Biomedical subjects

John A Stanford

Publications and source records attributed to John A Stanford.

14 recordsLinked to original sources

PubMed2006

CGP 56999A, a GABA(B) receptor antagonist, enhances expression of brain-derived neurotrophic factor and attenuates dopamine depletion in the rat corpus striatum following a 6-hydroxydopamine lesion of the nigrostriatal pathway.

Rats were injected (i.p.) once daily with either 1 mg/kg CGP 56999A, a gamma-aminobutyric acid(B) (GABA(B)) receptor antagonist, or an equivalent volume of saline beginning 7 days prior to, and continuing for 7 days following, a unilateral 6-hydroxydopamine lesion of the nigrostriatal dopamine (DA) pathway. At the end of the CGP 56999A treatment period the concentrations of DA and dihydroxyphenylacetic acid (DOPAC), as well as the expression of brain-derived neurotrophic factor (BDNF), were analyzed in corpus striatum ipsilateral and contralateral to the lesioning. No significant differences in these parameters were noted in the contralateral striatum between saline- and CGP 56999A-treated subjects. In contrast, as compared to animals receiving saline only, daily treatment with the GABA(B) receptor antagonist significantly attenuated the 6-hydroxydopamine-induced decline in DA and increased the expression of BDNF in the ipsilateral striatum. The results indicate that CGP 56999A enhances BDNF gene expression in the rat corpus striatum and prevents the decline in DA content that is a characteristic sequela of 6-hydroxydopapmine lesions of the nigrostraital dopamine pathway. These findings suggest that GABA(B) receptor antagonists may be of value in the treatment of Parkinson's disease and other conditions that would benefit from an enhanced production of neurotrophic factors in brain.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2006

Measuring forelimb force control and movement in Fischer 344/Brown Norway rats: effects of age and lorazepam.

The purpose of this study was to measure forelimb force control and movement kinetics in rats, as they are affected by normal aging and the benzodiazepine lorazepam. Young (6 months), middle-aged (18 months), and aged (24 months) rats were trained to emit discrete forelimb responses on an isometric force disk within a 20-25 g force band for water reinforcement. Dependent variables included number of responses, percentage of reinforced responses, peak response forces, and inter-response times. Inter-response times were divided into two categories: inter-response times <0.5 s (reflecting rapid, discrete forelimb responses) and inter-response times 4-8 s (reflecting movement sequences). Aged rats exhibited no apparent deficits in forelimb force control. Although older rats emitted fewer responses than younger rats, their response accuracy was greater. Peak forces did not differ among the groups. Both categories of inter-response times were slower in the aged group, reflecting slowed discrete movements and movement sequencing. Lorazepam increased the number of responses and peak forces, decreased response accuracy, and lengthened inter-response times within the 4-8 s range (but not the <0.5 s range) in all age groups. The results suggest that movement sequences may be more sensitive to the effects of acute benzodiazepines than rapid discrete movements.

Aging↗

PubMed2005

Bilateral effects of unilateral intrastriatal GDNF on locomotor-excited and nonlocomotor-related striatal neurons in aged F344 rats.

In order to determine its effects on locomotor-related striatal electrophysiology in aged rats, glial cell line-derived neurotrophic factor (GDNF) was infused (vehicle or 30mug) into the right striatum of 24-25-month-old Fischer 344 (F344) rats. Multi-wire electrode arrays were then chronically implanted in striatum bilaterally. Thirty days later, striatal electrophysiological activity was recorded during freely moving conditions. Individual neurons were classified as locomotor-excited if they exhibited significant increases in firing rates during locomotor bouts versus periods of nonmovement. GDNF produced a significant increase in overall firing rates in locomotor-excited striatal neurons. This effect was observed in both the infused and the contralateral striatum. GDNF also attenuated the bursting activity of nonlocomotor-related striatal neurons, an effect that was also present bilaterally. These results suggest that GDNF's antiparkinsonism effects are associated with increased excitability of motor-related striatal neurons and diminished activity of neurons that do not exhibit explicit motor-related changes in activity. Such studies may aid in understanding the mechanism of potential therapies for movement disorders seen in aging and Parkinson's disease.

Aging↗

PubMed2004

Aged F344 rats exhibit altered electrophysiological activity in locomotor-unrelated but not locomotor-related striatal neurons.

Multi-wire electrode arrays were chronically implanted and striatal electrophysiological activity was recorded in young (4-9 months) versus aged (24-29 months) Fischer 344 (F344) rats in order to determine whether locomotor-related striatal neurons exhibit age-related changes in electrophysiological activity during freely-moving conditions. Individual neurons were classified as locomotor-related if they exhibited significant differences in their firing rates between periods of locomotion versus periods of non-movement. While the activity of locomotor-related striatal neurons did not differ between young and aged rats, neurons that were not related to locomotion exhibited significantly greater activity in the aged rats during both periods of non-movement and bouts of locomotion. These results suggest that in the aged striatum, increased activity of nonlocomotor-related neurons may contribute to hypokinesia through their influence on basal ganglia output nuclei. Such studies may aid in the understanding of movement disorders seen in aging and Parkinson's disease.

Action Potentials↗

PubMed2004

Striatal GDNF administration increases tyrosine hydroxylase phosphorylation in the rat striatum and substantia nigra.

Glial cell line-derived neurotrophic factor (GDNF) improves motor dysfunction associated with aging in rats and non-human primates, in animal models of Parkinson's disease, and may improve motoric function in patients with advanced Parkinson's disease. These improvements are associated with increased dopamine function in the nigrostriatal system, but the molecular events associated with this increase are unknown. In these studies, 100 micro g of GDNF was injected into the striatum of normal aged (24-month-old) male Fischer 344 rats. The protein levels and phosphorylation of TH, ERK1/2, and related proteins were determined by blot-immunolabeling of striatum and substantia nigra harvested 30 days after injection. In GDNF-treated rats, TH phosphorylation at Ser31 increased approximately 40% in striatum and approximately 250% in the substantia nigra. In the substantia nigra, there was a significant increase in ERK1 phosphorylation. In striatum, there was a significant increase in ERK2 phosphorylation. Microdialysis studies in striatum showed that both amphetamine- and potassium-evoked dopamine release in GDNF recipients were significantly increased. These data show that GDNF-induced increases in dopamine function are associated with a sustained increase in TH phosphorylation at Ser31, which is greatest in the substantia nigra and maintained for at least one month following a single striatal administration of GDNF. These findings, taken from the nigrostriatal system of normal aged rats, may help explain the long lasting effects of GDNF on dopamine function and prior studies supporting that a major effect of GDNF involves its effects on dopamine storage and somatodendritic release of dopamine in the substantia nigra.

Amphetamine↗

PubMed2003

Differential effects of post-implantation time on potassium- versus D-amphetamine-evoked dopamine overflow in the striatum of F344 rats.

Effects of post-implantation time on potassium (K+)- versus D-amphetamine (D-AMPH)-evoked striatal dopamine (DA) overflow were measured using microdialysis in freely moving young and aged Fischer 344 rats. In one group, samples were collected on the day of probe insertion (Day 1 group). In a second group, samples were collected 24 h after probe insertion (Day 2 group). While analyses revealed no significant differences between the two age groups, the 100 mM K+ stimulus evoked a significantly greater amount of DA overflow in the Day 1 group compared to the Day 2 group. The decrease in 3,4-dihydroxyphenylacetic acid (DOPAC) produced by K+ stimulation was not influenced by post-implantation time. The effect of the 250 microM D-AMPH stimulus on DA overflow did not differ between the Day 1 and Day 2 groups, nor did the decrease in DOPAC that accompanied D-AMPH stimulation. These results support the hypothesis that under some stimulus conditions, post-implantation time is an important variable in microdialysis studies.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2003

Microdialysis studies of D-amphetamine-evoked striatal dopamine overflow in young versus aged F344 rats: effects of concentration and order of administration.

In order to measure the effects of different concentrations of D-amphetamine (D-AMPH) infusions on striatal dopamine (DA) overflow in young versus aged rats, and to determine the influence of preceding infusions on subsequent stimuli, two microdialysis studies were conducted. In the first study, D-AMPH (100, 200, and 2000 microM) was infused in ascending order of concentration, while in the second study the order of administration was reversed. The order of administration significantly affected DA overflow and extracellular levels of 3,4-dihydroxyphenylacetic acid (DOPAC). Generally, DA overflow was greater for a given concentration when it was administered first in a sequence than when it was administered later in a sequence. The two age groups did not differ on measures of DA overflow. The order of administration also significantly influenced the effect of D-AMPH on extracellular DOPAC, as the D-AMPH-related decreases in DOPAC were greater for a concentration when it was administered earlier versus later in the sequence. This effect was greater in the young rats than in the aged rats. D-AMPH also resulted in diminished levels of DOPAC in the aged rats compared to the young rats. These results suggest that between-groups studies may be more appropriate for determining the effects of different concentrations of D-AMPH on striatal DA overflow. They also demonstrate that while some measures of stimulus-evoked DA overflow may not differ between young and aged F344 rats, extracellular regulation of striatal DA (as measured by changes in DOPAC) may be altered. These alterations may contribute to age-related decreases in motor function.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2003

Glial cell line-derived neurotrophic factor increases stimulus-evoked dopamine release and motor speed in aged rhesus monkeys.

Changes in the functional dynamics of dopamine release and regulation in the basal ganglia have been posited to contribute to age-related slowing of motor functions. Here, we report the effects of glial cell line-derived neurotrophic factor (GDNF) on the stimulus-evoked release of dopamine and motor speed in aged monkeys (21-27 years of age; n = 10). Although no changes were observed in the vehicle controls (n = 5), chronic infusions of 7.5 microg of GDNF per day for 2 months into the right lateral ventricle initially increased hand movement speed up to 40% on an automated hand-reach task. These effects were maintained for at least 2 months after replacing GDNF with vehicle, and increased up to another 10% after the reinstatement of GDNF treatment for 1 month. In addition, upper-limb motor performance times of the aged GDNF-treated animals (n = 5) recorded at the end of the study were similar to those of five young adult monkeys (8-12 years of age). The stimulus-evoked release of dopamine was significantly increased, up to 130% in the right caudate nucleus and putamen and up to 116% in both the right and left substantia nigra of the aged GDNF recipients compared with vehicle controls. Also, basal extracellular levels of dopamine were bilaterally increased, up to 163% in the substantia nigra of the aged GDNF-treated animals. The data suggest that the effects of GDNF on the release of dopamine in the basal ganglia may be responsible for the improvements in motor functions and support the hypothesis that functional changes in dopamine release may contribute to motor dysfunctions characterizing senescence.

Aging↗

PubMed2002

Aged Fischer 344 rats exhibit altered locomotion in the absence of decreased locomotor activity: exacerbation by nomifensine.

A novel force plate actometer was used to measure locomotor activity and gait in young (6 months) versus aged (24 months) Fischer 344 rats. The actometer revealed altered gait in the aged rats in the absence of decreased locomotor activity. The catecholamine uptake inhibitor, nomifensine increased locomotor activity in both groups and exacerbated the gait alteration in the aged group. Analyses of whole brain tissue levels of dopamine (DA), 3,-4 dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) in the substantia nigra and dorsal striatum revealed no significant differences between the two age groups. In the young (but not aged) rats, distance traveled was negatively correlated with striatal DOPAC + HVA/DA tissue ratios (a measure of DA turnover). In the aged (but not the young) rats, positive correlations were observed between distance traveled and DOPAC + HVA/DA ratios in the substantia nigra. Neither striatal nor nigral DA content was significantly correlated with distance traveled in either age group. These findings demonstrate that aged rats may exhibit functional changes in locomotor activity in the absence of quantitative changes in nigrostriatal DA content.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2002

Dantrolene diminishes forelimb force-related tremor at doses that do not decrease operant behavior in the rat.

A behavioral preparation that affords concurrent measurement of forelimb force and tremor in rats was used to assess the effects of dantrolene sodium, a muscle relaxant and potential neuroprotective drug. Rats that were trained to press downward on an isometric force transducer while simultaneously licking water reinforcement were administered dantrolene (5.0 mg/kg, 7.5 mg/kg, and 10.0 mg/kg). Dantrolene diminished force output at the 7.5 mg/kg and 10.0 mg/kg doses and decreased tremor at all three doses. Dantrolene decreased the ratio of forelimb tremor to force output at all three doses. Dantrolene did not suppress operant behavioral output at these doses. These results suggest that dantrolene may affect fine motor control and decrease tremor at doses that do not produce behavioral suppression.

Animals↗

PubMedDate not supplied

Acute locomotor effects of fluoxetine, sertraline, and nomifensine in young versus aged Fischer 344 rats.

Spontaneous locomotor activity was measured in young (6-8 months) and aged (24-26 months) Fischer 344 (F344) rats. Following habituation to the activity monitors, aged rats demonstrated significantly diminished motor activity as quantified by total distance traveled and vertical activity. Movement speed did not differ significantly between the two groups. Following habituation, rats were administered acute doses of fluoxetine, sertraline, or nomifensine (1.0, 3.0, and 10.0 mg/kg). Fluoxetine diminished all three behavioral measures in the young rats, while in the old rats, fluoxetine's effects were limited to a robust attenuation of vertical activity. Sertraline decreased movement speed and vertical activity, but not total distance traveled, in the young rats. Unlike fluoxetine, sertraline produced no significant effects on any of the three behavioral variables in the old rats. Nomifensine increased behavioral scores for both age groups. The results are discussed in relation to acute motor side effects of selective serotonin reuptake inhibitors (SSRIs) in motor-impaired aged individuals, as these effects may influence their eventual use in the clinic.

Aging↗

PubMedDate not supplied

Aged F344 rats exhibit an increased proportion of dopamine agonist-excited striatal neurons.

In order to study age-related differences in striatal electrophysiological activity in freely-moving animals, multi-wire electrode arrays were chronically implanted in the striatum of young (6-8 months) and aged (24-26 months) Fischer 344 rats. After recording baseline activity, d-amphetamine (D-AMPH; 1.0 mg/kg) and apomorphine (APO; 0.5 mg/kg) were administered to the two age groups. For both the D-AMPH and APO series, the percentage of striatal neurons that increased firing rates as a result of the DA agonists was 19% higher in the old animals than in the young animals. In addition, D-AMPH increased the firing rates of D-AMPH-excited neurons to a greater extent in the old animals than in the young animals. While the rate-increasing effects of APO did not differ significantly as a function of age, its effects were slightly greater in the old animals as well. These results suggest that age-related decreases in nigrostriatal DA function may result in alterations in the way in which the striatum integrates corticostriatal and nigrostriatal inputs to influence motor function.

Aging↗

PubMedDate not supplied

Effects of chronic intraputamenal infusion of glial cell line-derived neurotrophic factor (GDNF) in aged Rhesus monkeys.

In this study, 17-23 year old Rhesus monkeys were used as an early model of Parkinson's disease (PD). Four animals received chronic infusions of GDNF and four received vehicle infusions into the right putamen via programmable pumps for 8 weeks. Weekly videotaping was performed to record general motor performance and a monkey movement analysis panel (mMAP) was used to quantify fine and coarse upper limb motor performance. The GDNF-treated animals showed significant improvements in their overall motor performance in the last 3 weeks of the study compared to controls. Fine motor time of the upper limbs improved significantly in both the GDNF-treated and control animals. After 8 weeks of drug administration, the animals were euthanized and tissue punches were taken from the basal ganglia for measures of dopamine (DA) and DA metabolite levels. In the right putamen, GDNF infusion produced a 217% increase in homovanillic acid (HVA) levels. In addition, DA levels increased by 50% in the right caudate nucleus and there were 122 and 76% increases in 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the right and left caudate nucleus, respectively. HVA levels were also seen to be increased by 212% in the right caudate nucleus. Finally, changes were seen in the right globus pallidus, with 390 and 171% increases in DA and HVA levels, respectively. These data support the hypothesis that GDNF may be beneficial for the treatment of damaged or degenerating DA neurons in aged monkeys and possibly in aged humans.

3,4-Dihydroxyphenylacetic Acid↗

PubMedDate not supplied

Aged Fischer 344 rats exhibit altered orolingual motor function: relationships with nigrostriatal neurochemical measures.

The present study utilized a novel behavioral preparation to measure differences in orolingual motor function between young (6 months) and aged (24 months) Fischer 344 (F344) rats. Rats were trained to lick an isometric force-sensing operandum for water reinforcement so that the number of licks per session, licking rhythm and lick force could be compared between the two groups. The aged rats exhibited a greater number of licks per session, but a slowed licking rhythm, compared to the young rats. Lick force did not differ significantly between the groups. The dopamine (DA) uptake inhibitor nomifensine decreased all three measures in both groups. Analyses of whole brain tissue content of DA, 3,4 dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) in the substantia nigra and dorsal striatum revealed no significant differences between the two age groups. Differences were observed between the two groups with respect to relationships between behavioral and neurochemical tissue measures. Striatal DA content and the number of licks per session were positively correlated for the young rats but not for the aged rats. In the aged rats, but not the young rats, positive correlations were also observed between licking rhythm and the DOPAC+HVA/DA ratio in the substantia nigra. These findings suggest that age-related alterations in orolingual motor function may relate in part to functional changes in DA neuronal circuits.

3,4-Dihydroxyphenylacetic Acid↗