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Biomedical subjects

G A Gerhardt

Publications and source records attributed to G A Gerhardt.

At least 127 records · Page 7Linked to original sources
PubMed1988

In vivo electrochemical studies of the effects of cocaine on dopamine nerve terminals in the rat neostriatum.

In vivo electrochemical measurements, involving chronoamperometric recordings using monoamine-selective Nafion-coated electrodes, were used to study the effects of locally applied cocaine (50-500 micromolar barrel concentrations) on dopamine (DA) nerve terminals in the neostriatum of the anaesthetized rat. Local application of cocaine did not elicit detectable increases in basal levels of extracellular DA. However, locally applied cocaine significantly augmented the concentration of DA detected following a potassium (K+)-evoked depolarization. Data obtained with a new high-speed chronoamperometric recording technique further support that DA is the predominant species detected electrochemically following potassium-evoked depolarizations both before and after local application of cocaine. Unlike other locally applied uptake inhibitors that we have studied, cocaine failed to augment the time dynamics of released DA. In addition, large doses of the highest concentration of cocaine caused an attenuation of K+-evoked DA release, presumably due to cocaine's local anaesthetic properties. These data suggest that cocaine elevates synaptic levels of DA, but in a manner that is not identical to other potent monoamine uptake inhibitors.

Animals↗
PubMed1987

Age-related changes in cerebellar noradrenergic pre- and postsynaptic mechanisms: intrinsic vs extrinsic determinants evaluated with brain grafts in oculo.

Intrinsic versus extrinsic determinants of changes in cerebellar noradrenergic transmission during senescence in the rat were measured using homologous cerebellar grafts in oculo. Postsynaptic sensitivity of Purkinje neurons to catecholamines was determined by perfusing the anterior eye chamber with known concentrations of norepinephrine (NE) dissolved in a balanced salt solution. NE elicited a dose-dependent slowing of spontaneous Purkinje neuron discharge in both young (3-6 months) and aged (20-22 months) cerebellar grafts. Hill plots demonstrated that the dose-response relationships in both age-groups were linear and parallel to one another. Aged transplant Purkinje neurons manifested a marked and highly significant subsensitivity to NE with an EC50 of 583 microM, as compared with an EC50 of only 15.9 microM in the young grafts. Young grafts in 15-21-month-old hosts manifested an EC50 of 20 microM for the depressant actions of NE. Collaterals of host iris sympathetic fibers innervate the grafts. Activity of these fibers can be reflexly altered by changing illumination of the retina. The dynamics of presynaptic NE release from these fibers was evaluated using in vivo electrochemistry with Nafion-coated graphite epoxy capillary electrodes, which are highly selective for the monoamine neurotransmitters. As illumination of the ipsilateral retina is increased, the release of catecholamine in the cerebellar graft decreases. A mean change in the extracellular electroactive species of 4.2 +/- 0.6 microM was found in young cerebellar grafts. Equivalent stimuli induced a mean change of 2.3 +/- 0.8 microM in aged grafts. However, this diminished release was not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1987

In vivo electrochemical demonstration of potassium-evoked monoamine release from rat cerebellum.

In vivo electrochemical methods were employed to study the potassium (K+)-evoked release of monoamines from the cerebellum of the chloral hydrate anesthetized rat. K+-evoked releases were elicited using micropipette-Nafion-coated graphite epoxy electrode arrays in the granule/Purkinje cell layer, molecular layer, and white matter. These recorded releases were generally found to be reversible, moderately dose-dependent, and reproducible. However, the temporal dynamics of the releases were different for the cell layer versus molecular layer records. Releases were infrequently observed in cerebellar white matter, an area which is relatively devoid of monoamine containing terminals. The signals recorded from the cell and molecular layers were significantly attenuated by pretreatment with the selective noradrenergic neurotoxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4). Local pretreatment with nomifensine, a potent catecholamine reuptake blocker, significantly prolonged the K+-evoked signals observed in both the granule/Purkinje cell and molecular layers. These data, taken together with earlier reports on the electrophysiological responses to activation of cerebellar noradrenergic inputs, support the conjecture that in vivo electrochemical recording methods have the sensitivity and spatial resolution for studies of functional monoamine release from brain regions that have a diffuse or laminated monoamine innervation.

Action Potentials↗
PubMed1987

Characterization of the techniques of pressure ejection and microiontophoresis using in vivo electrochemistry.

Catecholamine levels in frontal cortex were determined in vivo by electrochemical detection after the local application of dopamine (DA) from multibarrel micropipettes by pressure ejection or microiontophoresis. Tissue DA levels were linearly related to microapplication doses with either technique and reached steady state with longer application times. Furthermore, the plateau DA tissue concentrations were clearly related to ejection pressure or iontophoretic current. Using either microapplication technique, the tissue DA levels decreased as distance between the recording electrode and the tip of the drug pipette increased. However, pressure ejected and iontophoretically applied drug differed in their concentration versus time dynamics. Thus, although similar tissue concentrations of drug can be generated by the two techniques, the time dynamics of the drug effects may not be comparable. The quantitative use of these drug application techniques requires a minimal amount of variance in release between pipettes in order to effectively measure small sensitivity differences. Although the 10-fold variance with microiontophoresis does not appear resolvable at present, improved pipette construction techniques permit the variability in dosage to be limited to a maximum of 3-fold with pressure ejection. In addition, the present data also suggest that this variance can be further minimized by holding either ejection duration or ejection pressure constant when establishing dose-response relationships.

Animals↗
PubMed1987

Neurobiological studies of sensory gating in schizophrenia.

The sensory disturbance in schizophrenia is often described as an inability to filter out extraneous noise from meaningful sensory inputs. The neurobiological basis of this inability to filter has been examined using auditory evoked potentials, which are computerized averages of the brain's electrical response to sound. The sounds are presented in pairs to test the ability of the brain to inhibit, or gate, its response to a repeated stimulus. Schizophrenic patients lack the ability to gate the neuronal response shown by a particular wave, the P50 wave. The measurement of this deficit in human subjects and the exploration of its neurobiology in animals has produced evidence about several issues in the pathophysiology of schizophrenia: (1) the role of dopamine in improvement of sensory function in schizophrenic patients treated with neuroleptic drugs, (2) the interaction between familial or genetic deficits in sensory functioning in schizophrenic patients and possible abnormalities in dopamine metabolism, and (3) a mechanism by which noradrenergic hyperactivity in mania and other psychiatric illnesses might mimic some pathophysiological deficits in schizophrenia.

Antipsychotic Agents↗
PubMed1987

Effect of chronic nicotine administration on monoamine and monoamine metabolite concentrations in rat brain.

The effects on rat brain tissue monoamine and monoamine metabolite concentrations of chronic nicotine administration at two doses (3 and 12 mg/kg/day) using constant infusion were studied. After 21 days of treatment, tissue concentrations of dopamine (DA), norepinephrine (NE), 5-hydroxytryptamine (5-HT), and several metabolites in striatum, hypothalamus, and frontal cortex were determined by high performance liquid chromatography with electrochemical detection. Compared with a control group, nicotine treatment significantly decreased NE in frontal cortex but not in other regions. The concentration of 5HT also was decreased in frontal cortex but increased in the hypothalamus at the higher dose of nicotine. The 5HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) was not significantly altered in any region. The 5HT index (5-HIAA/5-HT) was significantly decreased in the hypothalamus and increased in frontal cortex at the higher dose. Concentrations of DA and the metabolite homovanillic acid (HVA) were not significantly altered by nicotine. Nevertheless, significant decreases in the DA metabolite dihydroxyphenyl-acetic acid (DOPAC) were observed in both striatum and hypothalamus. Moreover, the DA index [(DOPAC + HVA)/DA] was significantly decreased in all three brain regions. In contrast to other studies using acute dose and in vitro perfusion paradigms that have reported increased CNS catecholamine release stimulated by nicotine, chronic administration appears to be associated with decreased catecholamine turnover in some brain regions.

Animals↗
PubMed1987

In vivo electrochemical demonstration of the presynaptic actions of phencyclidine in rat caudate nucleus.

In vivo electrochemical recordings, coupled with local application of drugs from micropipettes, were used to determine the presynaptic effects of phencyclidine (PCP) on dopamine-containing nerve terminals in the intact rat striatum. Local application of PCP did not elicit an observable increase in extracellular levels of the monoamine neurotransmitters. However, pretreatment with PCP significantly potentiated the potassium-evoked release of monoamines. Nomifensine, a potent catecholamine reuptake blocker, produced effects that were analogous with PCP. Local pretreatment with PCP was also found to potentiate the electrochemical signal detected after pressure ejection of dopamine directly into the caudate nucleus. Finally, electrophysiological studies showed that locally applied PCP and nomifensine solutions had similar potencies in depressing the spontaneous firing of striatal neurons. Taken together, these data suggest that the major presynaptic action of PCP in the rat caudate nucleus is inhibition of the reuptake, and not alteration of release, of the monoamine neurotransmitters.

Animals↗
PubMed1986

Release of monoamines from striatum of rat and mouse evoked by local application of potassium: evaluation of a new in vivo electrochemical technique.

Local application of K+ via micropressure-ejection, coupled with in vivo electrochemical detection, was used to study stimulated release from monoaminergic nerve terminals in the striatum of anesthetized rats and mice. K+-evoked releases were reversible, reproducible, and dose-dependent. In contrast, releases of electroactive species could not be evoked by local ejection of Na+. The magnitudes and time courses of K+-evoked releases recorded from the caudate nucleus of mice were greater than those seen in rats. Local application of nomifensine, a putative catecholamine reuptake blocker, augmented the magnitudes and time courses of K+-evoked releases. Releases were also recorded from brain regions adjacent the striatum; these signals were always smaller than those seen in the caudate nucleus and had amplitudes that showed good correspondence to the relative degree of dopaminergic input to these areas. These data, taken together with other information in the literature, suggest that this new technique is well suited for in situ studies of monoamine release and reuptake in intact animals.

Amines↗
PubMed1985

Diffusion coefficients of neurotransmitters and their metabolites in brain extracellular fluid space.

Diffusion coefficients of catecholamine neurotransmitters, their metabolites and related species was measured in brain extracellular fluid using in vivo voltammetric techniques. Nanoliter volumes of the species were pressure-ejected into the rat caudate nucleus and their concentration profiles were determined at nearby voltammetric detector electrodes. Thorough testing was carried out to show that the present methodology gave results which agreed with brain diffusion coefficients measured previously by ion-selective microelectrode techniques. All of the species which are anionic at pH 7.4 have brain diffusion coefficients about one-third of their solution counterparts in accord with earlier studies of diffusion in tortuous media. However, the brain diffusion coefficients of all the cation species are about three-times slower than those of the anions. This phenomenon is believed to be caused by ion binding with the polyanionic glycosaminoglycans and related species in brain tissue. In vitro model experiments lend support to this interpretation. This new information on biogenic amines and their metabolites provides meaningful predictions of the spatio-temporal concentration distribution of these species in the extracellular fluid.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1984

Adrenergic transmission in hippocampus-locus coeruleus double grafts in oculo: demonstration by in vivo electrochemical detection.

In vivo electrochemical detection was used to study transmitter release from a synaptically or pharmacologically stimulated noradrenergic isolated pathway formed by double in oculo brain tissue grafts. Retinal illumination, which activates cholinergic nerve fibers that grow into intraocular grafts from the autonomic ground plexus of the iris, produced increases in the concentration of electroactive species in the hippocampal portion of intraocular locus coeruleus-hippocampus double grafts. This response was potentiated after cholinesterase inhibition, and mimicked by perfusion of carbachol, a muscarinic agonist. Much smaller increases in the electroactive species were measured in reserpinized animals, and this minimal response was completely eliminated by the subsequent inhibition of catecholamine synthesis with alpha-methyl-p-tyrosine. Taken together, the data suggest that synaptically released transmitter in these isolated brain circuits can be measured using in vivo electrochemical detection techniques, and lend further support to the hypothesis that in oculo locus coeruleus grafts develop a functional catecholaminergic input to sequentially grafted hippocampus.

Animals↗
PubMed1984

Nafion-coated electrodes with high selectivity for CNS electrochemistry.

A major improvement in the selectivity of small graphite electrodes used for in vivo electrochemistry is described. The electrodes are coated with Nafion, a perfluorosulfonated polymer. This coating is practically impermeable to ascorbic acid and anionic biogenic amine metabolites and only slightly responsive to neutral metabolites. Thus it becomes selective for the cationic primary neurotransmitters, dopamine, norepinephrine and 5-hydroxytryptamine. Responses of Nafion-coated and untreated electrodes in vivo are compared.

Animals↗
PubMed1984

Brain catecholamine content during the estrous cycle and in steroid-primed rats.

Norepinephrine (NE) and dopamine (DA) levels were measured in several estrogen concentrating brain regions over the estrous cycle and in steroid-primed ovariectomized rats under experimental conditions used to study sexual receptivity. Norepinephrine content in the ventromedial hypothalamus (VMH), lateral septum (LS) and medial preoptic area (POA) varied during the estrous cycle. The highest NE levels were found during metestrus in these brain regions. In the ovariectomized rat, NE levels were increased in the POA and LS 12 hours (hr) after the injection of 3 micrograms of estradiol benzoate (65% and 33%, respectively). Norepinephrine content in the POA and LS remained elevated 24 hr and 48 hr (0.5 mg progesterone at 42 hr) after treatment but were not different from control levels at 96 hr. Dopamine concentrations were not significantly altered over the estrous cycle or by the administration of estradiol benzoate in any of the brain regions studied. These results suggest that estrogen may selectively alter noradrenergic activity in brain regions that are implicated in the control of sexual receptivity and/or ovulation.

Amygdala↗
PubMedDate not supplied

Age-related alterations in monoamine release from rat striatum: an in vivo electrochemical study.

In vivo electrochemistry was used to examine presynaptic alterations in dopamine release in the striatum of aged rats. Chronoamperometric determinations of monoamine release, induced by local micro pressure-ejection of K+, were made using Nafion-coated graphite epoxy electrodes. Recordings were made from the striatum of urethane-anesthetized Fischer 344 rats at 6, 24, and greater than or equal to 29 months of age. Following the in vivo electrochemical experiments, the animals were sacrificed and the caudate nucleus removed for analysis of whole tissue levels of monoamines and their metabolites using standard HPLC techniques. Overall, mean amplitudes of K+-evoked releases from the striatum of 6 month and 24 month F344 rats did not differ significantly (p greater than 0.1). However, this result was complicated by the observation that the mean values obtained from two separate groups of 24 month animals, recorded 6 months apart, were significantly different from each other (p less than 0.001). Mean releases for the later 24 month group were significantly less than for the 6 month group (p less than 0.01). No difference was found in the release magnitudes of 6 month animals recorded contemporaneously with the two groups of 24 month rats. Release amplitudes for the greater than or equal to 29 month group were clearly less than from the 6 month animals (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMedDate not supplied

Age-induced changes in single locus coeruleus brain transplants grown in oculo: an in vivo electrochemical study.

Brain stem tissue from fetal Sprague-Dawley rats containing the nucleus locus coeruleus (LC) was transplanted into the anterior chamber of the eye of young adult host rats and was studied at 4-6 months (young control) or 24-28 months after grafting (old). High-speed in vivo electrochemical measurements were used to characterize the potassium-evoked synaptic overflow of norepinephrine (NE) in both young and aged LC brain grafts. The amplitudes of potassium-evoked NE overflow were attenuated in the aged grafts as compared to the young LC grafts. In addition, the rise times of potassium-evoked responses were longer in the old LC grafts than in the young transplants. In contrast, the NE content of aged LC grafts, as determined by high-performance liquid chromatography coupled with electrochemical detection (HPLC-EC), was only slightly diminished and not significantly different from the NE levels seen in young LC grafts. However, light microscopical evaluation using tyrosine-hydroxylase immunocytochemistry revealed pyknotic cell bodies and fluorescent accumulations in aged locus coeruleus transplants which were indicative of degeneration in these grafts. The present data demonstrate a significant age-related decline in the presynaptic function of NE-containing neurons in intraocular locus coeruleus transplants of Sprague-Dawley rats.

Aging↗
PubMedDate not supplied

Regional effects of aging on dopaminergic function in the Fischer-344 rat.

To examine the consequences of aging on nigrostriatal (A9) and mesolimbic (A10) dopamine (DA) function, neurochemical and behavioral measurements were performed in male Fischer-344 rats 6, 12, 18, 24, and 30 months old. Regional analyses of dopaminergic overflow and uptake processes were examined using high-speed (5 Hz) in vivo electrochemical recordings and local drug application techniques. When potassium was used to elicit the presynaptic overflow of dopamine (DA) in striatal areas predominantly innervated by the substantia nigra, the amplitude of DA overflow was significantly lower in 24- and 30-month-old rats (p less than 0.05 and p less than 0.01 vs. 6 months, respectively). Furthermore, in ventral striatum (including the nucleus accumbens) which is innervated primarily by A10 DA cell bodies, potassium-evoked DA overflow release amplitudes were significantly lower in the 18, 24, and 30 month groups (p less than 0.01 vs. 6 months). In addition, age-related differences between the dorsal and ventral striatum were found in a preliminary investigation of DA diffusion and clearance. Local application of nomifensine, a DA uptake inhibitor, significantly increased (p less than 0.05 vs. control) the amplitude of the signal recorded after local application of 25-30 pmol DA in the ventral striatum of 6 month-old but not 24-month-old rats. High-performance liquid chromatography coupled with electrochemical detection (HPLC-EC) was used to analyze whole striatal DA levels, DA metabolite levels and turnover indices. However, no age-related differences in any of these variables were observed. Finally, a rod walking test was used to measure motor coordination and balance in animals prior to in vivo electrochemical recording.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMedDate not supplied

Impaired acquisition of novel locomotor tasks in aged and norepinephrine-depleted F344 rats.

Performance of rats on a motor learning paradigm that has been demonstrated to be dependent upon cerebellar norepinephrine (NE) was studied in 20-month-old F344 rats. The behavioral task is identical to that described by Watson and McElligott: Rats are trained on a runway consisting of aluminum pegs arranged in a regular pattern. Rats receive a water reward at either end of the runway. Subsequent to training, rats are tested for running times on a runway with irregularly spaced rods. The ability of rats to improve their performance (decrease their running times) on this novel motor task is diminished in young rats that have received 6-hydroxydopamine lesions. Rats at 20 months of age are known to have deficits in cerebellar noradrenergic transmission; thus, the hypothesis to be tested was to determine if aged rats demonstrated performance deficits similar to young rats depleted of central stores of NE. The rate of acquisition of the task was determined by the decrease in running times with successive days of training. The ability of 20-month-old F344 rats to acquire proficiency on the novel motor task was impaired and the rate of acquisition of the novel motor task was not different from the young 6-hydroxydopamine-lesioned rats. In an attempt to distinguish between alterations in motor coordination and motor learning, additional tests of psychomotor performance were assessed for all groups of rats. These tests included a walking on 2.5- and 5-cm rods, speed of running on the motor task, and number and types of mistakes made on the motor learning task.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗