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Biomedical subjects

T R Insel

Publications and source records attributed to T R Insel.

At least 145 records · Page 8Linked to original sources
PubMed1987

Serotonergic responsivity in obsessive-compulsive disorder. Comparison of patients and healthy controls.

To examine the "serotonin hypothesis" of obsessive-compulsive disorder (OCD), we studied the behavioral and neuroendocrine effects of metachlorophenylpiperazine (mCPP), a serotonergic agonist, in patients with OCD and healthy controls. Twelve patients and 20 controls were given a single dose of 0.5 mg/kg of mCPP, administered orally under double-blind, placebo-controlled, random-assignment conditions. Following mCPP, but not following placebo, patients with OCD experienced a transient but marked exacerbation of obsessive-compulsive symptoms. Moreover, compared with healthy controls, patients exhibited greater other behavioral (but not endocrinologic or thermal) changes after mCPP. These findings are consistent with a special role for the neurotransmitter serotonin in OCD psychopathology.

Adult↗
PubMed1987

Obsessive-compulsive disorder: psychobiological approaches to diagnosis, treatment, and pathophysiology.

The diagnosis, treatment, and pathophysiology of obsessive-compulsive disorder (OCD) were examined in a series of studies utilizing psychobiological approaches. Putative biological markers previously reported in depression were studied in this disorder and revealed that on some measures [Dexamethasone Suppression Test and rapid eye movement (REM) latency on sleep electroencephalogram (EEG)], OCD patients resemble those with major depressive disorder (MDD), whereas on others [REM density, platelet serotonin uptake, probably platelet 3H-imipramine binding, and 5-hydroxy-indoleacetic acid (5-HIAA) in cerebral spinal fluid (CSF)] they do not. The relationship between OCD and MDD was further explored in a double-blind, randomized crossover study designed to compare the antiobsessional effects of two tricyclic antidepressants, clomipramine (CMI) and desipramine (DMI), in a nondepressed cohort of OCD patients. CMI was found to have significant antiobsessional effects in this group, whereas in the same patients, DMI lacked therapeutic effects. These results suggest that not all antidepressants are antiobsessive and that some property of CMI, such as its potent serotonergic effects, may be of pathophysiological relevance for OCD. The role of serotonin in this disorder was then tested using the pharmacological challenge strategy. A novel serotonin postsynaptic receptor (5HT-1) agonist, m-chlorophenylpiperazine (m-CPP), was administered orally (0.5 mg/kg) under double-blind, placebo-controlled conditions to OCD patients and controls. In addition, a serotonergic receptor antagonist, metergoline (4 mg), was given to a subset of OCD patients. Relative to healthy volunteers, the OCD patients became significantly more anxious, depressed, and dysphoric after m-CPP administration. Moreover, in the OCD patients, obsessive-compulsive symptoms increased markedly after m-CPP and decreased significantly following metergoline administration. These results demonstrate that agents that bind to the 5HT-1 receptor can acutely affect the symptoms of OCD patients. The striking behavioral effects of these direct postsynaptic receptor ligands and the relative specificity of clomipramine as an antiobsessional agent suggest that serotonergic neurons may play a role in the pathophysiology, as well as mediating the pharmacological reduction, of obsessional symptoms.

Adult↗
PubMed1987

Eye-tracking, attention and amphetamine challenge.

Smooth pursuit eye movement (SPEM) performance has been linked to nonvoluntary attentional processes. Amphetamine is a psychotropic drug with documented effects on attentional performance. In order to evaluate the relationship between SPEM performance and amphetamine's attentional effects, SPEM performance was measured prior to and following amphetamine administration in five bipolar patients and eight obsessive-compulsive patients. In these 13 patients, amphetamine did not significantly alter the accuracy of SPEM in the two patient groups. However, significant negative correlations were observed in the obsessive-compulsive patients and in the combined patient groups between baseline SPEM impairment and changes in eye-tracking accuracy following amphetamine, i.e. individuals with poorer SPEM accuracy improved while better SPEM performers deteriorated in tracking accuracy during amphetamine treatment.

Attention↗
PubMed1987

The ability of oxytocin to induce short latency maternal behavior is dependent on peripheral anosmia.

Nulliparous female Sprague-Dawley rats, cannulated in the left lateral ventricle, were ovariectomized and estrogen primed, then either rendered anosmic via intranasal irrigation with zinc sulfate or left with intact olfaction. Forty-eight hr later, after a 2-hr habituation to the test cage, these animals were injected with either intracerebroventricular oxytocin (400 ng in 2 microliter saline) or saline (2 microliter). Only the group receiving both zinc sulfate and oxytocin became maternal. Additionally, approximately one third of the olfaction-intact rats and none of the anosmic rats cannibalized the rat pups. These results are discussed in regard to discrepancies in the literature regarding oxytocin's role in inducing maternal behavior, as well as the functional connection of the olfactory and oxytocin systems.

Animals↗
PubMed1986

Rat pup ultrasonic isolation calls: possible mediation by the benzodiazepine receptor complex.

Rat pups, while separated from their littermates and placed in a novel environment, emit ultrasonic isolation calls. These ultrasonic calls decrease in number, power, and frequency following administration of the anxiolytic, diazepam (0.5 mg/kg). Pentylenetetrazol (20 mg/kg), which has been reported to be clinically anxiogenic, increases the number and the power of these calls. These changes following diazepam and pentylenetetrazol administration are dose dependent and do not appear to be secondary to nonspecific effects of these drugs on arousal or thermoregulation. The benzodiazepine receptor antagonist RO 15-1788, which has generally been reported to lack intrinsic activity at low doses, also decreases the number of rat pup isolation calls. These findings suggest that the benzodiazepine-GABA receptor-chloride channel complex may play a role in the physiologic mediation of the rat pup isolation call.

Animals↗
PubMed1986

Postpartum increases in brain oxytocin binding.

The binding of 3H-oxytocin in the forebrains of pregnant and postpartum rats was measured using an in vitro autoradiographic method. Binding increased selectively in the bed nucleus of the stria terminalis early in the postpartum period. This effect may be due to the physiologic changes in sex steroids late in pregnancy as the combination of ovariectomy and estrogen administration induced a similar increase in binding.

Animals↗
PubMed1986

Obsessive-compulsive disorder with psychotic features: a phenomenologic analysis.

The authors review the literature on obsessive-compulsive disorder and present clinical vignettes to illustrate that delusions can arise in the course of this illness. These delusions do not signify a schizophrenic diagnosis but represent reactive affective or paranoid psychoses, which are generally transient. Using a phenomenologic analysis of 23 patients, the authors further argue that obsessive-compulsive disorder represents a psychopathological spectrum varying along a continuum of insight. Patients at the severe end of this spectrum are best described as having an "obsessive-compulsive psychosis." The authors discuss the implications of these considerations for DSM-III revisions.

Adjustment Disorders↗
PubMed1985

Differential regulation of corticotropin-releasing factor receptors in anterior and intermediate lobes of pituitary and in brain following adrenalectomy in rats.

The effects of adrenalectomy on corticotropin-releasing factor (CRF) receptors in anterior and intermediate lobes of rat pituitary and in forebrain were examined using in vitro autoradiography with the radioiodinated analogue of ovine CRF, Nle21, [125I]Tyr32-CRF. The concentration of CRF receptors in the anterior pituitary was significantly reduced at 4 days and remained decreased at 9 weeks after adrenalectomy. In contrast, adrenalectomy did not alter CRF receptors in the intermediate lobe or in a variety of forebrain regions. The adrenalectomy-induced change in CRF receptors in the anterior pituitary was completely reversed by glucocorticoid replacement with dexamethasone. These data indicate that endogenous CRF is capable of modulating its receptor density in the anterior pituitary and suggest that different sources of CRF or other factors may be important in regulating intermediate lobe hormone secretion and neuronal activity in brain.

Adrenal Glands↗
PubMed1985

Obsessive-compulsive disorder and serotonin: is there a connection?

Reports of the antiobsessional efficacy of clomipramine have led to a "serotonin hypothesis" of obsessive-compulsive disorder (OCD). To test this hypothesis, 16 outpatients with DSM-III OCD were studied using several measures of serotonergic function. Platelet 3H-imipramine binding and serotonin uptake were not significantly different between the OCD patients and a normal, age-matched control group. The level of the metabolite 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) was significantly higher in a small cohort of obsessionals compared with healthy volunteers, possibly reflecting increased brain serotonin turnover. In a direct test of the role of serotonin uptake in clomipramine's antiobsessional effects, the serotonin uptake inhibitor zimelidine was compared with the noradrenergic uptake inhibitor desipramine in a double-blind, controlled study. Zimelidine reduced CSF 5-HIAA, but was clinically ineffective in this group. Desipramine had weak but significant clinical effects. Nonresponders to zimelidine or desipramine improved significantly during a subsequent double blind trial of clomipramine. These findings demonstrate that pharmacological blockade of serotonin reuptake alone is not sufficient for an antiobsessional response.

Adult↗
PubMed1985

Therapeutic responses to tricyclic antidepressants and related drugs in non-affective disorder patient populations.

Although therapeutic responsiveness to tricyclic antidepressants has been primarily associated with the affective disorders, clinical investigations in the last decade have suggested that non-affective disorders such as panic disorder, obsessive-compulsive disorder, anxiety disorder, bulimia, enuresis, migraine, and the chronic pain syndrome may also respond to tricyclics and other antidepressants. This therapeutic responsiveness may sometimes be related to improvement in secondary depressive symptoms, but may also clearly occur in the absence of secondary depression; in particular, improvement in the core symptoms of at least some of these disorders may occur without a change in mood. Furthermore, many patients with these disorders display psychobiologic abnormalities that show many similarities, but also some differences, compared to those observed in patients with affective disorders, despite the frequent absence of affective symptoms. While an improvement in subclinical or "masked" depression remains one hypothesis linking tricyclic responsiveness and shared biological abnormalities in this diverse group of diagnostic entities, an alternative hypothesis (the "ven disorder" hypothesis) is presented, suggesting the possibility that tricyclic and other antidepressant-responding patients have a core disorder with common psychobiologic abnormalities but multiple clinical and diagnostic presentations. An alternative hypothesis (the "shotgun" hypothesis) suggests that the multiple actions of tricyclics (e.g. on adrenergic receptors vs. muscarinic receptors vs. serotonin system changes) may each be differentially important in the therapeutic outcome in patients with specific or predominant problems in one or another of these areas. An examination of both the similarities and differences among the non-affective, tricyclic-responsive disorders and the affective disorders may provide clues about the important psychobiologic elements in these disorders, and to the mode of action of tricyclic antidepressants and related drugs across the psychiatric disorder spectrum.

Anorexia Nervosa↗
PubMed1985

Biological alterations in the primary affective disorders and other tricyclic-responsive disorders.

Noradrenergic function was studied in patients with primary affective disorder and other tricyclic-responsive disorders including obsessive-compulsive disorder, anorexia nervosa and panic attack/agoraphobia in medication-free states. Pre-synaptic noradrenergic activity was assessed by assaying plasma concentrations of norepinephrine (NE) and its metabolite 3-methoxy,4-hydroxyphenylglycol (MHPG). Noradrenergic receptor responsiveness was evaluated by measuring plasma growth hormone (GH), MHPG, and NE responses to clonidine. Binding of tritiated dihydroergocriptine (3H-DHE) and biochemical responsiveness of alpha 2-adrenergic receptors were measured in platelet preparations. These studies suggest that noradrenergic activity may be altered in several tricyclic-responsive disorders and are consistent with the possibility that tricyclic antidepressants may serve to stabilize a dysregulated noradrenergic system in patients from several diagnostic categories.

Adult↗
PubMed1985

Tricyclic response in obsessive compulsive disorder.

Therapeutic responses to the tricyclic antidepressant clomipramine have been demonstrated in five double blind studies of patients with obsessive compulsive disorder. Biological alterations in patients with obsessive compulsive disorder resemble those of depressed patients for the dexamethasone suppression test, for some measures of sleep physiology, and in similar neuroendocrine responses to clonidine. Clomipramine's antiobsessional effect does not require high baseline depression ratings or biological abnormalities similar to those seen in depressives. Preliminary results suggest that in contrast to depressives, patients with obsessive compulsive disorder may respond to clomipramine but not to the tricyclic antidepressant desipramine.

Adolescent↗
PubMed1985

Binding sites for corticotropin releasing factor in sensory areas of the rat hindbrain and spinal cord.

Binding sites of 125I-Tyr-O-ovine corticotropin releasing factor have been demonstrated in sensory areas of the rat hindbrain and spinal cord mainly in the posterior part of the nucleus tractus solitarii, the substantia gelatinosa nervi trigemini and the superficial layers of the spinal cord (laminae I and II). Specific binding was inhibited in the presence of unlabeled synthetic ovine or rat/human CRF indicating that the receptors recognize both forms of CRF.

Animals↗
PubMed1985

Corticotropin-releasing factor receptors are widely distributed within the rat central nervous system: an autoradiographic study.

Corticotropin-releasing factor (CRF) receptor-binding sites have been localized and quantified in the rat central nervous system (CNS) by autoradiography with an iodine-125-labeled analogue of ovine CRF substituted with norleucine and tyrosine at amino acid residues 21 and 32, respectively. High affinity and pharmacologically specific receptor-binding sites for CRF were found in discrete areas within the rat CNS. CRF receptors were highly concentrated in laminae 1 and 4 throughout the neocortex, the external plexiform layer of the olfactory bulb, the external layer of the median eminence, several cranial nerve nuclei in the brainstem including the facial, oculomotor, trochlear, vestibulocochlear, and trigeminal nuclei, the deep cerebellar nuclei, and the cerebellar cortex. Moderate concentrations of CRF receptors were present in the olfactory tubercle, caudate-putamen, claustrum, nucleus accumbens, nucleus of the diagonal band, basolateral nucleus of the amygdala, paraventricular nucleus of the hypothalamus, mammillary peduncle, inferior and superior olives, medullary reticular formation, inferior colliculus, and brainstem nuclei including tegmental, parabrachial, hypoglossal, pontine, cuneate, and gracilis nuclei, and in spinal cord. Lower densities of CRF binding were found in the bed nucleus of the stria terminalis, central and medial amygdaloid nuclei, and regions of the thalamus, hypothalamus, hippocampus, and brainstem. The distribution of CRF-binding sites generally correlates with the immunocytochemical distribution of CRF pathways and with the pharmacological sites of action of CRF. These data strongly support a physiological role for endogenous CRF in regulating and integrating functions in the CNS.

Animals↗