Aphagia and adipsia after preferential destruction of nerve cell bodies in hypothalamus.

Microinjections of the excitatory neurotoxin kainic acid into the lateral hypothalamus of rats produced a period aphagia and adipsia. Kainate-treated rats displayed transient motor effects during the first hours after the injection but did not show the persisting sensory-motor and arousal disturbances typically observed in animals with electrolytic lesions in this part of the hypothalamus. Histological examination revealed a significant reduction in the number of nerve cell bodies in the lateral hypothalamus. Silver-stained material indicated no evidence of damage to fiber systems passing through the affected region. Assays of dopamine in hypothalamus, striatum, and telencephalon did not indicate significant differences between experimental and control animals. These results are in agreement with recent reports of the anatomical and biochemical effects of intracerebral kainic acid injections and suggest that the observed effect on feeding behavior is related to the destruction of neurons in the lateral hypothalamus.

Comorbidity between depression and cardiovascular disease.

Morbidity and mortality of cardiovascular disease (CVD) is exceedingly high worldwide. Depressive illness is a serious psychiatric illness that afflicts a significant portion of the population in all countries. Numerous epidemiological studies have confirmed that high comorbidity exists between these two conditions. Apparently healthy individuals with depression have at least a two-fold higher risk of developing CVD. Following myocardial infarction the emergence of clinical depression poses heightened risk of morbidity and mortality. To understand the complex mechanisms accountable for this comorbidity, several factors have been considered. They include pathophysiologic factors, such as sympathoadrenal activation, homeostatic imbalance between the sympathetic and the parasympathetic systems with diminished vagal tone and loss of heart rate variability in depression. Neuroendocrine factors consist mainly of hypothalamic-pituitary-adrenal axis activation resulting in hypercortisolemia with associated sequelae. Platelet activation and hypercoaguability have been demonstrated in depression and appear to normalize with selective serotonin reuptake inhibitor (SSRI) treatment. Inflammatory processes and release of proinflammatory cytokines have also been described whether or not depression is comorbid with another disease entity. Endothelial dysfunction has been detected in depression and may prove to be a trait marker for this illness. Central and peripheral serotonergic transmission may be one common link between the two disease entities. Comorbid depression must be treated vigorously and SSRIs exert beneficial action not only in ameliorating depression but also in reversing platelet activation and inflammation, thereby reducing cardiovascular morbidity and mortality.

Desipramine lowers tritiated para-aminoclonidine binding in platelets of depressed patients.

Platelet adrenergic receptor binding has been studied by several groups of investigators as a possible marker for depression and other psychiatric conditions. Although some of the findings have been discrepant, the results of the majority of studies that have used imidazoline compounds as ligands have confirmed elevated alpha 2-adrenergic receptor binding in depression. We have emphasized the advantages of obtaining platelet-purified plasma membranes and using tritiated para-aminoclonidine as the ligand of choice. By using "site-selective" concentrations of tritiated para-aminoclonidine, we have identified two high-affinity-binding sites of the platelet alpha 2-adrenergic receptor that appear to be upregulated in depression before treatment. Depressed patients were treated with desipramine hydrochloride for 6 to 8 weeks, and platelet binding was reassessed. Desipramine reduced binding to nearly normal levels at both site-selective concentrations of tritiated para-aminoclonidine. The concentrations of plasma catecholamines could play a role in the downregulation of binding at posttreatment. We discuss these findings in the context of platelet imidazoline-binding sites being a possible state-dependent marker for depression.

Double-blind parallel comparison of three dosages of sertraline and placebo in outpatients with obsessive-compulsive disorder.

BACKGROUND: Anecdotal evidence suggests patients with obsessive-compulsive disorder (OCD) are treated with selective serotonin uptake inhibitors at dosages significantly higher than those used with depressed patients. The current study examined the efficacy, safety, and optimal dosing strategy of sertraline in patients with OCD. METHODS: Three hundred twenty-four nondepressed outpatients with OCD from 11 sites followed identical protocols using a double-blind parallel design. Following 1 week of single-blind placebo, patients were randomly assigned to 12 weeks of treatment with one of three fixed dosages of sertraline (50, 100, or 200 mg/d) or placebo. RESULTS: Sertraline patients exhibited significantly greater improvement (P < .05) at end point than placebo patients on all three main efficacy measures in the 50-mg/d and 200-mg/d groups and on one measure in the 100-mg/d group. The placebo response was larger in this population of subjects with OCD than in those previously studied. Adverse experiences were common in the sertraline and placebo groups and appeared to be dose-related in the sertraline-treated patients. CONCLUSIONS: Results support the safety and efficacy of daily dosages of 50, 100, and 200 mg of sertraline in the short-term treatment of patients with OCD.

Nerve terminal effects of indoleamine psychotomimetics on 5-hydroxytryptamine.

The mode of action of indoleamine psychotomimetics has been closely linked to 5-HT. Early work showed increases in rat brain levels of 5-HT which were later localized to the nerve-ending fraction. With improved methodology, the 5-HT increment was further detected in the synaptic vesicle fraction. These effects were obtained with several indoleamine hallucinogens but not with mescaline. LSD has been most thoroughly studied and has served as the prototypical compound in ascertaining the mode of action of these drugs. Pretreatment with reserpine abolished the 5-HT effects of LSD in the vesicular fraction. However, a new compartment, termed "juxtavesicular," displayed 5-HT increases following reserpine and LSD. A soluble binding site for 5-HT within the synaptoplasm has been postulated in confirmation of independent results by other groups of investigators. The origin of the 5-HT increment appears to be associated with newly synthesized amine. This was deduced from experiments involving various 5-HT synthesis blockers. To ascertain whether inhibition of raphé neuronal firing is responsible for the accumulation of 5-HT at the nerve terminal, two sets of experiments were performed. Destruction of the raphé cell bodies by radiofrequency lesions failed to abolish the LSD-induced 5-HT increase early after the lesion. Destruction of cortical 5-HT neurons with the neurotoxin 5,7-dihydroxytryptamine completely abolished the 5-HT effect of LSD. It was concluded that an intact nerve terminal is necessary for the expression of the LSD-mediated increases in 5-HT. A LSD "autoreceptor" is postulated, possibly identical to a 5-HT presynaptic receptor inhibiting the release of 5-HT.

Reductions in neuronal and glial density characterize the dorsolateral prefrontal cortex in bipolar disorder.

BACKGROUND: Bipolar disorder (BPD) is a mental illness in which depression and mania typically alternate, and both phases can present with psychotic features. The symptomatology of BPD, therefore, resembles major depressive disorder (MDD) and schizophrenia (SCHZ), posing diagnostic dilemmas. Distinct alterations in cellular architecture of the dorsolateral prefrontal cortex distinguish SCHZ and MDD, whereas the cellular neuropathology of BPD has not been studied. METHODS: Dorsolateral prefrontal area 9 was analyzed using a three-dimensional morphometric method in postmortem brains from 10 BPD patients and 11 matched nonpsychiatric control subjects. RESULTS: Area 9 in BPD was characterized by reduced neuronal density in layer III (16%-22%) and reduced pyramidal cell density in layers III and V (17%-30%). A 19% reduction in glial density was found in sublayer IIIc coupled with enlargement and changes in shape of glial nuclei spanning multiple layers. CONCLUSIONS: The morphologic signature of BPD, i.e., decreased neuronal and glial density in association with glial hypertrophy, is distinct from previously described elevations in neuronal density in SCHZ, instead resembling the reductions in cell density found in MDD. Thus, the neuropathologic distinctions between BPD and SCHZ are indicative of separate mental illnesses, each with a unique morphologic disturbance of specific neural circuits.

Disruption of circadian MHPG rhythmicity in major depression.

Plasma concentrations of total (free plus conjugated) 3-methoxy-4-hydroxyphenylglycol (MHPG) were determined every 3 hr for a 24-hr period in 32 unipolar depressed patients, 11 bipolar depressed patients, and 12 healthy subjects. Each subject's circadian MHPG rhythmicity was modeled by a sinusoidal function. Temporal parameters were estimated by linear least squares regression with a fixed 24-hr period. The variabilities associated with estimates of circadian amplitude and acrophase were roughly twice as large in the patients compared to healthy subjects. Phase advances were associated most significantly with the agitated rather than the retarded subtype of depression, and with first episode depressions. Treatment with desipramine (n = 26) did not alter significantly any of the model parameters and had no effect on circadian variability in any patient group. The data overall support a dysregulation theory for depressive illness with phase advances representing one manifestation of such dysregulation.

Increased imidazoline and alpha 2 adrenergic binding in platelets of women with dysphoric premenstrual syndromes.

An association between dysphoric premenstrual syndromes (PMS) and a lifetime history of major depressive disorders has previously been documented. Other studies have demonstrated an increase in the binding of radiolabeled imidazoline compounds to platelets of depressed patients. Clonidine and related imidazoline compounds interact with alpha 2 adrenoceptors to inhibit neuronal noradrenergic activity and in higher concentrations, they stimulate noradrenergic activity through their interaction with imidazoline receptors. Here we report increased 3H para-aminoclonidine binding to high affinity alpha 2 adrenoceptor sites as well as to nonadrenergic imidazoline binding sites in platelets of women with dysphoric PMS. This higher binding was most pronounced during the late-luteal-symptomatic phase of the menstrual cycle and, to a lesser degree, during the non-symptomatic mid-follicular phase. Binding to the imidazoline site distinguished women with dysphoric PMS from women with no such symptoms, was highly positively correlated with the severity of symptoms, and was negatively correlated with plasma levels of progesterone. These findings suggest that platelet imidazoline binding sites might be a biological marker for dysphoric states in PMS or for the vulnerability to develop them. These findings also point to a possible biological link between dysphoric PMS and major depressive disorders.

Imidazoline receptor proteins are decreased in the hippocampus of individuals with major depression.

BACKGROUND: A downregulation of I(2)-imidazoline binding sites has been reported in frontal cortices of depressed suicide victims, according to I(2)-radioligand binding and confirmed by Western blotting. We now report Western blots of imidazoline receptor proteins in hippocampi of subjects with and without depression at the time of death. METHODS: Postmortem diagnoses were obtained from 17 cases of Axis I major depressive disorder and 17 cases without Axis I psychopathology. No psychotropic compounds were found in body fluids. Hippocampi were removed, sectioned, and assessed histologically. Throughout the analysis, each major depressive disorder sample was paired with a sample from a psychiatrically healthy subject based on equivalent life spans and postmortem delays. The antiserum was identical to that used in previous studies that reported a downregulation of cortical 29/30-kd imidazoline receptor-binding proteins in depression. RESULTS: A triad of imidazoline receptor-binding protein bands (40-50 kd) was detected in the human hippocampus. Subjects with major depressive disorder had significantly less intensity in each imidazoline receptor-binding proteins band compared with control subjects (p =. 01 for overall bands). CONCLUSIONS: The present results can be aligned with previous reports of downregulation of I(2)-radioligand binding sites in both cortices and platelets of depressed patients.

Circadian rhythm of tryptophan, serotonin, melatonin, and pituitary hormones in schizophrenia.

Circadian rhythm abnormalities have been described mostly with respect to manic-depressive illness; little information is available concerning circadian rhythms and schizophrenia or their influence on neuroleptic drugs. We showed previously that the MESOR of dopamine is higher in schizophrenic patients than in healthy subjects and that women who are drug-free schizophrenic have lower prolactin MESORs and lower amplitudes than healthy women. We now report the data of a cosinor analysis of tryptophan, serotonin, melatonin, and pituitary hormones in the blood of 34 healthy subjects, 90 drug-free schizophrenics, and 25 neuroleptic-treated schizophrenic patients. This data indicated a significant phase advance of serum tryptophan, prolactin, and melatonin concentrations, a trend toward a phase advance in serotonin. Thyroid stimulating hormone (TSH), and growth hormone concentrations, and decreases in the TSH MESORs among patients compared to healthy subjects. These results suggest that circadian changes, such as phase advances and alterations in MESOR, are not only present in depression but also in schizophrenia. Although neuroleptic treatment raised the prolactin MESOR and amplitude, it did not elicit any change in circadian rhythmicity among the other parameters.

Ion transport and adrenergic function in major affective disorder.

Altered functional levels of norepinephrine (NE) have been implicated in the etiology of affective disorders. Abnormalities of membrane ion transport have been postulated to underlie such neurotransmitter imbalances. To evaluate the role of these systems in the pathophysiology of specific affective syndromes, we have examined the NE metabolite MHPG and ion transport function in a cross-section of affective patients in different mood states. Analysis of those data reveals that plasma MHPG levels are dependent on mood state, with bipolar patients in the manic phase having significant elevations of this metabolite. In contrast, the red cell: plasma lithium ratio (LR) was independent of mood state and significantly elevated in a group of bipolar patients.

Apparent phase advance in diurnal MHPG rhythm in depression.

Several investigators have proposed that diurnal rhythms, particularly that of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG), show abnormalities in affective disorders. The present study compared diurnal MHPG rhythms in the plasma of 18 male depressed patients and 12 healthy male volunteers. A diurnal rhythm of MHPG closely fit to a cosine model was observed in volunteers and, to a lesser extent, in depressed patients. Patients, especially those with endogenous depression (N = 11), demonstrated an earlier acrophase (mean +/- SD = 12.53 +/- 3.38 hours), and treatment with desipramine was associated with a significant (3-hour) phase delay. This study confirms and extends previous reports of apparent phase advances in circadian noradrenergic rhythms in depressed patients.

Normal thyroid function in desipramine nonresponders converted to responders by the addition of L-triiodothyronine.

The results of complete thyroid function testing were normal in four desipramine nonresponders who were converted to responders by addition of L-triiodothyronine (T3). These findings suggest that the effectiveness of T3 is not due to correction of subtle thyroid deficiencies.

Hippocampal innervation by serotonin neurons of the midbrain raphe in the rat.

The organization of the brainstem serotonin neuron projection to the hippocampal formation was analyzed in the rat. This projection arises in the raphe nuclei of the midbrain. Following destruction of the midbrain raphe nuclei, chiefly nucleus centralis superior, there is a 72% decrease in hippocampal serotonin content. Injection of tritiated amino acid into the midbrain raphe nuclei results in transport of tritiated protein to the hippocampal formation and this transport is blocked in animals pretreated by intraventricular administration of 5,6-dihydroxytryptamine (5,6-DHT). Autoradiographic analysis indicates that the transport reaches the hippocampal formation primarily via two major pathways, the cingulum and the fornix. Cingulum fibers terminate predominantly in the dorsal hippocampus whereas the fornix distributes throughout the entire hippocampal formation. Some fibers reach the ventral hippocampus from the entorhinal area. Within the hippocampus there is dense labeling in a restricted lamina of the CA1 stratum lacunosum-moleculare with moderate labeling in stratum radiatum. Stratum oriens is sparsely labeled in CA1 and moderately so in CA2 and CA3. Stratum radiatum and stratum lacunosum-moleculare are moderately densely labeled in CA2 and Ca3. The area dentata is sparsely to moderately labeled in the molecular layer and heavily labeled in a thin lamina of the hilar zone immediately beneath the granule cell layer. The remaining hilar zone is moderately labeled. All of the discrete labeling of the hippocampus and area dentata described above is absent in animals pretreated with 5,6-DHT. These observations indicate that serotonin neurons of the midbrain raphe provide a highly organized innervation of the hippocampal formation in the rat.

Serotonin neurons of the midbrain raphe: ascending projections.

The ascending projections of serotonin neurons of the midbrain raphe were analyzed in the rat using the autoradiographic tracing method. Axons of raphe serotonin neurons ascend in the ventral tegmental area and enter the medial forebrain bundle. A number of fibers leave the major group to ascend along the fasciculus retroflexus. Some fibers enter the habenula but the majority turn rostrally in the internal medullary lamina of the thalamus to innervate dorsal thalamus. Two additional large projections leave the medial forebrain bundle in the hypothalamus; the ansa peduncularis-ventral amygdaloid bundle system turns laterally through the internal capsule into the striatal complex, amygdala and the external capsule to reach lateral and posterior cortex, and another system of fibers turns medially to innervate medial hypothalamus and median eminence and form a contrelateral projection via the supraoptic commissures. Rostrally the major group in the medial forebrain bundle divides into several components: fibers entering the stria medullaris to terminate in thalamus; fibers entering the stria terminalis to terminate in the amygdala; fibers traversing the fornix to the hippocampus; fibers running through septum to enter the cingulum and terminate in dorsal and medial cortex and in hippocampus; fibers entering the external capsule to innervate rostral and lateral cortex; and fibers continuing forward in the medial olfactory stria to terminate in the anterior olfactory nucleus and olfactory bulb.

Elevated 3H-para-aminoclonidine binding to platelet purified plasma membranes from depressed patients.

Purified platelet plasma membranes were used to compare 3H-para-aminoclonidine binding in 18 depressed patients and 24 sex- and age-matched, healthy control subjects. Two site-selective concentrations of the radioligand were used (0.06 and 1.5 nmol/L) to investigate two high-affinity 3H-para-aminoclonidine binding sites. Radioligand binding was significantly elevated in platelets of depressed patients at both concentrations of 3H-para-aminoclonidine whether expressed per milligram protein, per platelet, or per square micrometer of platelet surface area (each p less than 0.02). These data agree with most previous studies, suggesting that a subset of platelet alpha 2 adrenoceptors, recognized by clonidine and its derivative para-aminoclonidine, is upregulated in depressed patients. By using purified plasma membranes, our data rule out the possibility that an inhibitor may have masked receptor binding in previous studies which used total platelet lysates. The present findings thus support the alpha 2 adrenoceptor hypersensitivity theory of depression.

Autoradiographic comparison of [3H]-clonidine binding to non-adrenergic sites and alpha(2)-adrenergic receptors in human brain.

UNLABELLED: Clonidine is a partial agonist at brain alpha(2)-adrenoceptors (alpha(2)AR), but also has high affinity (K(D) = 51 nM) in homogenate binding assays for non-adrenergic imidazoline-binding sites (I-sites; imidazoline receptors). Herein, an autoradiographic comparison of [3H]-clonidine binding to I-sites and alpha(2)AR in sections of human brain is reported. For I-sites, the adrenergic component of 50 nM [3H]-clonidine binding was masked with either 60 microM norepinephrine (NE; alpha(2)AR agonist) or 12.5 microM methoxy-idazoxan (MIDX; selective alpha(2)AR antagonist), whereas the remaining non-adrenergic sites were studied by displacement with 20 microM cirazoline. Levels of [3H]-clonidine binding to alpha(2)AR and I-sites, determined in adjacent tissue sections, were positively correlated across 27 brain regions (p = 0.0003; r(2) = 0.385). The principal olivary nucleus and the rostral portion of the ventrolateral medulla had highest ratios of I-sites: alpha(2)AR (>4:1). Quantitative transepts drawn across hippocampal images revealed alpha(2)AR enrichments in the CA-1 and inner molecular layers of the dentate gyrus-areas not enriched in I-sites. Competition curves were generated for I-sites in caudate sections using 10 ligands known to distinguish between I(1) and I(2) subtypes. The rank-order of affinities were cirazoline > harmane > BDF6143 > idazoxan = tizanidine (affinities of agmatine, efaroxan, moxonidine, NE, and oxymetazoline were too low to be reliable). Only the endogenous I-site ligand, harmane, had a monophasic displacement curve at the non-adrenergic sites (Ki = 521 +/- 12 nM). IN CONCLUSION: 1) the distribution of non-adrenergic [3H]-clonidine binding sites in human brain sections was correlated with, but distinct from alpha(2)AR; and 2) the affinities of these sites was distinct from alpha(1)AR, alpha(2)AR, I(1) or I(2) sites as previously defined in membrane binding assays. The properties of this non-adrenergic [3H]-clonidine binding site are consistent with I-sites previously labeled by [3H]-cirazoline in rat brain.

CSF and endocrine studies of premenstrual syndrome.

Eight women with prospectively documented premenstrual syndrome (PMS) underwent multiple samplings for estradiol, progesterone, prolactin, cortisol, and plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) during an asymptomatic midcycle (late follicular) and a symptomatic premenstrual (late luteal) phase of the menstrual cycle. Cerebrospinal fluid (CSF) was collected for analysis of MHPG, norepinephrine (NE), 5-hydroxyindoleacetic acid (5-HIAA), dihydroxyphenylacetic acid (DOPAC), gamma-aminobutyric acid (GABA), homovanillic acid (HVA), tyrosine, tryptophan, beta-endorphin, prostaglandins, adrenocorticotropic hormone (ACTH), and arginine vasopressin (AVP). In subsequent months, a dexamethasone suppression test (DST) and a thyrotropin-releasing hormone (TRH) stimulation test were performed during midcycle and premenstrual phases. Significant results included increased CSF concentrations of MHPG in the premenstrual, as compared with the midcycle, phase of the cycle, and increased plasma cortisol concentrations during the midcycle phase. The DST showed a 62% overall rate of nonsuppression, irrespective of menstrual cycle phase. Though there were no abnormalities of thyrotropin-stimulating hormone (TSH) after TRH stimulation, the mean delta maximum prolactin values after TRH stimulation were higher than reported normal values both at midcycle and premenstrually. These pilot data suggest hormonal axes that might be worthy of further systematic investigation in future studies of PMS.

The raphe neuronal system and serotonergic effects of LSD.

Earlier work from this laboratory had shown that LSD caused significant increases in rat brain serotonin (5-HT). The increase was later localized to a subsynaptosomal fraction consisting largely of synaptic vesicles. However, the source of the increase and the mechanism by which LSD caused the enhanced 5-HT binding or retention had not been elucidated. The present study was undertaken to evaluate the serotonergic effects of LSD following destruction of raphe nuclei with radiofrequency lesions. When LSD was given to animals with large midbrain raphe lesions, it caused significant increases in forebrain of cortical 5-HT up to 48 hr, or 7 days post-lesion, respectively. It was concluded that an intact cell body is not necessary for the expression of the LSD-mediated increases in 5-HT occurring in the nerve-ending. The possible mechanisms by which LSD could act directly at the nerve-ending are discussed.

Psychopharmacology of imidazoline and alpha 2-adrenergic receptors: implications for depression.

The literature on alpha 2-adrenoceptors in depression is replete with seemingly contradictory findings, including reports of both hypersensitive and hyposensitive alterations. Now, with the discovery of nonadrenergic imidazoline receptors (I receptors) and an endogenous I receptor ligand (agmatine), new light is being shed on this controversy. Specifically, those studies that had utilized allegedly "alpha 2-selective" imidazoline radioligands, i.e., 3H-clonidine, could be reinterpreted in terms of increased I receptors in depression. Although the molecular identity of the I1 binding site remains unknown, an I2 receptive site has been reported to be encoded by monoamine oxidase genes (both MAO-A and MAO-B), suggesting a novel explanation for the antidepressant efficacy of idazoxan, a prototypic I2 ligand. Platelet I1 binding sites are also reported to be elevated in patients with unipolar depression and are lowered by antidepressant treatments. Furthermore, clonidine challenge and animal studies of the behavioral effects of imidazolines may be reinterpreted to support a role for I1 sites in the central control of behavior. A hypothesis for depletion of brain clonidine-displacing substance (CDS) in depression is presented. Lowered concentrations of CDS could account for an elevation of I receptors, via compensatory upregulation. Our model offers an explanation for a number of previously discrepant observations as well as testable hypotheses for the study of imidazoline receptors in depression.