Childhood trauma increases vulnerability to attempt suicide in adulthood through avoidant attachment.

BACKGROUND: Childhood trauma and affective disorders are known risk factors for adult suicidal behavior. Studies have shown a mediating effect of insecure attachment on the effect of childhood trauma and suicidal behavior but so far it is not clear whether this effect is related to an attachment dimension (anxiety, avoidance). AIM: The present study sought to examine the mediating effect of attachment anxiety and avoidance on suicidal behavior. METHODS: We analyzed data on childhood trauma, attachment style, depression severity, presence of prior suicide attempts and current suicide ideation from 96 patients diagnosed with an affective disorder. Two mediation analyses were conducted to assess the effect of childhood trauma on 1) prior suicide attempts and 2) current suicidal ideation through its effect on attachment. RESULTS: We found that childhood trauma had a complete mediated effect on the presence of prior suicide attempts through its effect on avoidant attachment (a1b1 = 0.0120, 95%-CI [0.0031, 0.0276]). However, only emotional abuse had a direct influence on suicidal ideation (c' = 0.0273, p < 0.01) without any indirect effect of anxious or avoidant attachment. LIMITATIONS: Variables were not assessed in a prospective way and sample size was small. CONCLUSIONS: Our findings suggest that individuals with avoidant attachment and childhood trauma are likely to present a high suicide risk. Since avoidant attachment is associated with altered perceptions and eventual rejection of social support, we recommend to screen for attachment early and to engage patients in therapeutical approaches focusing on the client-therapist alliance.

[Affective disorders and impulsivity]. / Troubles affectifs et impulsivité.

Impulsivity is a complex and important phenomenon in mood disorders. Impulse control disorders, as defined in DSM, are more frequent in mood disorders especially in Bipolar Disorder type I, and are associated with a more severe course of illness. Dimensional studies demonstrate that impulsivity is a core manifestation of bipolar disorder both as state- and trait-dependent markers in patients. Comorbid substance use disorders are often associated with a higher level of impulsivity whereas the relation between suicidal behaviors and higher impulsivity remains uncertain. Moreover, neuropsychological tests were used to study correlation between clinical impulsivity and laboratory measurements of impulsivity. Level of correlation remains weak and several explanations are proposed in the literature.

[Are variations of structural neuro-anatomy promising endophenotype candidates in bipolar disorder?]. / Les variations de la neuro-anatomie structurale cérébrale sont-elles des endophénotypes candidats prometteurs dans le trouble bipolaire ?

Bipolar disorder is a complex pathology which has a strong heritability component. Epidemiologic studies have pinpointed the contribution of genetic factors to the heritability component. The molecular studies, that have used classical genetic approaches, have been inconclusive at indentifying genes involved in the etiology of this disorder. To overcome these difficulties, a number of strategies have been developed. One of them is the endophenotypic approach. Its main scope is to identify biological markers that are influenced by genetic factors that are less complex than those involved in the clinical expression of the disorder. Thus, it is likely these markers will be more readily linked to specific genetic loci. In this article, we describe the main phenotypes of neuro-anatomic measurements that are widely used in research, and report data on their heritability in the general population. Then, we focus on the results of the few structural neuro-imaging studies that have been carried out in families of patients suffering of bipolar disorders. The current data converge to indicate that subtle structural abnormalities, particularly at the level white matter tracts, seem to be promising endophenotype candidates for bipolar disorder.

Impulsivity and neural correlates of response inhibition in schizophrenia.

BACKGROUND: The clinical picture of schizophrenia is frequently worsened by manifestations of impulsivity. However, the neural correlates of impulsivity in this disorder are poorly known. Although impulsivity has been related to disturbances of the neural processes underlying response inhibition, no studies have yet examined the relationship between these processes and psychometric measures of impulsivity in schizophrenia. This was the aim of the current investigation. METHOD: Event-related functional magnetic resonance imaging in conjunction with a Go/NoGo task was employed to probe the neural activity associated with response inhibition in 26 patients with schizophrenia and 30 healthy comparison subjects. All participants also completed the Barratt Impulsiveness Scale - version 11 (BIS-11). Voxel-wise regression analyses were used to examine the relationship between the BIS-11 score and brain activation during response inhibition in each group. RESULTS: Patients with schizophrenia were more impulsive than healthy subjects, as indicated by higher BIS-11 scores. Patients, but not healthy subjects, were found to display a positive correlation between these scores and cerebral activation associated with response inhibition. This correlation involves a unique cluster localized within the right ventrolateral prefrontal cortex (VLPFC), a key node of the brain network subserving response inhibition. CONCLUSIONS: We evidenced in patients with schizophrenia that greater BIS-11 scores are associated with greater activation within the right VLPFC during response inhibition. This finding suggests that the efficiency of this brain region to process inhibitory control is reduced in the more impulsive patients.

[What perspectives for cognitive remediation in schizophrenia?]. / Quelles perspectives pour la remédiation cognitive dans la schizophrénie?

Cognitive deficits are routinely evident in schizophrenia, and are of sufficient magnitude to influence functional outcomes in work, social functioning and illness management. Cognitive remediation is an evidenced-based non-pharmacological treatment for the neurocognitive deficits seen in schizophrenia. Narrowly defined, cognitive remediation is a set of cognitive drills or compensatory interventions designed to enhance cognitive functioning, but from the vantage of the psychiatric rehabilitation field, cognitive remediation is a therapy which engages the patient in learning activities that enhance the neurocognitive skills relevant to their chosen recovery goals. Cognitive remediation programs vary in the extent to which they reflect these narrow or broader perspectives but a metaanalytic study reports moderate range effect sizes on cognitive test performance, and daily functioning. Reciprocal interactions between baseline ability level, the type of instructional techniques used, and motivation provide some explanatory power for the heterogeneity in patient response to cognitive remediation. Recent studies indicate that intrinsic motivation mediates the relationship between neurocognition and functional outcomes. Results of these studies suggest that intrinsic motivation should be a viable treatment target in cognitive remediation intervention. In this perspective, NEAR (Neuropsychological Educational Approach to Remediation) program was created to enhance intrinsic motivation by employing more engaging and interesting software packages for cognitive practice, involving consumers in choosing the focus of training and having the NEAR leader serve as a coach to engage the consumers in active guidance of their own treatment program.

[Schizophrenia, executive control and memory]. / Schizophrénie, fonctions exécutives et mémoires.

Schizophrenia affects 1% of the general population. In addition to disabling clinical symptoms, cognitive deficits have also been updated. It has further been proposed that the well-known diversity of schizophrenia in terms of functional outcome and recovery from acute episode is best characterized by cognitive deficits, but not by its classical symptoms. DSM-V acknowledges the importance of cognition in schizophrenia, and could recommend a formal neuropsychological assessment in individuals with psychosis. Schizophrenic patient's cognitive functioning has been studied extensively in the domain of memory and executive control. To date, the studies highlight important deficits in both of these domains. However, within the memory systems, some of them remain unaffected. Altogether, the data invalidate the hypothesis of a global damage and are in favor of specific cognitive deficits. The observed deficits would depend on the dominant symptoms and pre-morbid functioning. The interest of these results was to give impulse to the development of comprehensive assessment battery designed to evaluate the cognitive profiles of each patient and develop a personalized program of cognitive remediation.

[Brain structural abnormalities of bipolar disorder]. / Les anomalies structurales observées en imagerie cérébrale dans le trouble bipolaire.

The number of structural neuroimaging studies of bipolar disorder have increased during recent years, expanding the literature on the nature of cerebral abnormalities underlying this disorder. The purpose of this paper is to provide a selective review on the main issues concerning this literature. Consistent findings are higher rate of periventricular and deep subcortical white matter hyperintensites seen on MRI. Although there is strong evidence for links between hyper-intense lesions and age or cardio-vascular risk factors, some authors have observed the presence of these abnormalities early in the course of the illness. There are also frequent reports on ventricular enlargement, which has been described as mild and predominant in the right lateral ventricle. Total cerebral volume appears to be preserved. Whereas changes in total grey matter volume are uncertain, evidence suggests that reduced white matter volume reflects genetic factors predisposing to the disorder. Recent studies have reported volume changes in several cortical areas including the subgenual cingular, frontal and temporal cortices. Additionally, a number of reports described morphometric abnormalities in various subcortical structures, such as amygdala, basal ganglia and thalamus. Part of the variability in the morphometric abnormalities might be attributable to differences in clinical status and demographic characteristics of patient groups. Despite some inconsistencies across the studies, it emerges that abnormalities are asymmetrically distributed throughout the two cerebral hemispheres. When increase in volume is reported, it is preferentially localised in the left cerebral hemi-sphere and more specifically in prefrontal and temporal cortices and in amygdala. By contrast, when structural abnormalities concern the right cerebral hemisphere, they are identified as deficits. These latter results are in direct line with those of studies of mania following brain injuries, which report that these secondary mania result mainly from right cerebral lesions. It is also important to notice that most of the abnormalities concern both the cortical and subcortical level, ie frontal, striatal, thalamic and limbic regions. These abnormalities highlight the role in the pathophysiology of bipolar disorder of the loops involved in emotional information processing. The particular role of fronto-limbic loops in the phenomenology of bipolar disorder have been emphasised by recent data from functional neuroimaging studies.

Chronic effects of triiodothyronine in combination with imipramine on 5-HT transporter, 5-HT(1A) and 5-HT(2A) receptors in adult rat brain.

Triiodothyronine (T3) has been shown to accelerate and potentiate the clinical response to tricyclic antidepressant (TCA) treatment in depressive disorders. The neurobiological mechanisms underlying these therapeutic effects of T3 are still unknown. Since brain serotonin (5-HT) changes have been implicated in the mode of action of TCA drugs, the effects of a chronic (7 or 21 days) administration of imipramine (10 mg/kg/day) and of a low dose of T3 (4 microg/kg/day), given alone or in combination, were investigated on the density of midbrain 5-HT transporters and of hippocampal 5-HT(1A) and cortical 5-HT(2A) receptors in adult Wistar rats. Neither single nor combined administration of imipramine and T3 for 7 days modified the density of 5-HT transporters and of 5-HT(1A) receptors. On day 21, the combination did not change imipramine- or T3-induced decrease in 5-HT transporter density whereas it prevented imipramine-induced increase in 5-HT(1A) receptor density. Whatever the treatment duration, imipramine-T3 combination potentiated imipramine-induced decrease in 5-HT(2A) receptor density. On both day 7 and day 21, T3 given alone had no effects on the density of 5-HT(1A) and 5-HT(2A) receptors. These data indicate that T3 is able to modulate the long-term adaptive changes which occur at the postsynaptic level of 5-HT neurotransmission after antidepressant treatment.

Functional subsensitivity of 5-HT2A and 5-HT2C receptors mediating hyperthermia following acute and chronic treatment with 5-HT2A/2C receptor antagonists.

In the present study, we investigated the duration of attenuation of the temperature increases produced by (+/-) 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and m-chlorophenylpiperazine (m-CPP) which followed pretreatment with four serotonin (5-HT) antagonists; metergoline, mesulergine, mianserin and ritanserin. The duration of attenuation of m-CPP-induced hyperthermia lasted less than 1 day for ritanserin, more than 1 day for the 5 mg/kg doses of both mianserin and metergoline and more than 2 days for the 5 mg/kg dose of mesulergine. The duration of attenuation of DOI-induced hyperthermia lasted less than 1 day for ritanserin, more than 1 day for mianserin, more than 2 days for the 5 mg/kg dose of metergoline and more than 4 days for mesulergine. Daily administration of a low (1.0 mg/kg per day) dose of ritanserin for 14 days led to an attenuation of the temperature increases produced by m-CPP given 24 h after the last dose of ritanserin, but did not cause a similar desensitization of DOI-induced hyperthermia. On the other hand, daily administration of both low (1.0 mg/kg per day) and high (5.0 mg/kg per day) doses of mianserin for 14 days caused desensitization of DOI-induced hyperthermia but did not cause desensitization of m-CPP-induced hyperthermia when these agonists were administered 48 h after the last dose of mianserin. These findings demonstrate functional subsensitivity of both 5-HT2A and 5-HT2C receptors mediating hyperthermia following both acute and chronic administration of 5-HT2A/5-HT2C receptor antagonists; some differences in time course and in responses to individual antagonists at 5-HT2A versus 5-HT2C sites were also observed.

Repeated administration of meta-chlorophenylpiperazine or 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane produces tolerance to its stimulatory effect on adrenocorticotropin hormone but not prolactin or corticosterone secretion in rats.

In an attempt to clarify whether m-chlorophenylpiperazine-(m-CPP) and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane-(DOI) induced increases in plasma adrenocorticotropin hormone, corticosterone and prolactin secretion are mediated by the same or different mechanisms, we studied the time course of development of tolerance to the neuroendocrine effects of m-CPP (2.5 mg/kg/day) and DOI (2.5 mg/kg/day) in rats and, furthermore, also evaluated possible cross-tolerance in responses to m-CPP and DOI. We observed the development of tolerance in adrenocorticotropin hormone responses after a single i.p. injection of m-CPP. However, there was no cross-tolerance to DOI when chronic (13 days) m-CPP-treated animals were challenged with DOI (2.5 mg/kg). Injections of DOI (2.5 mg/kg) for six days were required before tolerance developed to the effect of DOI on adrenocorticotropin hormone. Furthermore, cross-tolerance was observed when DOI-treated animals (2.5 mg/kg/day x 6) were challenged with m-CPP (2.5 mg/kg) on day 7. In contrast, daily administration of m-CPP and DOI for 13 days did not produce tolerance to their stimulating effects on corticosterone and prolactin secretion. Hypothalamic levels of 5-hydroxyindoleacetic acid but not 5-HT were significantly reduced after acute or subchronic administration of both m-CPP and DOI. Furthermore, no change in the approximate 50% reduction in 5-hydroxyindoleacetic acid after m-CPP was observed after subchronic administration of this drug. These findings suggest that separate mechanisms mediate m-CPP and DOI-induced adrenocorticotropin hormone secretion in rats.

Long-term antidepressant treatment restores clonidine's effect on growth hormone secretion in a genetic animal model of depression.

We have recently demonstrated that various doses of clonidine failed to increase growth hormone (GH) in Fawn-hooded (FH) rats (a rat strain suggested to represent a genetic model of depression). In the present study, we investigated whether long-term antidepressant treatment might normalize clonidine's effect on GH secretion in male FH rats. Long-term (16 days) treatment with the tricyclic antidepressant, imipramine (5 mg/kg/day), the 5-HT uptake inhibiting antidepressant, fluoxetine (2.5 mg/kg/day), and the noradrenergic uptake inhibiting antidepressant, desipramine (5 mg/kg/day), accentuated clonidine's effect on GH levels. On the other hand, long-term treatment with the monoamine oxidase type-A inhibiting antidepressant, clorgyline (1 mg/kg/day) and the alpha 2-noradrenergic antagonists, yohimbine and 1-phenylpiperazine (1 mg/kg/day, each) did not modify clonidine's effect. These findings suggest enhancement of 5-HT2c receptor-mediated function following long-term treatment with uptake inhibiting antidepressants in a genetic animal model of depression.

NMDA receptor antagonists block development of tolerance to m-CPP-induced increases in ACTH concentrations in rats.

We have recently demonstrated that a single administration of m-chlorophenylpiperazine (m-CPP, a preferential 5-HT2C receptor agonist) produces tolerance to its stimulatory effect on adrenocorticotropic hormone (ACTH) concentrations when challenged 24 h later with the same dose of m-CPP. In the present study, we studied the effects of pretreatment with various N-methyl-D-aspartate (NMDA) receptor antagonists on development of tolerance to m-CPP's stimulatory effect on ACTH concentrations. Pretreatment with various NMDA receptor antagonists such as 5.7-dichlorokynurenic acid (1.0 mg/kg), 3-amino-1-hydroxy 2-pyrrolidone (1.0 mg/kg), dizocilpine (0.1 mg/kg) and ifenprodil (1.0 mg/kg) injected 30 min before the first injection of m-CPP (2.5 mg/kg) blocked development of tolerance to m-CPP's stimulatory effect on ACTH concentrations in rats injected 24 h later with the same dose (2.5 mg/kg) of m-CPP. These findings suggest that tolerance to postsynaptic 5-HT2C receptor-mediated response is initiated though stimulation of NMDA receptor complex and, furthermore, demonstrate a functional interaction between the 5-HT and glutamate systems.

Evidence that m-chlorophenylpiperazine-induced hyperthermia in rats is mediated by stimulation of 5-HT2C receptors.

Intraperitoneal administration of m-chlorophenylpiperazine (m-CPP) to Wistar rats produced hyperthermia with a peak effect at 30 min. Pretreatment with low doses of metergoline (5-HT1/5-HT2 antagonist), mesulergine and mianserin (5-HT2C/5-HT2A antagonists) blocked m-CPP-induced hyperthermia. Pretreatment with propranolol (beta-adrenergic receptor antagonist that also has binding affinity for 5-HT1A, 5-HT1B and 5-HT2B sites), yohimbine (alpha 2-noradrenergic antagonist that also has binding affinity for 5-HT2B sites), MDL-72222 or ondansetron (5-HT3 antagonists) did not attenuate m-CPP-induced hyperthermia. Only high doses of ketanserin, LY-53857 and ritanserin (5-HT2A/5-HT2C antagonists) as well as spiperone (5-HT1A/5-HT2A/D2 antagonist) attenuated m-CPP-induced hyperthermia. Daily administration of m-CPP produced complete tolerance to its hyperthermic effect by day 5. However, there was no cross-tolerance to 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI, a 5-HT2A agonist that also has high affinity for 5-HT2C receptors)-induced hyperthermia. m-CPP-induced increases in temperature were found to be significantly less in the Fawn-Hooded (FH) rat strain as compared to the Wistar rat strain; in prior studies, FH rats have been found to be subsensitive to other 5-HT2C-mediated pharmacologic responses. Altogether, these findings suggest that m-CPP-induced hyperthermia in rats is mediated by selective stimulation of 5-HT2C receptors.

Neuroendocrine responses to serotonergic agonists as indices of the functional status of central serotonin neurotransmission in humans: a preliminary comparative analysis of neuroendocrine endpoints versus other endpoint measures.

The status of central serotonergic neurotransmission and of specific serotonin (5-HT) receptor subtype sensitivity has been inferred from neuroendocrine and other endpoint responses to serotonergic agents given to humans. The question of whether changes in neuroendocrine responsivity to the 5-HT2C partial agonist, meta-chlorophenylpiperazine (m-CPP), are accompanied by similar changes in other endpoints (temperature, behavior) is addressed in this brief review of published studies. These studies were selected based on the following criteria: (1) neuroendocrine (cortisol, prolactin increases) and at least one other endpoint (behavior and/or temperature increases) were measured in the same populations, and (2) statistically significant changes were observed after m-CPP in the healthy volunteer control or pre-long-term-treatment subjects. Parenthetically, in the 13 of 14 studies that reported both prolactin and cortisol responses, the results were congruent for the two neuroendocrine measures in 12 of the 13 (92%). However, neuroendocrine versus behavioral results were in agreement in fewer (7 of the 13) studies (54%). Neuroendocrine vs. temperature results were non-concordant in all 4 of the studies which included temperature measurements. These generally disparate findings suggest that these different endpoints may reflect brain serotonin neuroanatomic and receptor subsystem complexity and/or m-CPP's complex pharmacological properties. Thus, these neuroendocrine response measures cannot at this time be considered a general index of the other response measures, nor necessarily an index of the functional status of central serotonergic neurotransmission until this is established by more direct experimental investigations.

Temperature, food intake, and locomotor activity effects of a 5-HT3 receptor agonist and two 5-HT3 receptor antagonists in rats.

This study investigated three physiologic functions known to be modulated by serotonin-temperature, food intake and locomotor activity - using the 5-HT3 receptor agonist, m-chlorophenylbiguanide (m-CPBG), and two 5-HT3 antagonists, MDL-72222 and ondansetron. m-CPBG produced dose-dependent elevations in rectal temperature. MDL-72222, which had no effects on temperature when given alone, significantly attenuated m-CPBG-induced hyperthermia. Food intake in food-deprived rats was reduced during the first hour by the highest dose of m-CPBG. Food intake was also dose-dependently reduced by MDL-72222; m-CPBG plus MDL-72222 led to greater reductions in food intake. Food intake in freely fed rats was unaffected by m-CPBG or MDL-72222. Locomotor activity was unaffected by m-CPBG, but was dose-dependently reduced by MDL-72222, an effect which may have contributed to its hypophagic effects. Ondansetron, used in ten-fold lower doses than MDL-72222, was inactive in all of these paradigms. These data: (1) provide some evidence for 5-HT3 receptor-mediated changes in temperature; (2) are in agreement with two prior studies which reported locomotor activity reductions following 5-HT3 antagonists; but (3) do not support an important role for 5-HT3 receptors in the regulation of food intake in rats.

Lack of cross-tolerance for hypophagia induced by DOI versus m-CPP suggests separate mediation by 5-HT2A and 5-HT2C receptors, respectively.

Intraperitoneal administration of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) produced significant decreases in the first-hour food intake on day 1 and on day 2 relative to saline-treated animals. Complete tolerance developed to DOI-induced hypophagia by day 3. However, there was no cross-tolerance to m-chlorophenyl-piperazine (m-CPP)-induced hypophagia. Similarly, complete tolerance developed to m-CPP-induced hypophagia by day 3, but again there was no cross-tolerance to DOI-induced hypophagia. These findings suggest that DOI and m-CPP-induced hypophagia are mediated by different mechanisms, most likely by selective stimulation of 5-HT2A receptors by DOI and 5-HT2C receptors by m-CPP. The functional sensitivity changes did not parallel changes in hypothalamic [3H]-mesulergine-labeled 5-HT2C receptors or [3H]-ketanserin-labeled 5-HT2A receptors following chronic m-CPP or DOI treatment, although both treatments significantly reduced 5-HT2A and 5-HT2C receptors in cortex. Thus, future studies investigating the effects of daily m-CPP and DOI administration on phosphoinositide hydrolysis or mRNA for 5-HT2C and 5-HT2A receptors in the hypothalamus might help explain the functional sensitivity changes observed in the present study.

Long-term antidepressant treatments alter 5-HT2A and 5-HT2C receptor-mediated hyperthermia in Fawn-Hooded rats.

We have recently demonstrated that hyperthermia induced by 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and m-chlorophenylpiperazine (m-CPP) are separately mediated by selective stimulation of 5-HT2A and 5-HT2C receptors, respectively in Wistar rats. Furthermore, hyperthermia induced by either DOI or m-CPP was found to be significantly less in Fawn-Hooded rats (a rat strain suggested to represent a genetic model of depression) relative to Wistar rats. In the present study, we studied the effects of long-term antidepressant treatments on DOI (2.5 mg/kg)-induced and m-CPP (2.5 mg/kg)-induced hyperthermia in male Fawn-Hooded rats. Long-term (21 days) treatment with the tricyclic antidepressants, imipramine or clomipramine (each 5 mg/kg/day), attenuated DOI-induced hyperthermia, while m-CPP-induced hyperthermia was accentuated. On the other hand, long-term (21 days) treatment with the monoamine oxidase type-A inhibiting antidepressant, clorgyline (1 mg/kg/day), did not modify m-CPP-induced hyperthermia, but significantly attenuated DOI-induced hyperthermia. These findings demonstrate that long-term antidepressant treatments alter 5-HT2A and 5-HT2C receptor-mediated hyperthermia in a genetic animal model of depression.

The NMDA receptor complex modulates clonidine-induced increases in growth hormone levels in rats.

Intraperitoneal administration of clonidine (50 micrograms/kg) produced increases in growth hormone levels in male Wistar rats. Pretreatment with NMDA receptor antagonists including (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP/NMDA site), ifenprodril (polyamine site), and dizocilpine maleate (MK-801) or phencyclidine (PCP) (channel blockers) did not have any significant effect on clonidine-induced increases in growth hormone levels. In contrast, pretreatment with 5,7-dichlorokynurenic acid and 6,7-dinitroquinoxaline-2,3-dione (DNQX) (NMDA receptor-associated glycine site antagonists) significantly attenuated clonidine-induced increases in growth hormone levels. Attenuation of clonidine's effect on growth hormone levels by NMDA receptor-associated glycine site antagonists appears most likely due to an interaction between their effects on the NMDA receptor complex with growth hormone releasing factor.

Evidence that 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced hyperthermia in rats is mediated by stimulation of 5-HT2A receptors.

The effects of various 5-HT receptor subtype-selective antagonists were studied on phenylisopropylamine hallucinogen 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced hyperthermia in Wistar rats, in an attempt to characterize the 5-HT receptor subtype mediating DOI-induced hyperthermia. Intraperitoneal administration of DOI to rats produced hyperthermia with a peak effect at 60 min. Pretreatment with propranolol (beta-adrenoceptor antagonist that also has binding affinity for 5-HT1A, 5-HT1B and 5-HT2C sites), MDL-72222 or ondansetron (5-HT3 antagonists) did not attenuate DOI-induced hyperthermia. In contrast, pretreatment with metergoline (5-HT1/5-HT2 antagonist), ketanserin, LY53857, mesulergine, mianserin and ritanserin (5-HT2C/5-HT2A antagonists), as well as spiperone (5-HT1A/5-HT2A/D2 antagonist), significantly attenuated DOI-induced hyperthermia. Furthermore, daily administration of DOI (2.5 mg/kg per day) for 17 days did not produce either tolerance to its hyperthermic effect or modify m-CPP-induced hyperthermia in rats. These findings suggest that DOI-induced hyperthermia in rats is mediated by stimulation of 5-HT2A receptors.

Role of various 5-HT receptor subtypes in mediating neuroendocrine effects of 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) in rats.

The phenylisopropylamine hallucinogen 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) produced dose-related increases in plasma concentrations of prolactin, adrenocorticotropic hormone (ACTH) and corticosterone but not growth hormone in rats. Pretreatment with metergoline (serotonin, 5-HT1/5-HT2 antagonist), ritanserin and mianserin (5-HT2A/5-HT2C antagonists) significantly attenuated DOM-induced increases in prolactin, ACTH and corticosterone, whereas mesulergine (5-HT2A/5-HT2C antagonist) pretreatment significantly attenuated DOM-induced increases in plasma prolactin and ACTH but not corticosterone. Pretreatment with propranolol (beta adrenoceptor antagonist that also has high binding affinity for 5-HT1A, 5-HT1B and 5-HT2C sites), MDL-72222 and ondansetron (5-HT3 antagonists) attenuated DOM's effect on plasma prolactin, but did not attenuate DOM-induced increases in either ACTH or corticosterone. On the other hand, spiperone (5-HT1A/5-HT2A/D2 antagonist) pretreatment significantly attenuated DOM-induced increases in ACTH but not corticosterone. These findings demonstrate involvement of 5-HT2A/5-HT2C and 5-HT3 receptors in mediating DOM-induced increases in plasma prolactin, whereas DOM-induced increases in ACTH appear to be mediated by stimulation of 5-HT2A receptors. DOM-induced corticosterone secretion appears to be mediated by stimulation of 5-HT2A and/or 5-HT2C receptors. DOM does not affect growth hormone secretion in rats.