Biomedical subjects

D J Reis

Publications and source records attributed to D J Reis.

At least 55 records · Page 3Linked to original sources

PubMed1997

Autonomic and vasomotor regulation.

The cerebellum not only modulates the systemic circulation, but also profoundly influences cerebral blood flow (rCBF) and metabolism (rCGU), and initiates long-term protection of the brain from ischemia. Electrical stimulation of the rostral ventral pole of the fastigial nucleus (FN), elevates arterial pressure (AP), releases vasoactive hormones, elicits consummatory behavioral and other autonomic events and site specifically elevates rCBF independently of changes in rCGU. Cerebral vasodilation results from the antidromic excitation of axons of brain stem neurons which innervate cerebellum and, through their collaterals, neurons in the rostral ventrolateral reticular nucleus (RVL). RVL neurons initiate cerebral vasodilation over polysynaptic vasodilator pathways which engage a population of vasodilator neurons in the cerebral cortex. In contrast, intrinsic neurons of FN, when excited, elicit widespread reductions in rCGU and, secondarily, rCBF, along with sympathetic inhibition. Electrical stimulation of FN can reduce the volume of a focal cerebral infarction produced by occlusion of the middle cerebral artery by 50%. This central neurogenic neuroprotection is long lasting (weeks) and is not due to changes in rCBF or rCGU. Rather, it appears to reflect alterations in neuronal excitability and/or downregulation of inflammatory responses in cerebral vessels. The FN, therefore, appears to be involved in widespread autonomic, metabolic, and behavioral control, independent of motor control. The findings imply that the FN receives inputs from neurons, probably widely represented in the central autonomic core, which may provide continuing information processing of autonomic and behavioral states. The cerebellum may also widely modulate the state of cortical reactivity to ischemia, hypoxia, and possibly other neurodegenerative events.

Animals↗

PubMed1997

An antiserum to idazoxan recognizes an immunoreactive substance in human serum and cerebral spinal fluid which is not agmatine.

A polyclonal antibody was generated in rabbits to an idazoxan-albumin antigen. The anti-idazoxan antiserum had high affinity for unconjugated 3H-idazoxan (Kd of 19.8 nM) in a radio-immunoassay (RIA). Of various drugs and native molecules only idazoxan potently (Ki of 24 nM) inhibited 3H-idazoxan binding to the anti-idazoxan antibody. A few drugs weakly inhibited 3H-idazoxan binding (IC50 > 605 microM) with rank order of UK 14304 > guanabenz > cirazoline > amiloride > naphazoline. Neither agmatine, an endogenous clonidine displacing substance (CDS), catecholamines or imidazoles inhibited the binding of 3H-idazoxan to the anti-idazoxan antibody. The anti-idazoxan RIA was 4-6 fold more sensitive than an antibody to para-amino clonidine. The CDS detected by ligand displacement from bovine brain dose-dependently inhibited 3H-idazoxan binding. This immunoreactive (ir-) CDS activity was present in human (0.9-4.1 U/ml) and rat sera (1-2 U/ml) and in the cerebro-spinal fluid of eight patients with serious disease of the central nervous system, but not in controls. We conclude: (1) an anti-idazoxan RIA is a sensitive, selective and clinically applicable RIA for measuring ir-CDS; (2) ir-CDS is not agmatine; (3) CDS represents a family of endogenous ligands for imidazoline receptors including ir-CDS and agmatine.

Agmatine↗

PubMed1997

Uptake of agmatine into rat brain synaptosomes: possible role of cation channels.

Agmatine (decarboxylated arginine), an endogenous ligand for imidazoline receptors, has been identified in brain where it is synthesized from arginine by arginine decarboxylase. Here we report a mechanism for the transport of agmatine into rat brain synaptosomes. The uptake of agmatine was energy- and temperature-dependent and saturable with a Km of 18.83 +/- 3.31 mM and a Vmax of 4.78 +/- 0.67 nmol/mg of protein/min. Treatment with ouabain (Na+,K+-ATPase inhibitor) or removal of extracellular Na+ did not attenuate the uptake rate. Agmatine transport was not inhibited by amino acids, polyamines, or monoamines, indicating that the uptake is not mediated by any amino acid, polyamine, or monoamine carriers. When we examined the effects of some ion-channel agents on agmatine uptake, only Ca2+-channel blockers inhibited the uptake, whereas a reduction in extracellular Ca2+ increased it. In addition, some imidazoline drugs, such as idazoxan and phentolamine, were strong noncompetitive inhibitors of agmatine uptake. Thus, a selective, Na+-independent uptake system for agmatine exists in brain and may be important in regulating the extracellular concentration of agmatine.

Agmatine↗

PubMed1997

Gigantocellular vasodepressor area is tonically active and distinct from caudal ventrolateral vasodepressor area.

The gigantocellular depressor area (GiDA) is a functionally defined subdivision of the medullary gigantocellular reticular formation where vasodepressor responses are evoked by glutamate microinjections (Aicher, S. A., D. J. Reis, D. A. Ruggiero, and T. A. Milner. Neuroscience 60: 761-779, 1994). The present experiments sought to determine whether the GiDA 1) tonically inhibits the sympathetic nervous system; 2) is necessary for baroreflex function; and 3) is functionally distinct from adjacent vasodepressor regions in the medullary reticular formation, including the midline raphe nuclei and the caudal ventrolateral medulla (CVL). Excitotoxic lesions of the GiDA abolished the baroreflex and significantly increased sympathetic nerve activity in anesthetized rats. Equivalent injections into the midline raphe nuclei elevated sympathetic activity but did not alter baroreflex responses. Therefore, the GiDA is functionally distinct from the raphe nuclei, although both contain tonically active sympathoinhibitory neurons. Because the effects of GiDA lesions were identical to those seen after lesions of the CVL, further studies were required to demonstrate that the GiDA and CVL are functionally and anatomically distinct. First, intramedullary injections of kynurenic acid produced hypertension and blocked the baroreflex when placed in the CVL, but not when placed in the GiDA. Second, muscimol inactivation of the RVL blocked the hypertension produced by excitotoxic lesions of the CVL, but failed to block the hypertension produced by similar lesions of the GiDA. Third, CVL neurons project to the RVL but not the spinal cord, whereas GiDA neurons project to the spinal cord but not the RVL. These studies show that the CVL and GiDA are both tonically sympathoinhibitory regions, but they are distinct with regard to their functional connectivity with other autonomic regions.

Afferent Pathways↗

PubMed1997

The imidazoline receptor in control of blood pressure by clonidine and allied drugs.

Clonidine, moxonidine, and rilmenidine are centrally acting antihypertensive agents that lower arterial pressure by inhibiting the tonic activity of sympathoexcitatory neurons in the rostral ventrolateral medulla. Competing hypotheses have been put forward by different investigators to explain the sympathoinhibition evoked by "imidazoline drugs": either via central actions at alpha 2-adrenergic receptors or novel I1-imidazoline receptors. These different perspectives are presented in the accompanying reviews.

Animals↗

PubMed1997

Stimulation of imidazoline receptors inhibits proliferation of human coronary artery vascular smooth muscle cells.

Vascular smooth muscle cells of rat aorta express imidazoline receptors whose stimulation, by drugs or an endogenous ligand, agmatine, inhibits serum-stimulated proliferation. We investigated whether imidazoline receptors are expressed in human vascular smooth muscle cells if their stimulation is antiproliferative. Cultured human coronary artery vascular smooth muscle cells express a nonadrenergic binding site for 3H-idazoxan and an imidazoline receptor-binding protein as revealed by immunocytochemical and immunoblot analyses with a specific antibody. Idazoxan and agmatine dose-dependently inhibited serum-stimulated proliferation of these cells as measured by the incorporation of 3H-thymidine (IC50: 5 and 70 micromol/L, respectively) and serum-stimulated expression of proliferating cell nuclear antigen and cell numbers. The agents inhibited proliferation of human and rat (aorta) smooth muscle cells stimulated by either norepinephrine (6560+/-440 disintegrations per minute norepinephrine versus 3345+/-220 norepinephrine and idazoxan), angiotensin II (7680+/-335 disintegrations per minute angiotensin II versus 3769+/-450 angiotensin II and idazoxan), or platelet-derived growth factor (IC50: 3 micromol/L for idazoxan and 40 micromol/L for agmatine), indicating inhibition of mitosis mediated by G-protein or receptor tyrosine kinase pathways. We conclude that human vascular smooth muscle cells express imidazoline-receptors whose activation inhibits proliferation by interacting at a distal step in an intracellular signal cascade common to G-protein and receptor tyrosine kinase mitogenic pathways. Agmatine, synthesized in endothelium, may act as a paracrine regulator of vascular smooth muscle cell proliferation through imidazoline receptors, and agents acting at this site may be useful in treating vascular hyperplasia.

Adrenergic alpha-Antagonists↗

PubMed1996

Monosynaptic projections from the nucleus tractus solitarii to C1 adrenergic neurons in the rostral ventrolateral medulla: comparison with input from the caudal ventrolateral medulla.

The rostral ventrolateral medulla (RVL) contains reticulospinal adrenergic (C1) neurons that are thought to be sympathoexcitatory and that form the medullary efferent limb of the baroreceptor reflex pathway. The RVL receives direct projections from two important autonomic regions, the caudal ventrolateral medulla (CVL) and the nucleus tractus solitarii with immunocytochemical identification of C1 adrenergic neurons in the RVL to compare the morphology of afferent input from these two autonomic regions into the RVL. NTS (n = 203) and CVL (n = 380) efferent terminals had similar morphology and vesicular content, but CVL efferent terminals were slightly larger than NTS efferent terminals. Overall, efferent terminals from either region were equally likely to contact adrenergic neurons in the RVL (21% for NTS, 25% for CVL). Although efferents from both regions formed both symmetric and asymmetric synapses, NTS efferent terminals were statistically more likely to form asymmetric synapses than CVL efferent terminals. CVL efferent terminals were more likely to contact adrenergic somata than were NTS efferents, which usually contacted dendrites. These findings 1) support the hypothesis that a portion of NTS efferents to the RVL may be involved in sympathoexcitatory, e.g., chemoreceptor, reflexes (via asymmetric synapses), whereas those from the CVL mediate sympathoinhibition (via symmetric synapses); and 2) provide an anatomical substrate for differential postsynaptic modulation of C1 neurons by projections from the NTS and CVL. With their more frequent somatic localization, CVL inhibitory inputs may be more influential than excitatory NTS inputs in determining the discharge of RVL neurons.

Animals↗

PubMed1996

Ethanol inhibits chemoreflex excitation of reticulospinal vasomotor neurons.

In anesthetized and ventilated rats, activation of carotid chemoreceptors with intracarotid administration of 100 nmol sodium cyanide rapidly excited the spinal cord-projecting vasomotor neurons in the rostroventrolateral reticular nucleus (RVL) of the medulla oblongata and sympathetic nerves and increased arterial pressure. The chemoreflex sympathoexcitatory pressor responses were attenuated by an acute systemic administration of ethanol at 0.45 g/kg, but not at 45 mg/kg. The ethanol effects were observed at the level of RVL-spinal vasomotor neurons, in attenuating the neuronal responses to the chemoreflex excitation and direct iontophoresis of N-methyl-D-aspartic acid (NMDA) but without altering responses of the carotid sinus nerves to intracarotid cyanide. The effect of ethanol on the RVL neurons was further defined as blocking NMDA-evoked inward current in the corresponding spontaneously active RVL neurons in vitro. The results indicate that acute ethanol intoxication markedly influences NMDA receptor activation and arterial chemoreflexes. The relevance of the type of action to clinical hypertension in chronic and heavy drinkers is discussed.

Animals↗

PubMed1996

Contribution of oxygen-sensitive neurons of the rostral ventrolateral medulla to hypoxic cerebral vasodilatation in the rat.

1. We sought to determine whether hypoxic stimulation of neurons of the rostral ventrolateral reticular nucleus (RVL) would elevate regional cerebral blood flow (rCBF) in anaesthetized paralysed rats. 2. Microinjection of sodium cyanide (NaCN; 150-450 pmol) into the RVL rapidly (within 1-2 s), transiently, dose-dependently and site-specifically elevated rCBF1 measured by laser Doppler flowmetry, by 61.3 +/- 22.1% (P < 0.01), increased arterial pressure (AP; +30 +/- 8 mmHg; P < 0.01)1 and triggered a synchronized 6 Hz rhythm of EEG activity. 3. Following cervical spinal cord transection, NaCN and also dinitrophenol (DNP) significantly (P < 0.05) elevated rCBF and synchronized the EEG but did not elevate AP; the response to NaCN was attenuated by hyperoxia and deepening of anaesthesia. 4. Electrical stimulation of NaCN-sensitive sites in the RVL in spinalized rats increased rCBF measured autoradiographically with 14C iodoantipyrine (Kety method) in the mid-line thalamus (by 182.3 +/- 17.2%; P < 0.05) and cerebral cortex (by 172.6 +/- 15.6%; P < 0.05) regions, respectively, directly or indirectly innervated by RVL neurons, and in the remainder of the brain. In contrast regional cerebral glucose utilization (rCGU), measured autoradiographically with 14C-2-deoxyglucose (Sokoloff method), was increased in proportion to rCBF in the mid-line thalamus (165.6 +/- 17.8%, P < 0.05) but was unchanged in the cortex. 5. Bilateral electrolytic lesions of NaCN sensitive sites of RVL, while not altering resting rCBF or the elevation elicited by hypercarbia (arterial CO2 pressure, Pa,CO2, approximately 69 mmHg), reduced the vasodilatation elicited by normocapnic hypoxaemia (arterial O2 pressure, Pa,O2, approximately 27 mmHg) by 67% (P < 0.01) and flattened the slope of the Pa,O2-rCBF response curve. 6. We conclude that the elevation of rCBF produced in the cerebral cortex by hypoxaemia is in large measure neurogenic, mediated trans-synaptically over intrinsic neuronal pathways, and initiated by excitation of oxygen sensitive neurons in the RVL.

Animals↗

PubMed1996

Heat shock protein 70 suppresses astroglial-inducible nitric-oxide synthase expression by decreasing NFkappaB activation.

In brain glial cells, expression of calcium independent nitric-oxide synthase (NOS-2) is induced following stimulation with bacterial endotoxin (lipopolysaccharide (LPS)) and/or pro-inflammatory cytokines. We have investigated the effects of heat shock (HS), which can reduce inflammatory responses in several cell types, on the induction of glial NOS-2 expression. Preincubation of cells for 20-60 min at 43 degrees C decreased subsequent levels of NOS-2 induction, with a maximal 80% reduction after 60 min of HS. Following HS, cells were refractory to NOS inducers for up to 4 h, after which time little or no suppression was observed. HS reduced cytosolic NOS-2 enzymatic activity (3-fold), steady state mRNA levels (2-3-fold), and gene promoter activity (by 50%). HS also reduced LPS-induced nuclear accumulation of transcription factor NFkappaB p65 subunit, suggesting perturbation of NFkappaB activation. A role for HS protein (HSP) 70 in NOS-2 suppression by HS is supported by the demonstration that 1) transfection with human HSP70 cDNA partially replicated HS effects; 2) antisense, but not sense, oligonucleotides directed against rat HSP70 partially blocked HS effects; and 3) rat fibroblasts stably expressing human HSP70 did not express NOS-2 in response to LPS plus cytokines. As with heat-shocked cells, HSP70-expressing cells also exhibited decreased NFkappaB p65 subunit nuclear accumulation. These results demonstrate that in glial cells, as well as other cell types, NOS-2 induction can be modulated by the HS response, mediated at least in part by HSP70 expression.

Animals↗

PubMed1996

Electrical stimulation of cerebellar fastigial nucleus fails to rematch blood flow and metabolism in focal ischemic infarctions.

Electrical stimulation of the cerebellar fastigial nucleus (FN) in rat (1 h) reduces, by 50%, the infarction produced by occlusion of the middle cerebral artery (MCAO). We investigated whether salvage was associated with elevations in regional cerebral blood flow (rCBF) and/or reductions of regional cerebral glucose utilization (rCGU) in the retrievable zone (RZ). rCGU and rCBF were measured autoradiographically 1 h after MCAO. MCAO reduced rCBF to < 15% in the irretrievable zone (IZ) and approximately 50% in the RZ (P < 0.01 for each) while FN stimulation alone globally elevated rCBF by approximately 60% (P < 0.01). rCGU was not changed. After MCAO, FN stimulation failed to increase the reduced rCBF but elevated rCGU globally (to approximately 30%). Reductions of focal ischemic infarctions by stimulating FN cannot be attributed to changes in rCBF and or rCGU.

Animals↗

PubMed1996

Intracisternally applied angiotensin II does not excite reticulospinal vasomotor neurons in anesthetized rats.

We examined whether vasomotor neurons in the rostroventrolateral reticular nucleus of the medulla oblongata might be responsible for an acute increase in arterial pressure, elicited by application of angiotensin II in the central nervous system, as suggested by others. In urethane-pentobarbital-anesthetized and ventilated rats, intracisternal administration of angiotensin II (1-30 nmol, infused over a period of 30 s) produced a dose-dependent pressor response, which was abolished by intracisternal application of [Sar1, Thr8]angiotensin II (100 nmol), an angiotensin II receptor antagonist. The pressor response, however, was neither preceded by nor associated with increased discharges of vasomotor neurons with slow- and fast-conduction axons in the rostroventrolateral reticular nucleus and of lumbar sympathetic chain and renal sympathetic nerves. Intravenous injections of [beta-mercapto-beta, beta-cyclopentamethylenepropinyl1,-O-Et-Tyr2, Val4, Arg8]vasopressin, a vasopressin receptor antagonist, largely abolished the central angiotensin II-induced pressor response, while a blockade of ganglionic transmission with hexamethonium and disruption of descending sympathoexcitatory output were ineffective. We conclude that central administration of angiotensin II, under the experimental conditions and at the doses, evokes an acute pressor response largely through the release of vasopressin, not by exciting vasomotor and sympathetic neurons.

Angiotensin II↗

PubMed1996

Inhibition of mammalian nitric oxide synthases by agmatine, an endogenous polyamine formed by decarboxylation of arginine.

Agmatine, decarboxylated arginine, is a metabolic product of mammalian cells. Considering the close structural similarity between L-arginine and agmatine, we investigated the interaction of agmatine and nitric oxide synthases (NOSs), which use L-arginine to generate nitric oxide (NO) and citrulline. Brain, macrophages and endothelial cells were respectively used as sources for NOS isoforms I, II and III. Enzyme activity was measured by the production of nitrites or L-citrulline. Agmatine was a competitive NOS inhibitor but not an NO precursor. Ki values were approx. 660 microM (NOS I), 220 microM (NOS II) and 7.5 mM (NOS III). Structurally related polyamines did not inhibit NOS activity. Agmatine, therefore, may be an endogenous regulator of NO production in mammals.

Agmatine↗

PubMed1996

Cerebral cortical neurons with activity linked to central neurogenic spontaneous and evoked elevations in cerebral blood flow.

We recorded neurons in rat cerebral cortex with activity relating to the neurogenic elevations in regional cerebral blood flow (rCBF) coupled to stereotyped bursts of EEG activity, burst-cerebrovascular wave complexes, appearing spontaneously or evoked by electrical stimulation of rostral ventrolateral medulla (RVL) or fastigial nucleus (FN). Of 333 spontaneously active neurons only 15 (5%), in layers 5-6, consistently (P < 0.05, chi-square) increased their activity during the earliest potential of the complex, approximately 1.3 s before the rise of rCBF, and during the minutes-long elevation of rCBF elicited by 10 s of stimulation of RVL or FN. The results indicate the presence of a small population of neurons in deep cortical laminae whose activity correlates with neurogenic elevations of rCBF. These neurons may function to transduce afferent neuronal signals into vasodilation.

Animals↗

PubMed1996

Excitatory amino acid-mediated chemoreflex excitation of respiratory neurones in rostral ventrolateral medulla in rats.

1. In anaesthetized rats, extracellular and intracellular recordings were made from 119 respiratory neurones in the rostroventrolateral reticular nucleus (RVL) of the medulla oblongata. 2. Two types of active respiratory neurones were detected in RVL: expiratory (E) and pre-inspiratory (Pre-I), based on the relationship between their discharge and that of the phrenic nerve. Some Pre-I but none of the E neurones could be antidromically excited from the C(3)-C(4) level of the spinal cord. 3. E and Pre-I neurones of RVL were excited by stimulation of the arterial chemoreceptors by a close arterial injection of sodium cyanide. The reflex excitation of RVL E neurones was preceded by increased phrenic nerve activity, while the excitation of RVL Pre-I neurones preceded the increases in phrenic nerve activity. 4. The chemoreflex excitation of the two types of RVL respiratory neurones as well as their resting discharge was abolished or significantly depressed by microionophoresis of kynurenate, a wide-spectrum antagonist of excitatory amino acid receptors, while xanthurenate, an inactive analogue of kynurenate, was without effect. 5. In ventilated rats, bilateral microinjection into RVL of kynurenate, but not xanthurenate, abolished resting activity and chemoreflex excitation of phrenic nerve activity, whilst in spontaneously breathing rats, kynurenate microinjection into RVL produced apnea and silenced phrenic nerves. 6. We conclude: (a) chemoreflex excitation of the phrenic nerves is mediated by stimulating Pre-I neurones of RVL by excitatory amino acidergic inputs and (b) RVL Pre-I neurones may directly and/or indirectly excite spinal phrenic motor neurones and hence are involved in inspiratory rhythmogenesis.

Animals↗

PubMed1996

Expression of I2-imidazoline sites in rat prostate. Effect of castration and aging.

Clonidine, idazoxan, and related imidazoline adrenergic drugs bind to non-adrenergic sites in brain and several peripheral tissues. These sites, termed imidazoline receptors, appear to exist in two major subclasses, I1 sites labeled by clonidine and I2 sites labeled by idazoxan. In this study, we investigated whether rat prostate expresses imidazoline receptors and, if so, whether their expression can be regulated by circulating testosterone. Studies in rat ventral prostate membrane revealed that [3H]idazoxan, but not [3H]p-aminoclonidine, bound to non-adrenergic sites. The binding of [3H]idazoxan was saturable (Bmax: 941 +/- 105 fmol/mg protein) and high affinity (KD: 16.4 +/- 2.3 nM). The rank order of the inhibition of binding by imidazoline ligands was cirazoline > clonidine > UK 14,304 > guanabenz, indicating an I2 subclass of imidazoline receptors. Bilateral orchiectomy increased the number of binding sites (Bmax) for [3H]idazoxan without changing the affinity (KD). Testosterone replacement, while completely restoring the plasma testosterone levels, only partially reversed the increase in Bmax. In contrast, the binding of [3H]idazoxan to prostate membranes of rats in different age groups (4, 7, and 16 months) revealed a progressive decrease in the Bmax without any change in KD. We conclude that the rat prostate expresses the I2 subclass of imidazoline receptors and that the expression is regulated by circulating testosterone.

Adrenergic Agonists↗

PubMed1996

Afferent sources of substance P in the C1 area of the rat rostral ventrolateral medulla.

To examine the potential extrinsic sources of substance P (SP)-containing terminals in the C1 area of the RVL, immunoperoxidase localization of SP was combined with retrograde transport of wheat germ agglutinin-conjugated horseradish peroxidase (WGA-HRP). In all cases examined, several neurons containing SP and WGA-HRP were found in the nucleus raphe pallidus and a few dual labeled neurons were found in the nucleus of the solitary tract and the paraventricular nucleus of the hypothalamus. In some cases, one or two double labeled neurons were detected in the lateral hypothalamic area and nucleus raphe obscurus. The results demonstrate that although several brain structures contribute SP afferents to the RVL, the nucleus raphe pallidus is the major extrinsic source.

Afferent Pathways↗

PubMed1996

Immunodetection and quantitation of imidazoline receptor proteins in platelets of patients with major depression and in brains of suicide victims.

BACKGROUND: Imidazoline receptors are a newly discovered family of receptors, some of which, like alpha 2-adrenoceptors, have a presynaptic inhibitory effect on the release of norepinephrine. The aim of this study was to identify by immunodetection imidazoline receptor proteins in human platelets and the brain to assess their status in depression and suicide. METHODS: Platelets were collected from 26 drug-free depressed patients and 26 controls. Specimens of frontal cortex (Brodmann area 9) were collected from 13 suicide victims and 11 controls. Levels of imidazoline receptor proteins were assessed by immunoblotting techniques. Solubilized imidazoline receptors were separated by gel electrophoresis, transferred to nitrocellulose membranes, labeled with a specific anti-imidazoline receptor antiserum, and quantitated by image analysis. RESULTS: Platelet and brain membranes expressed similar 45-kd imidazoline receptor proteins, and their mean +/- SEM immunoreactivities were found to be increased in depressed patients (platelets, 40% +/- 5%) and suicide victims (brain, 51% +/- 14%). Platelets also expressed a 35-kd imidazoline receptor protein that was also found to be up-regulated in depressed patients (21% +/- 4%). In contrast, brain membranes did not express this 35-kd protein but revealed a 29/30-kd imidazoline receptor protein that was found to be down-regulated in suicide victims (19% +/- 3%). In a subset of depressed patients who underwent antidepressant treatment, a change in the immunoreactivity of the up-regulated 45-kd platelet imidazoline receptor protein (-35% +/- 5%), but not of the 35-kd protein, was observed. CONCLUSION: The results support a role for the newly discovered imidazoline receptors (mainly the 45-kd receptor expressed in the brain and platelets) in the pathogenesis of depression.

Adult↗