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J A Joseph

Publications and source records attributed to J A Joseph.

15 recordsLinked to original sources
PubMed1992

The effects of aging on muscarinic receptor/G-protein coupling in the rat hippocampus and striatum.

In the striatum and hippocampus, there is a loss of sensitivity to muscarinic agonists with age which has been traced to events early in the signal transduction pathway. Our laboratory has therefore focussed on investigations at this level. The current experiments investigate the effects of age on G-protein/receptor interactions by using competitive binding assays to measure the ability of GppNHp to decrease the proportion of receptors bound to G-proteins in the absence and the presence of added Mg2+. L-[3H]Quinuclidinyl benzilate was used as a nonselective ligand and [3H]pirenzepine as an M1 selective ligand. We find that: (1) muscarinic receptors and G-proteins in the striatum appear to become loosely coupled with age, with no change in Mg2+ sensitivity. (2) M1-receptor/G-protein complexes in the hippocampus display increased sensitivity to the presence of Mg2+ with age, with those from old but not young tissue requiring added Mg2+ in order to uncouple. This effect, however, may not be M1 specific.

Aging↗
PubMed1992

Comparison of the level of mRNA encoding m1 and m2 muscarinic receptors in brains of young and aged rats.

We compared the concentration of mRNA encoding the m1 and m2 muscarinic receptors in several brain regions obtained from young (5-8 months) and aged (24-28 months) male Fischer 344 rats. DNA-excess solution hybridization was employed as a quantitative measure of mRNA concentration. The results indicate the absence of changes in the m1 receptor message with aging in the cerebral cortex, hippocampus and striatum. While there was no statistically significant aging-associated alteration in the concentration of the message encoding the m2 receptor in the thalamus, midbrain, cerebellum and brainstem, there was a decrease in the message level in the hypothalamus.

Aging↗
PubMed1992

Alpha 1-adrenergic stimulation of low Km GTPase in rat striata is diminished with age.

The effect of norepinephrine and epinephrine on the activity of low Km GTPase was studied in striata from young and old rats. Results showed that the amines stimulated the low Km GTPase activity of both young and old animals in a concentration-dependent manner. There was no differential effect of the amines as a function of age, but the stimulated low Km GTPase activity was significantly lower in the aged tissue.

Aging↗
PubMed1992

Decrement of muscarinic receptor-stimulated low-KM GTPase in striatum and hippocampus from the aged rat.

Previous studies have shown that there is an age-related loss of responsiveness in several different receptor systems (e.g. beta-adrenergic, dopaminergic and muscarinic). Our research, using perifused striatal slices and examining muscarinic agonist enhancement of K(+)-evoked dopamine release, has determined that at least part of the loss of sensitivity in muscarinic receptors (mAChR) may occur early in the post-receptor signal transduction process. The present study was carried out to further characterize and localize this deficit by examining carbachol- and oxotremorine-stimulated low-KM guanosine triphosphatase (GTPase) activity in striatal as well as hippocampal tissue obtained from adult (6 months) and old (24 months) Wistar rats. Receptor stimulated low-KM GTPase catalyzes the conversion of GTP to GDP to end the signal transduction cycle and is an indicator of receptor-G-protein coupling/uncoupling. The results showed that stimulated GTPase activity was significantly reduced in hippocampal and striatal tissue from the old animals. These findings suggest that there may be an age-related coupling/uncoupling deficit between muscarinic receptor and G-proteins, and that this deficit may contribute to the reduced mAChR responsiveness in senescence.

Aging↗
PubMed1992

Selective susceptibility of cultured striatal neurons to kainic acid.

Previous work has shown a selective sensitivity of striatal D2-receptor-containing neurons (D2 cells) to kainic acid (KA). In order to see whether this phenomenon exists in cultured cells, which could provide a very accessible model for subsequent mechanistic studies, we examined striatal cultures grown for up to 30 days and labeled with either [3H]spiperone, for D2 receptors, or with [3H]-SCH23390, for D1 receptors. Analysis of the cells was performed with a digital imaging system (RAS). The cultured cells were examined for ligand binding to receptors, cell size, and susceptibility to KA. The D2 cells showed an increased mortality over D1-receptor-containing neurons (D1 cells) in the presence of KA, of a magnitude similar to in vivo loss, with larger D2 cells showing the greatest vulnerability.

Aging↗
PubMed1992

Emesis in ferrets following exposure to different types of radiation: a dose-response study.

Ferrets were exposed to gamma rays (60Co), fission neutrons, high-energy electrons (18.5 MeV) or iron particles (56Fe, 600 MeV/amu) in order to establish the dose-response relationships for emesis following exposure to different types of radiation. The results showed that the mean effective doses (ED50s) for iron particles (35 cGy) and neutrons (40 cGy) were similar. High-energy electrons were the least effective radiation, with an ED50 of 138 cGy. Gamma rays, with an ED50 of 95 cGy, showed an intermediate effectiveness. The results suggest that the relative effectiveness of different types of radiation generally increases with an increase in linear energy transfer (LET), although LET is not completely predictive of relative behavioral effectiveness.

Animals↗
PubMed1992

Possible "accelerated striatal aging" induced by 56Fe heavy-particle irradiation: implications for manned space flights.

The present experiments were carried out to determine the effects of energy deposition from energetic iron (56Fe particles, an important component of cosmic rays) on motor behavioral performance and to determine if the observed deficits were caused by alterations in the neostriatum (an important motor control area). Neostriatal function was assessed with two correlated parameters, i.e., motor behavioral performance (wire suspension task), and oxotremorine-enhanced K(+)-evoked release of dopamine from perifused striatal slices. Rats were exposed to one of several doses of 56Fe-particle irradiation (0.10-1.0 Gy) and tested on a wire suspension task at 3-180 days postirradiation. Results indicated that profound decrements occurred in both of these indices. The effects on K(+)-evoked release of dopamine were evident for as long as 180 days after irradiation, and a subsequent experiment indicated that these effects appeared as early as 12 h postirradiation. Since similar findings have been observed in aged rats, the results are discussed in terms of these particles producing a possible accelerated striatal aging effect.

Aging↗
PubMed1978

Age-related changes in the nigrostriatum: a behavioral and biochemical analysis.

Rotational behavior was examined prior to (Exp. 1) and following unilateral lesions (Exp. 2) in the substantia nigra of young and old rats. Before lesioning no preferences for turning to the left or right were seen in either age group following graded doses of amphetamine. However, after radiofrequency lesions of the left substantia nigra both young and old rats turned predominantly to the left, and the ratio of left to right turns increased as a function of amphetamine dose. However, there were significant differences between young and old rats in the effect of amphetamine on rotational behavior, with old rats showing decided decrements in response strength. Direct dopaminergic stimulation under apomorphine or dopaminergic receptor blockade with haloperidol produced no such age related deficits. The results are discussed in terms of possible presynaptic alterations in dopaminergic functioning with aging.

Aging↗
PubMed1977

Behavioral sensitivity to LSD: dependency upon the pattern of central 5HT depletion.

Two experiments were carried out using a fixed ratio (FR) schedule of water reinforcement to determine the efficacy of two serotonin (5HT) depleting agents (p-chloroamphetamine, 5, 7-dihydroxytryptamine) in altering sensitivity to a low dose of LSD (0.02 MG/KG). The results showed that while both p-chloroamphetamine (PCA) and 5, 7 dihydroxytryptamine (5, 7 DHT) were efficacious in reducing whole brain 5HT, only 5, 7 DHT altered LSD sensitivity such that a 0.02 mg/kg dose of LSD given 12 days after 5, 7 DHT administration disrupted bar press behavior. This was not observed in animals given PCA within similar parameters. Moreover, 4 animals given PCA that did not show increased sensitivity to LSD, did show behavioral disruption to LSD (0.02 mg/kg when they were pretreated with p-chlorophenylalanine, Results are discussed on terms of a possible particular pattern of 5HT depletion that must be achieved before sensitivity to LSD is observed.

Animals↗
PubMed1976

Alterations in the behavioral effects of LSD by motivational and neurohumoral variables.

Forty naive male albino rats were trained to press a bar on a fixed-ratio (FR 32) schedule of water reinforcement. They were then divided into two groups, one of which (N = 20) received 5 min of extra water 12 hr before each experimental session; the other group (N = 20) received no extra water. Half of the animals in each group was given three daily doses (100 mg/kg) of the trytophan hydroxylase inhibitor p-chlorophenylalanine methyl ester (PCPA) while the remaining animals were given control injections of the PCPA vehicle. Ten days following the last administration of PCPA (or vehicle) all animals were given a low dose of LSD (20 mug/kg). Bar-pressing behavior was significantly disrupted only in those animals receiving both PCPA and extra water. Central (whold brain) concentrations of serotonin (5-HT) were significantly lower in all animals which had been treated with PCPA. These results, along with those previously reported, suggest that amount of deprivation can be an important determinant of both the ability of drugs to alter behavior and the dependence of such alterations upon underlying neuronal activity.

Animals↗
PubMedDate not supplied

The putative role of free radicals in the loss of neuronal functioning in senescence.

One of the hallmarks of the aging process is a loss of sensitivity in central neuronal receptors to agonist stimulation. This appears to be especially true in central (hippocampal, striatal) muscarinic cholinergic systems and in the striatal dopamine systems. For these two systems, any decline in their sensitivity can be of extreme importance in determining the behavioral capabilities of the organism. Decrements in the striatal dopamine system may be reflected as motor behavioral deficits, while the central cholinergic systems play a major role in the processing of memory through the activation of muscarinic receptors (mAChR). Declines in the function of these receptors appear to be at least partially responsible for the marked deterioration of cognitive function in normal aging and, more notably, in Alzheimer's disease (AD). Previous work has indicated only minimal success in improving performance in tasks that assess memory in senescent animals or humans with pharmacological agents which enhance cholinergic functioning. The present review describes research that indicates that two of the factors involved in this decline in receptor sensitivity include: (a) decreased receptor concentrations and (b) age-related decrements in signal transduction pathways. Studies are reviewed that indicate that the oxidative neural damage that occurs via kainic acid or ionizing radiation parallel those seen in aging. It is suggested that the common mechanism that may exist among all of the age-, disease-, excitatory amino acid- or radiation-induced deficits in neuronal transmission may involve free-radical-mediated alterations in membrane integrity through lipid peroxidation.

Aging↗
PubMedDate not supplied

Muscarinic receptor concentrations and dopamine release in aged rat striata.

The extent to which age-related decreases in muscarinic enhancement of K(+)-evoked dopamine release (K(+)-ERDA) from perifused striatal slices is dependent upon the loss of striatal muscarinic receptors (mAChR) was determined. Both K(+)-ERDA and mAChR (M1, M2) concentrations were assessed from the same animals (3, 5-7 and 24-27 months). Results indicated associated decreases of 70% in oxotremorine-enhanced K(+)-ERDA and 36% in Bmax (3H-QNB) (3 and 24-27 months groups). Decrease of mAChR Bmax was not the result of membrane sequestration. Although both the concentrations of M1 and M2 muscarinic receptor subtypes decline with age, only the M2 receptor decline was correlated with the age-related decreases in muscarinic enhancement of K(+)-ERDA (r = .71, p less than 0.001). Results suggest that age-related decreases in mAChR concentrations as being partially responsible for deficits in muscarinic enhancement of K(+)-evoked release of DA.

Aging↗