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Biomedical subjects

K Y Little

Publications and source records attributed to K Y Little.

At least 37 records · Page 2Linked to original sources
PubMed1996

Alteration of brain dopamine and serotonin levels in cocaine users: a preliminary report.

OBJECTIVE: This study tested the hypothesis that cocaine depletes dopamine levels in the brain. METHOD: Levels of dopamine, serotonin, and their metabolites in the frontal cortex and striatum of nine cocaine users and nine matched control subjects who had never used cocaine were determined from postmortem autopsy material. RESULTS: The cocaine users had significantly lower dopamine levels and higher serotonin levels in the frontal cortex than the control subjects. Levels in other brain areas did not differ between the two groups. CONCLUSIONS: Alterations of dopamine and serotonin levels might contribute to symptoms of cocaine withdrawal and craving.

Adult↗
PubMed1995

Characterization and localization of [125I]RTI-121 binding sites in human striatum and medial temporal lobe.

Dopamine Transporter (DAT) binding sites in medial temporal lobe structures are much less dense than in striatum and have been difficult to image and quantitate. The recently synthesized compound [125I]RTI-121 ([125I]2 beta-carboxylic acid isopropyl ester-3 beta-(4-iodophenyl)tropane) has demonstrated high specificity and affinity for the DAT in preliminary animal studies. The present experiments were designed to delineate the pharmacological and anatomical characteristics of [125I]RTI-121 binding sites in the striatum and medial temporal lobe of normal humans. A series of saturation experiments performed with striatal membrane preparations generated a one-site model with a KD averaging 1.49 +/- 0.06 nM, and a Bmax that was comparable to those of earlier reports. Competition experiments confirmed the selectivity of [125I]RTI-121 for DAT binding sites. After the assay conditions for autoradiography were optimized, [125I]RTI-121 binding was visualized, pharmacologically characterized and quantitated in human temporal lobe structures. In the hippocampus, specific binding was distributed in the CA4 and CA3 pyramidal cell layers, the outer stratum radiatum and the dentate molecular layer, but not in the dentate granule cells or outer pyramidal cells. In the amygdala specific binding was limited to the basolateral nuclei. Dopamine nerve terminals, as identified with [125I]RTI-121 binding, also displayed a discrete and homologous innervation pattern in the amygdala and hippocampus of several other mammalian species. In summary, the kinetic, saturation, competition and autoradiographic experiments demonstrated that [125I]RTI-121 can be used to identify DAT binding sites and to assess their functional state in post mortem human brain samples.

Animals↗
PubMed1994

Dose-response studies with protirelin.

BACKGROUND: A reduced thyrotropin (TSH) response to thyrotropin-releasing hormone (protirelin [TRH]) has been found consistently in a portion of patients with major depression. One hypothesis to explain this observation is that pituitary TRH receptors are down-regulated in major depression. One prediction stemming from this hypothesis is that prolactin (PRL) as well as TSH responses to TRH should be attenuated. To adequately test the pattern of protirelin-induced TSH and PRL responses with a protirelin dose-response design is necessary. METHODS: Four doses of protirelin (25, 100, 500, and 800 micrograms) were infused in an ascending schedule at intervals of 3 to 7 days in patients with major depression and in control subjects. Seven women and six men with major depression were compared with age- and gender-matched controls (five women and seven men). The TSH and PRL responses were measured at regular intervals following each dose of protirelin. RESULTS: No significant group differences in baseline levels of thyroid hormones or cortisol were present. Depressed men exhibited significant reductions in both TSH and PRL responses to protirelin across all doses compared with control men. Depressed women exhibited significant reductions in TSH responses but not in PRL responses compared with control women. CONCLUSIONS: The findings that men with major depression exhibit reductions in both protirelin-induced TSH and PRL responses support the hypothesis that TRH receptors are downregulated in depression. The findings in women are less clear and may represent the greater variance in the protirelin-induced PRL responses found in women.

Adult↗
PubMed1994

Dopamine receptor gene expression in the human medial temporal lobe.

The distributions of the messenger RNA molecules encoding the five known dopamine receptors have been determined in the medial temporal lobe of postmortem human brain. All five receptor mRNAs are present in temporal lobe structures, although their distributions are heterogeneous. The D1-like receptors, D1 and D5, have strikingly dissimilar distributions. D1 receptor mRNA is abundant in temporal neocortex but is rare elsewhere. D5 receptor message, however, is seen in the hippocampus, subicular complex, and in temporal cortex. The D2-like receptors have similar distributions: D2, D3, and D4 receptor mRNAs are all identifiable in the hippocampal formation and in the cortical regions of the medial temporal lobe. Distinct patterns of relative regional concentrations for each message are observed, however, suggesting a neuroanatomical substrate for potential differences in dopaminergic regulation within discrete regions of the medial temporal lobe. These results provide a description of the distribution of these receptor mRNAs in normal humans and suggest multiple levels of complexity as well as regulation of the medial temporal lobe dopamine projection.

Adult↗
PubMed1994

Neuroanatomical specificity and dose dependence in the time course of imipramine-induced beta adrenergic receptor down-regulation in rat brain.

The time course of beta adrenergic receptor adaptation in response to chronic imipramine treatment (10 or 20 mg/kg) was assessed by quantitative autoradiographic analysis of 125I-pindolol binding in rat brain. Binding of the radioligand was assessed in 18 brain areas, including subregions of the hippocampus, amygdala, septum, hypothalamus and specific cerebral cortical regions. After only 2 days treatment with imipramine at a dose of 20 mg/kg, select cortical regions exhibited a reduction in 125I-pindolol binding. These rapidly adapting cortical regions included the medial prefrontal, lateral frontal, ventrolateral orbital and piriform cortices. After 7 or 21 days treatment with imipramine at 20 mg/kg, 16 of 18 brain regions examined exhibited significant reduction in 125I-pindolol binding. The only regions examined that did not show reduced 125I-pindolol binding for these treatment conditions were the caudate-putamen and anterior hypothalamic area. After 2 days treatment with 10 mg/kg of imipramine, down-regulation of beta adrenergic receptors was not observed in any region. After 7 days treatment with 10 mg/kg, down-regulation of beta adrenergic receptor binding was found only in certain cortical regions: medial prefrontal, lateral frontal, ventrolateral orbital and piriform cortices. Thus, the cortical regions that were most rapidly affected with the 20 mg/kg dose of imipramine (i.e., after 2 days) were also the first to respond with the 10 mg/kg dose of the drug. After 21 days treatment with imipramine at 10 mg/kg, 125I-pindolol binding was reduced in 13 of the 18 regions examined.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Cocaine use increases [3H]WIN 35428 binding sites in human striatum.

Animal studies suggest that chronic cocaine exposure may increase the function and/or synthesis of the dopamine transporter (DAT) under certain conditions, but the literature is complex. In order to test the hypothesis that cocaine exposure alters the DAT in humans, preliminary studies were done characterizing [3H]WIN 35428 binding in human striatum from normal controls. Following these experiments, the effects of chronic cocaine were examined in post mortem striatal specimens from 7 cocaine users and 7 controls matched for age and post mortem interval, employing quantitative autoradiography. Initial saturation experiments indicated that a one-site model was preferred with a Kd of 11 +/- 4 nM. [3H]WIN 35420 binding was then examined in cocaine users and controls at 0.5, 5, 10, and 50 nM radioligand concentrations. At each concentration of [3H]WIN 35420, optical densities for cocaine-exposed subjects were increased in caudate, putamen, and accumbens. The results suggest that total numbers of binding sites were increased in cocaine users. Based on the present and previous results, it appears that the regulation of the DAT is fairly plastic, and is highly sensitive to cocaine dosing regimes and withdrawal intervals. Chronic adaptations induced by cocaine in the DAT could contribute to the symptoms of binging, withdrawal depression, and/or craving.

Adult↗
PubMed1993

Beta-adrenergic receptor binding in frontal cortex from suicide victims.

Beta-adrenergic binding in frontal cortex samples from suicide victims has been reported to be increased, unaltered, and decreased compared to matched controls. Subject's diagnoses and drug exposures in these studies were not equivalently documented and were possibly different. In the present study, diagnostic and symptomatic information was systematically collected from family members of 15 subjects committing suicide and 15 matched controls using standardized interview techniques. The goal was to test the hypothesis that alterations in beta-adrenergic binding were more likely to be found in subjects with evidence of depressive disorders. [125I]pindolol binding in frontal cortex was found to be significantly lower in the group committing suicide compared to the matched controls (21.1 +/- 1.1 fmol/mg protein vs. 24.8 +/- 0.8 fmol/mg protein, p < .02). However, no diagnostic subgroup among the suicide victims appeared distinct.

Adolescent↗
PubMed1993

Effects of cocaine on dopamine receptor gene expression: a study in the postmortem human brain.

The effects of chronic cocaine exposure on dopamine D1 and D2 receptor gene expression in the human brain were studied in postmortem samples from chronic cocaine abusing and matched control subjects. Using in situ hybridization of receptor autoradiography to examine messenger ribonucleic acid (RNA) and binding sites, respectively, neither D1 nor D2 receptor expression was found to be changed in the nucleus accumbens, caudate, putamen, or substantia nigra of the cocaine-exposed subjects. Although chronic cocaine exposure can produce alterations in dopaminergic neurotransmission, sustained compensatory changes in dopamine receptor expression do not appear to occur in the human.

Adult↗
PubMed1993

Effects of concurrent subchronic treatments with desmethylimipramine and propranolol on beta-adrenergic and serotonin2 receptors in rat brain.

The effects of seven consecutive daily injections of desmethylimipramine (DMI 20 mg/kg) and propranolol (PRO 10 mg/kg) on 3H-dihydroalprenolol (3H-DHA) and 3H-ketanserin (3H-KET) binding in rat brain were examined. Analyses of saturation binding data using the iterative, nonlinear curve-fitting program LIGAND revealed that PRO increased, while DMI reduced, 3H-DHA binding site density in cerebral cortex without altering receptor affinity, as previously reported. DMI reduced 3H-KET binding site density without changing affinity, and PRO produced the same effect. In cerebral cortex and probably in hippocampus and striatum, DMI and PRO administered together increased the density of 3H-DHA binding sites (beta-adrenergic receptors) and reduced their affinity. This combination of drugs reduced the density of 3H-KET binding sites (5-HT2 receptors) in cerebral cortex, but did not change their affinity. These findings indicate a need for additional studies on the interactions of DMI and PRO and related drugs because of implications for the treatment of depressed patients with cardiovascular disorders.

Animals↗
PubMed1993

[125I]RTI-55 binding to cocaine-sensitive dopaminergic and serotonergic uptake sites in the human brain.

[125I]RTI-55 is a newly synthesized cocaine congener that may offer advantages over other ligands previously used to examine cocaine binding sites. However, the in vitro pharmacological and anatomical characterization of [125I]RTI-55 binding sites has not been previously performed in human brain. To determine the specificity, stability, and feasibility of [125I]RTI-55 for use in radioligand binding assays in postmortem human tissue, a series of experiments were performed characterizing [125I]RTI-55 binding sites in human brain using homogenized membrane preparations and quantitative autoradiography. Analysis of the association, dissociation, and saturation data favored two-phase processes. A curve-fitting analysis of the data derived in saturation experiments found a high-affinity site with KD = 66 +/- 35 pM and Bmax = 13.2 +/- 10.1 pmol/g of tissue and a low-affinity site with KD = 1.52 +/- 0.55 nM and Bmax of 47.5 +/- 11.2 pmol/g of tissue. Competition by ligands known to bind to the dopamine transporter showed a rank order of RTI-55 > GBR-12909 > maxindol > WIN 35428 > = methylphenidate > (-)-cocaine > buproprion > (+)-amphetamine. Binding to serotonergic sites was evaluated in the midbrain. Results of the saturation experiment performed autoradiographically in the midbrain showed a single site with KD = 370 +/- 84 pM. It appears that [125I]RTI-55 should be useful in further studies of the regulation of cocaine binding sites using postmortem human specimens.

Adult↗
PubMed1993

d-Amphetamine versus methylphenidate effects in depressed inpatients.

BACKGROUND: Both d-amphetamine and methylphenidate cause similar behavioral and subjective effects and can relieve depressive symptoms in some patients. However, the neurochemical effects of d-amphetamine and methylphenidate are distinct, and clinical experience suggests that individual depressed patients may respond dissimilarly to each stimulant. METHOD: d-Amphetamine and methylphenidate were administered sequentially to 18 DSM-III diagnosed depressed inpatients on consecutive days, and the acute effects were measured by a variety of instruments. RESULTS: Although many patients were acutely better after taking one drug or the other, as assessed by Hamilton Rating Scale for Depression and Global Visual Analogue Scale scores, relatively few responded with equal improvement to both. CONCLUSION: Acute symptomatic improvement after d-amphetamine or methylphenidate is unpredictable and can only be determined by an empirical trial on an individual basis. These data also suggest that even if one stimulant is not helpful therapeutically, another might be. The long-term benefits of selective stimulant therapy in depressed patients remain to be assessed.

Adult↗
PubMed1992

Autoradiographic characterization of [3H]imipramine and [3H]citalopram binding in rat and human brain: species differences and relationships to serotonin innervation patterns.

The neuroanatomical distribution of binding sites for [3H]imipramine and [3H]citalopram was assessed by in vitro autoradiography in select regions of the rat and human forebrain. To determine involvement of serotonin-containing terminals in the binding of [3H]imipramine and [3H]citalopram, binding of these compounds was measured in rats after destroying serotonin-containing neurons with 5,7-dihydroxytryptamine (5,7-DHT). Treatment with this neurotoxin decreased serotonin content by 90% and reduced [3H]citalopram binding to a similar extent. These results demonstrate that [3H]citalopram binding is a reliable marker for serotonin-containing terminals. Binding of [3H]imipramine was reduced by only 15-35% after 5,7-DHT treatment. These latter results suggest that only a small fraction of [3H]imipramine binding to brain sections is associated with serotonergic terminals under standard conditions used in autoradiographic studies with the ligand. Dose-response effects of fluoxetine and desipramine on displacement of [3H]imipramine binding in forebrain regions indicate that the ligand labels predominantly high capacity, low affinity binding sites. To determine the utility of the rat brain as a model for [3H]imipramine and [3H]citalopram binding in the human brain, binding of the ligands was compared in human and rat hypothalamus, amygdala, and hippocampus. The pharmacological characteristics of [3H]imipramine and [3H]citalopram binding were similar in the rat and human brain. However, substantial species differences were observed in topographic patterns of [3H]imipramine binding within the hippocampus and hypothalamus. The distribution of [3H]citalopram binding sites within the amygdala and hypothalamus were also strikingly different in rats compared to humans. This work provides the first demonstration that marked species differences exist in the topography of serotonergic innervation and in the distribution of [3H]imipramine binding sites within the rat and human brain regions examined.

5,7-Dihydroxytryptamine↗
PubMed1992

Beta-adrenergic receptor binding in human and rat hypothalamus.

Quantitative autoradiographic analysis of beta-adrenergic binding sites was conducted in human postmortem hypothalamus using the radioligand 125I-pindolol. The focus was on the hypothalamic nuclei most clearly involved in corticotropin-releasing hormone (CRH) release, the PVN and SON. For comparison, the distribution of hypothalamic beta-adrenergic receptors was evaluated in the rat. A high level of beta-adrenergic receptor binding was found in the human paraventricular nucleus (PVN) and supraoptic nucleus (SON), but not in the rat. The majority of the beta-adrenergic receptors found in the human hypothalamus were of the beta 2-subtype. In contrast, in the rat hypothalamus, the majority of receptors were of the beta 1-subtype. These results show that the anatomical loci exist for direct beta-adrenergic influence on hypothalamic neuroendocrine function in the human and that the topography of beta-adrenergic receptors is markedly different in the rat and human hypothalamus.

Adult↗
PubMed1991

Beta-adrenergic receptor distribution in human and rat hippocampal formation: marked species differences.

The topography of beta-adrenergic receptors in the rat and human hippocampal formation was assessed by in vitro binding of 125I-pindolol to tissue sections. Marked differences were found in the distribution of beta-adrenergic receptors and in the relative amounts of beta 1 and beta 2 receptor subtypes in the two species. In the human, the highest receptor densities were present in the pyramidal cell layer and in the stratum lacunosum-moleculare. In the rat hippocampus, those regions contained the lowest densities of 125I-pindolol binding sites. The highest densities of beta-adrenergic receptors in the rat hippocampal formation were found in the ventral subiculum and in the entorhinal cortex. In contrast, in the human hippocampus, the subiculum and entorhinal cortex contained relatively low densities of the receptors. Competition studies with beta 1- and beta 2-selective antagonists revealed that beta 2-adrenergic receptors predominate in the human hippocampus and beta 1-adrenergic receptors predominate in the rat hippocampus. The marked species differences observed suggest that the pharmacological responsivity of the hippocampus to adrenergic agents and the role of noradrenaline in regulation of hippocampal function could be very different in rats compared to humans.

Animals↗
PubMed1991

Dose-response studies with thyrotropin-releasing hormone (TRH) in abstinent male alcoholics: evidence for selective thyrotroph dysfunction?

A reduced thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) has been reported in subjects with a history of alcoholism whereas prolactin (PRL) responses have generally been normal. One hypothesis proposed to explain the reduced TSH response is down-regulation of pituitary TRH receptors. If this is correct, PRL response should also be diminished. To account for the different dose-response characteristics of TSH/PRL we have given four dosages of TRH (25, 100, 500 and 800 micrograms) to eight noncirrhotic, male alcoholics abstinent from ethanol a minimum of 28 days and to seven male control subjects. Across the TRH dose range the alcoholic subjects exhibited reduced basal TSH (p = .01) and a reduced TSH response (p = .0023) but no differences in basal and stimulated PRL levels. Alcoholic subjects had higher basal T4, T3 and FT4I values than did control subjects but covarying for T4, T3 and FT4I did not change the significance of either TSH or PRL findings. No significant differences in estradiol, estrone, testosterone, cortisol or glucose were noted between groups. The present study confirms the observation of a lower TSH response to TRH in abstinent alcoholics and indicates that the lower response cannot be overcome by increasing TRH dosage. The similar PRL response between groups suggests normal lactotroph function in noncirrhotic abstinent alcoholics and argues against the pituitary TRH receptor down-regulation hypothesis.

Adult↗
PubMed1990

Altered pineal serotonin binding in some suicides.

Serotonergic abnormalities have been regularly reported in the brains of suicide victims. Because of evidence that pineal function is altered in depressed subjects and that serotonin-releasing axons may innervate the pineal, we assayed tritiated serotonin binding in a series of control and suicide pineals. High affinity binding was present, and there were apparent differences between some suicides and controls.

Adult↗
PubMed1990

Increased detection of elevated TSH using immunoradiometric assay.

Using a highly sensitive immunoradiometric assay, the authors detected an increased rate of elevated thyrotropin in 2,099 patients vs 1,789 patients examined with radioimmunoassay. Closer scrutiny of mood disorder patients with elevations found confirmatory evidence of thyroid dysfunction in most.

Feeding and Eating Disorders↗