Biomedical subjects

G A Gerhardt

Publications and source records attributed to G A Gerhardt.

135 records · Page 8Linked to original sources

PubMedDate not supplied

Age-related changes in potassium-evoked overflow of dopamine in the striatum of the rhesus monkey.

Rapid (5 Hz) chronoamperometric recordings using Nafion-coated carbon fiber electrodes (30-90 microns o.d.) combined with pressure-ejection of potassium from micropipettes were used to investigate potassium-evoked overflow of dopamine (DA) in the striatum of young (5 to 10 years old) and middle-aged (19 to 23 years old) anesthetized rhesus monkeys. The potassium-evoked DA-like signals from the 19- to 23-year-old animals were significantly lower in amplitude than those recorded in the young animals. In addition, the temporal dynamics of DA signals in the caudate nucleus of middle-aged animals were faster, while the time courses of the signals recorded in the putamen of middle-aged monkeys were significantly longer as compared to the signals recorded from young animals. Moreover, home cage activity levels of the middle-aged animals were significantly lower. Taken together, these data support age-related changes in the output of DA from DA fibers in the striatum of middle-aged monkeys.

Age Factors↗

PubMedDate not supplied

Nomifensine reveals age-related changes in K(+)-evoked striatal DA overflow in F344 rats.

To investigate the influence of age-associated changes in DA uptake on measures of potassium-stimulated DA overflow in the striatum, microdialysis was conducted in anesthetized young (6-month-old) versus aged (24-month-old) F344 rats. Extracellular levels of DA, DOPAC, and HVA were measured under basal and potassium-stimulated (10, 25, 50, & 100 mM) conditions. Basal levels of DA and metabolites did not differ significantly between the two age groups. At the 50 and 100 mM concentrations, potassium stimuli significantly increased DA overflow and decreased DOPAC and HVA--effects that did not differ with age. The addition of the DA uptake inhibitor nomifensine (100 microM) to the perfusion solutions revealed differences between the two age groups. Nomifensine augmented potassium-evoked DA overflow at the 50 mM concentration in both groups, but only amplified the effect of the 100 mM concentration in the young animals. The results demonstrate that decreased DA transporter function in aged rats masks age-related differences in K(+)-evoked striatal DA release when microdialysis methods are used, resulting in net equalization of K(+)-evoked striatal DA overflow in young versus aged F344 rats.

3,4-Dihydroxyphenylacetic Acid↗

PubMedDate not supplied

Age-related changes in striatal function of freely-moving F344 rats.

Multi-wire electrode arrays were used to record extracellular electrophysiological activity in striatal medium spiny-like neurons of freely-moving young (6-8 months) and aged (24-26 months) Fischer 344 rats. While overall basal firing rates did not differ between the two groups, d-amphetamine (5.0 mg/kg) increased firing rates more in the young rats. D-Amphetamine had heterogeneous effects on firing rates, however, exciting 63% of the neurons while inhibiting 37%. Neurons were classified according to their response to d-amphetamine (excited vs. inhibited) to examine age-related differences in firing rates and bursting activity. In the d-amphetamine-excited neurons, pre-drug intraburst firing rates were higher in the old rats. This effect was reversed by d-amphetamine. D-Amphetamine increased the percentage of spikes within bursts to a greater extent in the aged animals and decreased burst durations greater in the young group. In d-amphetamine-inhibited neurons, firing rates were diminished in the old rats more than they were in the young rats. These results demonstrate age-related alterations in striatal electrophysiological activity that may help explain motor deficits seen in senescence.

Action Potentials↗

PubMedDate not supplied

Cerebellar noradrenergic systems in aging: studies in situ and in in oculo grafts.

Age-related changes in noradrenergic function in the rat cerebellum were examined using electrophysiological and electrochemical techniques. Sprague-Dawley and Fischer 344 rats showed subsensitivity to norepinephrine (NE) locally applied onto cerebellar Purkinje neurons. The modulatory actions of NE on Purkinje cell-evoked activity was also examined. In young rats NE preferentially inhibits spontaneous activity more than evoked excitations when compared to control. These modulatory actions of NE are not seen in senescent Fischer 344 rats. The intrinsic vs. extrinsic influences determining the loss of efficacy to NE were examined using three groups of rats with in oculo cerebellar grafts. The first group had young grafts grown in young hosts and these grafts showed a potent response to perfused NE. The second group, old grafts in old hosts, showed a diminished responsiveness to NE with respect to the first group. The third group consisted of young grafts in old hosts. These grafts demonstrated a responsiveness to NE that was indistinguishable from those in the first group. The integrity of the presynaptic NE fibers was examined in the grafts using electrochemical techniques. No difference in the release of NE was observed in the old grafts. Taken together, these results suggest a loss of postsynaptic NE function that is intrinsically determined. The change in NE modulation could influence information processing within the aged cerebellar cortex. This deficit could underlie behavioral changes seen in senescence.

Action Potentials↗

PubMedDate not supplied

Long-term treatment of male F344 rats with deprenyl: assessment of effects on longevity, behavior, and brain function.

L-Deprenyl (selegiline) was chronically administered to male Fischer 344 rats via their drinking water beginning at 54 weeks of age (estimated daily dose: 0.5 mg/kg/day). Beginning at 84 weeks of age, the rats were behaviorally evaluated using a sensorimotor battery, a motor-learning task, and the Morris water maze. At 118 weeks of age, cerebellar noradrenergic function was evaluated in the surviving rats using in vivo electrochemistry. The rats were then sacrificed to measure brain monoamine oxidase activity and perform quantitative autoradiography to evaluate the effect of chronic deprenyl treatment on beta-adrenergic receptors in the cerebellum, alpha 2-adrenergic receptors several brain regions, and D1 and D2 dopamine receptors in the striatum. Deprenyl treatment reduced brain monoamine oxidase B activity by 85%, but had no effect on brain monoamine oxidase A. A clear effect of chronic deprenyl treatment upon longevity was not observed. Several measures of CNS function were altered in the deprenyl-treated animals: 1) spatial learning in the Morris water maze was improved; 2) electrochemical signals recorded following local application of NE were reduced, and the responsiveness to the reuptake blocker nomifensine was enhanced, in the cerebellum; 3) beta-adrenergic receptor binding affinity was increased in the cerebellum; 4) alpha 2-adrenergic receptor density was increased in the inferior colliculus; and 5) striatal D1 dopamine receptor density was reduced but binding affinity was enhanced. In contrast, chronic deprenyl treatment did not cause changes in: 1) sensorimotor function, as evaluated by balance beam, inclined screen, or wire hang tasks; 2) motor learning; 3) alpha 2-adrenergic receptor density in any region examined except for the inferior colliculus, or binding affinity in any region examined; or 4) striatal D2 dopamine receptor number or affinity. Thus, long-term oral administration of deprenyl extended the functional life span of rats with respect to cognitive, but not motor, performance.

Animals↗

PubMedDate not supplied

In vivo microdialysis studies of age-related alterations in potassium-evoked overflow of dopamine in the dorsal striatum of Fischer 344 rats.

Intracerebral microdialysis was used to measure basal levels and potassium (K(+))-stimulated overflow of dopamine (DA), homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC), in the dorsal striatum of young (6 months) and aged (24 months) Fischer 344 (F344) rats. Basal levels of HVA were lower in aged rats whereas basal DA and DOPAC did not differ significantly between the two groups. The administration of three low to moderate doses of K(+) (10, 25, and 50 mM) through the microdialysis probe for one collection period revealed differences between the two age groups of F344 rats. DA overflow increased in a dose-dependent manner in the young but not aged rats. Extracellular levels of DOPAC and HVA decreased during the K(+) stimulation and there was a significant difference in the changes in HVA produced by K(+) stimulation in the young vs aged animals. These data support the hypothesis that low to moderate doses of K(+) may be necessary to demonstrate age-related differences in K(+)-evoked DA overflow, since previous microdialysis studies using higher doses have not reported age-related differences in DA overflow.

3,4-Dihydroxyphenylacetic Acid↗

PubMedDate not supplied

The effects of local application of ethanol in the n. accumbens on dopamine overflow and clearance.

The actions of ethanol on extracellular dopamine levels in the n. accumbens were examined in both anesthetized and unanesthetized rats using either in vivo voltammetry or microdialysis. In the voltammetry studies, ethanol was microinjected directly into the accumbens. For the microdialysis studies, the ethanol was injected systemically. The voltammetry studies failed to find any direct effect of local ethanol on extracellular dopamine levels. However, exposure to high ethanol concentrations directly injected into the n. accumbens showed the rise rate and the return to baseline rate to a n. accumbens KCl-stimulated dopamine release. In the microdialysis studies, increased levels of extracellular dopamine in the n. accumbens were found in unanesthetized rats, similar to those reported in the literature. However, in the anesthetized rats, the extracellular dopamine levels were not increased, even with similar local ethanol levels measured in the dialysate. Taken together, the data suggest that the actions of ethanol to increase extracellular dopamine levels in the n. accumbens are most likely not an effect of ethanol at the level of the accumbens but rather an action which increases neural activity within the mesoaccumbens pathway, perhaps via actions at the ventral tegmental area.

Anesthesia↗

PubMedDate not supplied

Effects of ethanol on striatal dopamine overflow and clearance: an in vivo electrochemical study.

Previous studies have shown that the neurotransmitter dopamine (DA) is implicated in the reinforcing effects of ethanol and other abused drugs. Ethanol also alters DA overflow and uptake in vivo. Further studies of the role of DA in the behavioral and neurochemical effects of ethanol may help explain the pharmacological mechanisms by which these effects are produced. In these studies we used in vivo electrochemical recordings to investigate the effects of ethanol (EtOH) on the dynamics of evoked DA overflow and DA uptake in rat dorsal striatum. Local applications of EtOH from a multibarrel micropipette did not produce detectable changes in extracellular levels of endogenous DA in the dorsal striatum. EtOH application did attenuate potassium (K+)-evoked overflow of DA in a time-dependent fashion. In contrast, tyramine-induced DA overflow, a calcium-independent process thought to be carrier mediated, was not altered by local EtOH application in the dorsal striatum. Striatal uptake of locally applied exogenous DA was decreased by nomifensine, an effect that was attenuated by locally applied EtOH. Taken together, these data suggest that one of the effects of EtOH on DA-containing nerve endings in the rat striatum involves functional changes in the high-affinity DA transporter associated with these nerve endings.

Adrenergic alpha-Agonists↗

PubMedDate not supplied

Kidney cografts enhance fiber outgrowth from ventral mesencephalic grafts to the 6-OHDA-lesioned striatum, and improve behavioral recovery.

Recent studies have demonstrated the presence of many different neurotrophic factors in the developing and adult kidney. Due to its production of this mixture of neurotrophic factors, we wanted to investigate whether fetal kidney tissue could be beneficial for neuritic fiber growth and/or cell survival in intracranial transplants of fetal ventral mesencephalic tissue (VM). A retrograde lesion of nigral dopaminergic neurons was performed in adult Fischer 344 male rats by injecting 6-hydroxydopamine into the medial forebrain. The animals were monitored for spontaneous locomotor activity in addition to apomorphine-induced rotations once a week. Four weeks following the lesion, animals were anesthetized and embryonic day 14 VM tissue from rat fetuses was implanted stereotaxically into the dorsal striatum. One group of animals received a cograft of kidney tissue from the same embryos in the same needle track. The animals were then monitored behaviorally for an additional 4 months. There was a significant improvement in both spontaneous locomotor activity (distance traveled) and apomorphine-induced rotations with both single VM grafts and VM-kidney cografts, with the VM-kidney double grafts enhancing the motor behaviors to a significantly greater degree. Tyrosine hydroxylase (TH) immunohistochemistry and image analysis revealed a significantly denser innervation of the host striatum from the VM-kidney cografts than from the single VM grafts. TH-positive neurons were also significantly larger in the cografts compared to the single VM grafts. In addition to the dense TH-immunoreactive innervation, the kidney portion of cografts contained a rich cholinergic innervation, as evidenced from antibodies against choline acetyltransferase (ChAT). The striatal cholinergic cell bodies surrounding the VM-kidney cografts were enlarged and had a slightly higher staining density for ChAT. Taken together, these data support the hypothesis that neurotrophic factors secreted from fetal kidney grafts stimulated both TH-positive neurons in the VM cografts and cholinergic neurons in the host striatum. Thus, these factors may be combined for treatment of degenerative diseases involving both dopaminergic and cholinergic neurons.

Animals↗