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J M Lakoski

Publications and source records attributed to J M Lakoski.

At least 19 recordsLinked to original sources
PubMed2001

Compensatory responses in the aging hippocampal serotonergic system following neurodegenerative injury with 5,7-dihydroxytryptamine.

This study utilized a multidisciplinary approach to examine injury-induced compensatory responses in the aging hippocampal serotonin transporter (5-HTT), a membrane protein implicated in a variety of neurodegenerative disorders. Age-dependent cellular, anatomical, and physiological changes of the 5-HTT were evaluated in female Fischer 344 rats (2 and 17 months) following denervation of the serotonergic afferents (fimbria-fornix and cingulum bundle) to the dorsal hippocampus using the neurotoxicant 5,7-dihydroxytryptamine (5,7-DHT). Seven days following 5,7-DHT administration, a uniform loss of the hippocampal 5-HTT immunoreactivity was observed in both age groups. However, at 21 days 5-HTT immunoreactivity in young 5,7-DHT-treated animals was similar to control levels, indicative of recovery, while older animals exposed to 5,7-DHT did not show recovery of hippocampal 5-HTT expression. 5-HTT binding site density, as determined by quantitative autoradiography ([3H]citalopram), supported the immunohistochemical results by demonstrating a recovery of 5-HTT binding sites in young, but not old animals, at 21 days following the lesion (P < 0.001). Furthermore, cellular electrophysiological function of hippocampal CA1 pyramidal neurons in 3- and 18-month-old F344 rats at 21 days following 5,7-DHT or vehicle treatment were assessed using in vivo microiontophoretic application of serotonin (5-HT). Independent of changes in sensitivity to the inhibitory effects of 5-HT application, the time to recovery of cell firing following application of 5-HT was significantly increased in the 18-month 5,7-DHT group compared to the 18-month vehicle and 3-month 5,7-DHT groups (60 and 59% increases, respectively; P < 0.05). Overall, these series of studies comprise a model which can be used to identify cellular events underlying both the formation of injury-induced compensatory processes in younger animals and the lack thereof with advancing age.

Afferent Pathways↗
PubMed2000

Regional heterogeneity of serotonin(1A) receptor inactivation and turnover in the aging female rat brain following EEDQ.

The turnover of serotonin(1A) (5-HT(1A)) receptors was investigated in several brain regions of young adult (3 months) and old (22 months) female Fischer 344 rats following irreversible inactivation by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). Equilibrium binding analyses for the 5-HT(1A) receptor binding site incorporated [(3)H]8-hydroxy-2-(di-N-propylamino)tetralin ([(3)H]8-OH-DPAT) and were conducted in the frontal cortex, amygdala and hippocampus at 1, 2, 7 and 14 days after treatment with EEDQ (6.0 mg/kg, s.c.) or vehicle. The pattern of 5-HT(1A) receptor recovery following EEDQ treatment was found to be age- and region-dependent. For example, in the hippocampus, receptor recovery occurred at a faster rate in the old rats compared to young adult rats. While a significant decrease in affinity for the 5-HT(1A) receptor was found in the frontal cortex and amygdala in young adult and old rats following EEDQ, B(MAX) values for [(3)H]8-OH-DPAT binding in these brain regions were unaltered by EEDQ across age groups. In the frontal cortex and amygdala, significant age-dependent decreases in affinity for the 5-HT(1A) receptor were revealed at day 1 following EEDQ administration. The significance of the present findings is discussed in terms of aging and a regionally-defined sensitivity of 5-HT(1A) receptors to the irreversible inactivator EEDQ.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1999

Corticosterone regulation of serotonin transporter and 5-HT1A receptor expression in the aging brain.

Hypercortisolemia is often observed in patients suffering from major depression. As the serotonergic (5-hydroxytryptamine; 5-HT) system plays a major role in the etiology of depression, a loss of endocrine and neurotransmitter system interactions, including corticosterone regulation of 5-HT transporter (5-HTT) and 5-HT receptor expression, may underlie age-related deficits in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis and correlate with an increased incidence of depression with advancing age. In this study, female Fischer 344 rats, ages 3, 13, and 18 months, were bilaterally adrenalectomized and supplemented for 3 weeks with corticosterone (0, 200, or 600 mg; LC, MC, or HC, respectively) containing 21 day sustained-release pellets implanted subcutaneously. Quantitative autoradiography of hippocampal and cortical regions using [3H]citalopram revealed a significant decrease in hippocampal 5-HTT binding in the 3-month HC treatment group compared to age-matched MC and LC groups; this loss was not present in the 13- or 18-month groups. Similarly, quantitative autoradiography using the radiolabeled 5-HT(1A) receptor agonist 8-hydroxy-2-(di-N-propylamino) tetralin demonstrated a significant decline in receptor density in 3- and 13-month MC and HC groups as compared to age-matched LC groups in the hippocampus. These hormone treatments (MC or HC), however, failed to alter hippocampal 5-HT(1A) binding site density in the 18-month groups as compared to the age-matched LC group. The 5-HT(2A) receptor was also evaluated using [3H]ketanserin and showed no age- or corticosterone-related changes in the cortex. Overall, an age-associated deficit in the regulation of the hippocampal serotonergic system by varied corticosterone treatment was revealed in the present study, which may underlie the increased incidence of depression and hypercortisolemia found with advancing age.

Adrenal Glands↗
PubMed1998

Age-dependent loss of corticosterone modulation of central serotonin 5-HT1A receptor binding sites.

A loss of endocrine and neurotransmitter system interactions, including corticosterone regulation of 5-HT1A receptors, may underlie the age-related deficits in the hypothalamic-pituitary-adrenal (HPA) axis including adapting to stress. In this study, female Fischer 344 rats, (ages 3, 13, and 18 months), were bilaterally adrenalectomized and supplemented for 3 weeks with placebo or corticosterone (200 mg or 600 mg) containing 21 day sustained-release pellets implanted subcutaneously (LC, MC, or HC, respectively). Scatchard analysis using the 5-HT1A receptor agonist [3H]8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT) demonstrated a significant decrease in hippocampal receptor density in 3 month and 13 month MC groups (-35.2 and -32.1%, respectively) as compared to age-matched LC groups; a significant decline in 5-HT1A receptor density in 3 month and 13 month HC groups was found compared to age-matched MC groups (-16.7 and -22.0%, respectively). However, these hormone treatments (LC or HC) failed to alter hippocampal 5-HT1A binding site density in the 18 month groups. Cortical 5-HT1A receptor densities were altered in a similar age-dependent manner. In contrast, the density of hypothalamic 5-HT1A receptors in the 18 month LC group was significantly increased above that in the 3 month LC group. An additional indicator of the hippocampal response to corticosterone, the distribution of glial fibrillary acidic protein (GFAP), revealed an age-related decline in responsiveness to hormone treatment in the oldest group. The present study has identified an age-associated deficit in the regulation of hippocampal 5-HT1A receptors by corticosterone which may underly the diminished capacity of the aging HPA axis to cope with stress.

Adrenalectomy↗
PubMed1998

Cellular electrophysiological effects of chronic fluoxetine and duloxetine administration on serotonergic responses in the aging hippocampus.

The pharmacological and physiological effects of chronic administration of the selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor (SSRI) fluoxetine and the dual 5-HT/norepinephrine (NE) reuptake inhibitor duloxetine were compared on 5-HT-mediated electrophysiological responses recorded in the hippocampus of young (3-5 months) and old (17-20 months) female Fischer 344 rats. Fluoxetine, duloxetine, or vehicle (saline) was administered once daily for 14 days (10 mg/kg, i.p.) and extracellular recordings of spontaneously firing CA1 and CA3 pyramidal neurons were conducted 24 h following the last injection using microiontophoretic drug application techniques in a chloral hydrate anesthetized preparation. The recovery times (RT50 values; sec) following 5-HT application on pyramidal neurons were significantly increased in the young and old chronic fluoxetine (FLX) treated groups (73% and 104%, respectively; P < 0.05), but not chronic duloxetine- (DLX) or vehicle- (VEH) treated groups. Following prolonged application of duloxetine (5-10 min), the 5-HT RT50 values were significantly increased in the young FLX groups as compared to the age-matched DLX- and VEH-treated groups. In contrast, a significant decline in the time to recovery produced by 5-HT (52%) was observed in the old vs. young FLX-treated group following the second co-application of 5-HT with duloxetine. Within each drug treatment and age group, co-application of duloxetine and 5-HT did not alter the inhibitory responses (IT50 values; nC) produced by the application of 5-HT alone. These results demonstrate cellular adaptive changes in serotonergic neuronal function occur following repeated exposure to 5-HT reuptake inhibitors in an age-dependent manner.

Aging↗
PubMed1998

Immunohistochemical localization and quantification of glial fibrillary acidic protein and synaptosomal-associated protein (mol. wt 25000) in the ageing hippocampus following administration of 5,7-dihydroxytryptamine.

Responses to injury in the ageing hippocampus were assessed utilizing the synaptic markers glial fibrillary acidic protein and synaptosomal-associated protein (mol. wt 25,000) following administration of the neurotoxin, 5,7-dihydroxytryptamine, into the fimbria-fornix and cingulum bundle to denervate serotonergic afferent input to the dorsal hippocampus. Age-dependent alterations in hippocampal immunohistochemical localization of glial fibrillary acidic protein and synaptosomal-associated protein were evaluated in female Fischer 344 rats following serotonergic deafferentation with 5,7-dihydroxytryptamine. Across the lifespan, as indicated by measurements taken at three, 18, 21 and 29 months, marked increases in glial fibrillary acidic protein, but not synaptosomal-associated protein immunoreactivity, occurred throughout the hippocampus at 21 and 29 months compared to three and 18 months. Following three weeks pretreatment with 5,7-dihydroxytryptamine (20 microg total dose) or vehicle (0.1% ascorbic saline; 2 microl total volume) infused in the fimbria-fornix/cingulum bundle, immunohistochemical analysis demonstrated marked increases of glial fibrillary acidic protein, but not synaptosomal-associated protein, in the 18-month 5,7-dihydroxytryptamine group compared to the 18-month vehicle and 3-month 5,7-dihydroxytryptamine groups. Additionally, a significant increase in glial fibrillary acidic protein concentration was found by enzyme-linked immunosorbent assay in the 18-month 5,7-dihydroxytryptamine group compared to the 18-month vehicle and three-month 5,7-dihydroxytryptamine groups. These results demonstrate that selective neurotoxicant damage of the hippocampal serotonergic system differentially alters the expression of glial fibrillary acidic protein. This approach may provide a valuable tool to determine the ability of the hippocampus to respond to age-related neurodegenerative injury.

5,7-Dihydroxytryptamine↗
PubMed1998

Expression of brain Gi protein in the aging F344 rat following exposure to corticosterone.

G protein expression has been shown to be modulated by circulating plasma corticosterone in young animals. A loss of G protein expression regulation by corticosterone in the elderly could explain declines in the function of G protein-coupled receptors and their effective signal transduction processes in the nervous system found in normal and pathological aging. In this study, adrenalectomized 3- and 18-months-old female Fischer 344 rats were exposed to low, moderate or high levels of plasma corticosterone to determine the effect of this hormone on Gi protein expression in the hippocampus and frontal cortex. Basal Gi protein expression, assessed by Western blot analysis, did not vary across age in either brain region. Hippocampal Gi protein levels increased following moderate and high corticosterone administration in the 3-months old animals (125%; P < 0.05) but not in the 18-months old animals. In contrast, in the frontal cortex, Gi protein expression increased significantly in the 18-months-old group (93%; P < 0.05) following exposure to high concentrations of corticosterone. These results suggest that steroid hormones, specifically corticosterone, may differentially modulate neurotransmitter-G protein coupling in an age-dependent manner.

Aging↗
PubMed1997

Electrophysiological effects of fluoxetine and duloxetine in the dorsal raphe nucleus and hippocampus.

The cellular electrophysiological effects of duloxetine (LY248686), a dual serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine reuptake inhibitor, and the selective serotonin reuptake inhibitor fluoxetine were compared on spontaneously active neurons in the dorsal raphe nucleus and the hippocampus of chloral hydrate-anesthetized male rat. Systemic intravenous administration of duloxetine or fluoxetine inhibited dorsal raphe nucleus cell firing in a dose-dependent manner; duloxetine suppressed cell firing at significantly lower doses (ED100 1.4 +/- 0.3 mg/kg) than fluoxetine (ED100 10.0 +/- 2.0 mg/kg). In the hippocampus, microiontophoretic application of duloxetine or fluoxetine (0.01 M, pH 5.5; 5-40 nA) produced minimal inhibition of cell firing. When duloxetine was co-applied with 5-HT, the recovery response (RT50 values) of hippocampal pyramidal neurons to 5-HT application was not altered. In contrast, co-application of fluoxetine with 5-HT at the same iontophoretic currents significantly increased (59%) the RT50 values produced by 5-HT application alone. This physiological and pharmacological study contributes to understanding the cellular mechanisms of these agents which may be useful in the treatment of depression.

Analysis of Variance↗
PubMed1997

Serotonergic function of aging hippocampal CA3 pyramidal neurons: electrophysiological assessment following administration of 5,7-dihydroxytryptamine in the fimbria-fornix and cingulum bundle.

Serotonergic (5-hydroxytryptamine; 5-HT) neurotransmission has been implicated in the regulation of cognitive function and this neurotransmitter system may underlie selective neuronal degeneration found in the aging hippocampus. Age-dependent changes in 5-HT function of hippocampal CA3 subfield pyramidal neurons were evaluated in female Fischer 344 rats (2 and 17 months) following denervation of the serotonergic afferents to the dorsal hippocampus using the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). Vehicle (ascorbic saline) or 5,7-DHT was administered bilaterally in the fimbria-fornix/cingulum bundle and dorsal pyramidal cell responses to microiontophoretic application of 5-HT, the 5-HT1A agonist (+/-)-8-hydroxy-2-(di-N-propylamino) tetralin, the 5-HT1A antagonist WAY 100,135 and N-methyl-D-aspartate were recorded at 3 weeks post-lesion. Independent of changes in sensitivity to the inhibitory effects of 5-HT with aging, the time to recovery of cell firing following application of 5-HT was significantly increased in the 18 months 5,7-DHT group compared to the 18 month Vehicle and 3 month 5,7-DHT groups (3.3- and 2.6-fold, respectively). These results demonstrate that serotonergic neurotransmission is altered with aging following a selective neurotoxic insult to the hippocampus.

5,7-Dihydroxytryptamine↗
PubMed1997

N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) administration for studies of 5-HT1A receptor binding site inactivation and turnover.

Alterations in the function of the neurotransmitter serotonin (5-HT) have been implicated in several neurobehavioral disorders, including depression, anxiety as well as a well-known disorder of aging, Alzheimer's disease. Age-dependent changes in the serotonergic system include a loss of 5-HT-containing fibers in brain areas which contain high levels of 5-HT1A receptors. Other changes with aging include decreased 5-HT levels, increases in monoamine oxidase (the major 5-HT degrading enzyme), and decreases in the density of 5-HT receptors. While age-related declines in the number of 5-HT1B and 5-HT2 receptors have been reported, little information is available describing the region-specific effects of aging on the functional dynamics of equilibrium binding at 5-HT receptors, including the 5-HT1A receptor subtype. For example, there are limited data showing a decrease in the maximal binding capacity (Bmax) of 5-HT1A receptors in the aging cortex of humans. However, changes in affinity (Kd) for this receptor subtype as a function of age and brain region have not been fully investigated. Other reports have failed to indicate age-related modifications in human and rat brain tissue 5-HT1A binding parameters. In contrast, electrophysiological studies suggest that the physiological function of the 5-HT1A receptor population is altered with aging. Therefore, to elucidate region-specific 5-HT1A receptor binding characteristics in aging rats, we have utilized a neurotoxic agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) to irreversibly inactivate 5-HT1A receptors. In this way, subsequent age-related changes that occur in 5-HT1A receptor binding characteristics may be investigated. EEDQ is an alkylating agent which irreversibly inactivates serotonergic receptors which are coupled to G proteins. This compound is appropriate for examining the binding profile of several 5-HT receptors, including the 5-HT1A receptor. The 5-HT1A binding site is among the most sensitive of the serotonergic receptor subtypes to inactivation by EEDQ and is also negatively coupled to adenylate cyclase via interaction with a Gi protein. Thus, EEDQ administration is a useful neurotoxicant to examine the relationship between aging and binding characteristics of 5-HT1A receptors. In addition, using EEDQ to inactivate 5-HT1A binding sites, we can further investigate the extent to which receptor binding characteristics (Bmax and Kd) return to baseline levels (i.e., recover) in an age- and brain region-dependent manner following a neurotoxic insult. That is, the age- and region-dependent recovery of 5-HT1A receptors may be monitored in a time-dependent manner to determine receptor turnover parameters, including receptor synthesis and degradation rate constants, and half-life values. Following receptor inactivation by EEDQ, 5-HT1A receptors repopulate (i.e., return to baseline levels) with time and exhibit region-specific turnover rates. Therefore, EEDQ administration is an effective pharmacological tool to investigate region-specific differences in 5-HT1A receptor turnover characteristics. Likewise, by utilizing this neurotoxicant the cellular mechanisms by which pharmacological agents interact with central 5-HT receptors and produce their effects in the aging brain can be addressed. We will illustrate the application of the neurotoxicant EEDQ to irreversibly inactivate 5-HT1A receptors. Following EEDQ administration, region-specific changes in 5-HT1A binding characteristics, including receptor density and drug affinity, and kinetics of receptor recovery will be demonstrated by Scatchard analyses and calculations of the recovery of these receptor populations illustrated. Based on the presence of high densities of 5-HT1A receptors in the hippocampus and frontal cortex, these brain regions will be studied for comparisons of both age- and region-specific alterations in receptor binding characteristics.

Aging↗
PubMed1997

Electrophysiological study of the effects of the reuptake inhibitor duloxetine on serotonergic responses in the aging hippocampus.

The pharmacological effects of the dual serotonin (5-hydroxy-tryptamine, 5-HT) and norepinephrine reuptake inhibitor, duloxetine, on serotonergic function in the aging hippocampus were studied using an in vivo chloral hydrate-anesthetized preparation in the female Fischer 344 rate across the life-span (3-8, 11-14, 18-22 and 24-27 months). Within each age group, duloxetine co-application did not alter the inhibitory responses (IT50 values) produced by the application of 5-HT alone. With continuous co-application of duloxetine (> or = 5 min), the recovery time (RT50 values) following 5-HT application did not change in the youngest ages, whereas in the 24- to 27-month-old group a significant increase in the time to recovery of baseline firing was found with co-application of duloxetine (68%; p < 0.05), followed by a return to baseline levels. These results contribute to identification of cellular mechanisms of duloxetine which may underlie its action as an antidepressant in the elderly.

Action Potentials↗
PubMed1996

Region-specific serotonin1A receptor turnover following irreversible blockade with EEDQ.

The neurotoxicant N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) irreversibly inactivates serotonin1A (5-HT1A) receptors and is a useful tool to investigate the kinetics of receptor recovery following administration of the drug. Recovery characteristics were determined for 5-HT1A receptors located in the frontal cortex and hippocampus of male Sprague-Dawley rats treated with EEDQ (6.0 mgth kg-1, s.c.) or vehicle. Saturation binding assays using [3H]8-OH-DPAT were conducted, using frontal cortex and hippocampal membrane homogenates, at several time points following EEDQ treatment (1, 2, and 8 days post-injection). Scatchard analyses revealed region-specific differences in the recovery of these receptors. 5-HT1A receptors in the hippocampus degraded more quickly but recovered faster than those in the frontal cortex; receptor half-life was also shorter in the hippocampus than in frontal cortex. These regional variations are discussed in terms of differential receptor synthesis. The pathophysiological relevance of these findings to aging and disorders involving 5-HT1A receptor dysfunction, including depression and anxiety, is discussed.

Animals↗
PubMed1996

Age-related assessment of central 5-HT1A receptors following irreversible inactivation by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ).

Age-dependent differences in the ability of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) to irreversibly inactivate 5-HT1A receptors were investigated in female Fischer 344 rats (ages 3 and 22 months). In the hippocampus, frontal cortex and amygdala, EEDQ reduced 5-HT1A receptor density (33-70%) and drug affinity (2.3-6.2 fold) as determined by Scatchard analyses using [3H]8-hydroxy-2-(di-N-propylamino)tetralin. In the frontal cortex, the reduction in Bmax values was significantly greater in 3 months vs. 22 months groups. These region-specific and age-dependent alterations in 5-HT1A receptors may be of pathophysiological significance in age-related cognitive decline and Alzheimer's disease.

Aging↗
PubMed1996

Identification of central 5-HT and 5-HT1A receptors in the turtle brain (Chrysemys picta).

Radiologand binding studies were undertaken in the turtle whole brain, cerebellum and raphe using the selective radioligands [3H]5-hydroxytryptamine trifluoroacetate ([3H]5-HT) amd [3H]+/-8-hydroxy-2-(di-N-propylamino) tetralin hydrobromide ([3H]DPAT) to identify serotonin (5-HT) receptors and the specific 5-HT1A receptor subtype. Scatchard analysis identified a nanomolar affinity binding site for [3H]5-HT (12 nM) in turtle whole brain assays. A low affinity 5-HT1A site (102 nM) was also identified in turtle whole brain assays, with a higher affinity site noted in binding studies performed with tissue from the inferior raphe (20 nM). The difference in affinity for 5-HT receptors in reptilian versus mammalian brain may prove characteristic of lower vertebrate brains with implications for the physiologic effects of this neurotransmitter in the central nervous system.

Animals↗
PubMed1991

Acute, but not repeated, cocaine administration decreases renin secretion in the conscious male rat.

The effects of cocaine on renin secretion have been addressed and a previously unreported inhibitory effect has been identified on this neuroendocrine system in the conscious male rat. Acute intraperitoneal administration of cocaine dose-dependently (1.5, 7.5, 15, and 30 mg/kg; at 15 min) produced a significant decrease in both plasma renin activity (PRA) and plasma renin concentration (PRC). The time course of inhibition by cocaine in PRA and PRC revealed maximal effects at 15 min following a 15 mg/kg dose. In contrast, the long term administration of cocaine for 1, 7, or 30 days (15 mg/kg, twice daily, i.p.) did not produce changes in PRC.

Animals↗
PubMed1990

The ontogeny of [3H]5-hydroxytryptamine binding in the lamb: effects of in vivo thyroidectomy.

The effects of congenital hypothyroidism in the late gestation ovine fetus include changes in serotonin concentrations in specific brain areas. To investigate possible ontogenic patterns of changes in 5-HT receptor function, we studied the binding characteristics of [3H]5-HT in the midbrain, hypothalamus and cerebral cortex in the late gestation ovine fetus and young lamb. We compared the binding characteristics of control fetuses to those of thyroidectomized fetuses, with or without thyroxine replacement therapy. In each of the areas examined, age-dependent changes in the receptor density (Bmax) for [3H]5-HT was observed. In cerebral cortex, Bmax was constant from 120 days gestation through the early neonatal period and increased significantly only at 25-30 days after birth. In hypothalamus, [3H]5-HT binding density decreased late in gestation (140-145 days) with a return after birth to values comparable to those at 120-125 and 130-135 days gestation. The midbrain also exhibited a significant age-dependent pattern of altered receptor density with a decrease in the 130-135 and 140-145 day gestational age groups compared to both younger and older lambs. In contrast, the affinity constant (Kd) for [3H]5-HT did not change over the ages evaluated in cerebral cortex or hypothalamus. In the midbrain, however, there was a significant increase in Kd at 1-5 days after birth compared to all other age groups. The ability of fetal thyroidectomy, with or without thyroxine replacement therapy, to alter patterns of [3H]5-HT binding was also tested.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗