benzodiazepines on raphe units occurred within 15–30 min of injection and the duration of action was dose-dependent and lasted from 1 to more than 6 hr. Doses of benzodiazepines that significantly decreased raphe unit activity (i.e. 2.5–10 mg/kg) also produced ataxia and decreased EMG activity. These data suggest that benzodiazepine-induced suppression of raphe unit activity is closely related to general motor behavior. Raphe unit activity remained suppressed during phasic increases in EMG activity during eating, grooming, or predatory behavior, suggesting that benzodiazepines also have a direct inhibitory action on raphe cells. The present results are discussed in the context of the serotonergic hypothesis of anxiety.

Action de la p-chlorophenylalanine sur le sommeil du babouin Papio papio

Administration of PCPA (150–300 mg/kg) to the baboon Papio papio induces changes in sleep, mainly involving slow wave sleep. While Stage 1 is not altered the duration of Stage 2 is reduced (decrease in length of episodes of this stage and secondarily of their number). The duration of Stage 3 is also reduced (decrease in number of episodes). Restoration of slow sleep by 5-hydroxytryptophane demonstrates the validity of the serotonergic hypothesis in the baboon. Reduction in the length of paradoxical sleep, which is less marked, seems to be secondary to the changes in slow wave sleep. On the other hand the changes in its distribution in time during the night cannot be interpreted. The changes in sleep induced by PCPA in the baboon are of the same type as those observed in Macaca mulatta but they are not identical. This no doubt is due to the different enzymes in the nervous systems of primates of different genera.