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Biomedical subjects

M F Jarvis

Publications and source records attributed to M F Jarvis.

At least 73 records · Page 4Linked to original sources
PubMed1988

Differences in adenosine A-1 and A-2 receptor density revealed by autoradiography in methylxanthine-sensitive and insensitive mice.

Two strains of inbred mice, CBA/J and SWR/J, have been identified which are, respectively, sensitive and insensitive to the behavioral and toxic effects of methylxanthines. Autoradiographic analyses of brain adenosine receptors were conducted with [3H]CHA to label adenosine A-1 receptors and [3H]NECA, in the presence of 50 nM CPA, to label adenosine A-2 receptors. For both mouse strains, adenosine A-1 receptors were most highly concentrated in the hippocampus and cerebellum whereas adenosine A-2 receptors were selectively localized in the striatum. CBA/J mice displayed a 30% greater density of adenosine A-1 receptors in the hippocampal CA-1 and CA-3 regions and in the cerebellum as compared to the SWR/J mice. The number of A-2 receptors (Bmax) was 40% greater in the striatum and olfactory tubercle of CBA/J as compared to SWR/J mice. No significant regional differences in A-1 or A-2 receptor affinities were observed between these inbred strains of mice. These results indicate that the differential sensitivity to methylxanthines between these mouse strains may reflect a genetically mediated difference in regional adenosine receptor densities.

Adenosine↗
PubMed1988

Adenosine antagonists as potential therapeutic agents.

The methylxanthine caffeine has been identified in more than 60 plant species and has been in human use for its various therapeutic actions for many hundreds of years and perhaps, with the exception of aspirin and related compounds, is the most widely consumed drug today. Pharmacologically, the xanthines are prototypic inhibitors of the enzyme, cyclic nucleotide phosphodiesterase, are calcium mobilizers and have been reported to inhibit the enzymes, monoamine oxidase and cyclooxygenase as well as affect uptake of the putative neuromodulator, adenosine. However, many of the therapeutic effects ascribed to caffeine are due to its selective ability to antagonize the actions of adenosine. Many xanthines, especially those substituted in the 8-position with a phenyl derivative, are potent and selective adenosine antagonists. The xanthine adenosine antagonists have mild psychostimulant, analgesic adjuvant, diuretic, cardiotonic and antiasthmatic activity. Adenosine antagonists also have nootropic activity. A major limiting factor to the development of this class of compound has been in the lack of selectivity for either of the major classes of adenosine receptor. Several non-xanthines including the pyrazolopyrimidine, DJB-KK, the pyrazoloquinoline, CGS 8216 and the pyrazolopyridine, etazolate have been shown to have adenosine antagonist activity. The triazoloquinazoline, CGS 15943 A has been identified as the first, potent (IC50 = 3 nM) nonxanthine, A2-selective adenosine antagonist while the phenylquinazoline, HTQZ, has 25-fold selectivity for the A2 receptor. The availability of such novel entities may permit the development of a new class of therapeutic agents able to affect neuromodulator, as opposed to neurotransmitter, function.

Adenosine↗
PubMed1988

The N-methyl-D-aspartate receptor complex.

The effects of agonists of the N-methyl-D-aspartate (NMDA) receptor can be blocked by dissociative anesthetics such as phencyclidine (PCP) in a non-competitive manner. This finding together with the fact that ligand binding to the PCP receptor is dependent on the presence of L-glutamate has led to the suggestion that there may exist an NMDA/PCP receptor complex in mammalian brain tissue. This concept has been extended to the inclusion of a cation channel based on the inhibitory actions of the divalent cation, magnesium. Evaluation of the binding of tritiated TCP (thienylcyclohexylpiperidine) a high affinity ligand for the PCP receptor, under four conditions: in basal, well washed rat cortical membranes; in the presence of L-glutamate; in the presence of magnesium; and in the presence of both magnesium and L-glutamate, with NMDA antagonists and dissociative anesthetics showed that these agents had distinct profiles of activity at the PCP receptor. Furthermore, while both classes of compound could modulate TCP binding, only NMDA receptor antagonists inhibited the binding of tritiated CPP (3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid) which labels central NMDA recognition sites. The present data support the existence of an NMDA/PCP receptor complex in mammalian brain tissue. The data currently available would suggest however, that the interface is sequentially NMDA to PCP with the latter site affecting NMDA-mediated responses at a step intermediate between receptor activation and physiological response.

Anesthetics, Dissociative↗
PubMed1987

Autoradiographic localization of adenosine A1 receptors in rat brain using [3H]XCC, a functionalized congener of 1,3-dipropylxanthine.

Quantitative autoradiography was used to visualize the anatomical distribution of adenosine receptors labeled by the carboxylic acid congener of 1,3-dipropylxanthine, [3H](8-(p-carboxymethyloxy)phenyl-1,3-dipropylxanthine)([3H]XCC ) in the rat brain. [3H]XCC was observed to specifically bind to rat brain sagittal sections in a heterogeneous pattern. Saturation experiments revealed that [3H]XCC binds with nanomolar affinity to 20-microns frozen tissue sections with the highest binding densities occurring in the hippocampus and cerebellum. Both the binding characteristics and regional receptor distribution obtained with [3H]XCC demonstrate the potential usefulness of this new ligand in the study of adenosine A1 receptors.

Animals↗
PubMed1987

Quantitative autoradiographic localization of NMDA receptors in rat brain using [3H]CPP: comparison with [3H]TCP binding sites.

The regional distribution of N-methyl-D-aspartate (NMDA) receptors in rat brain using the selective NMDA receptor ligand [3H]3-[+/-)-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) has been quantitated by in vitro autoradiography. [3H]CCP binding was highest in the CA1 region of the hippocampus. Relatively high levels of binding were also observed in the cerebral cortex, while moderate binding was obtained in the thalamus, striatum and granule cell layer of the cerebellum. Concurrent studies examining the phencyclidine receptor ligand [3H]1-[1-(2-thienyl)cyclohexyl]-piperidine (TCP), revealed a similar pattern of binding that correlated well with the localization of [3H]CPP-labeled NMDA receptors (r = 0.88, P less than 0.01).

Animals↗
PubMed1987

Characterization of adenosine receptors in the PC12 pheochromocytoma cell line using radioligand binding: evidence for A-2 selectivity.

Examination of the binding characteristics of the adenosine agonist radioligands [3H]N6-cyclohexyladenosine [( 3H]CHA), [3H]cyclopentyladenosine [( 3H]CPA), and [3H]5'-N-ethylcarboxamido adenosine [( 3H]NECA) to membranes prepared from PC12 cells showed that the A-1-selective ligands (CHA and CPA) had minimal binding, which was not amenable to analysis using curve-fitting programs. However, [3H]NECA, a nonselective A-1/A-2 agonist, gave reproducible binding, which was enhanced by removal of endogenous adenosine, using the catabolic enzyme adenosine deaminase. This binding was of high affinity (KD = 4.7 nM) with limited capacity (263 fmol/mg of protein). Specific binding of [3H]NECA was unaffected by the presence of either CPA (50 nM) or MgCl2 (10 mM) but was sensitive to guanylylimidodiphosphate (100 microM), a finding suggesting involvement of an N-protein mechanism in the coupling of the adenosine receptor labeled by [3H]NECA to other components of the receptor complex. Binding of [3H]NECA to PC12 cell membranes was stereo-selective, with the R isomer of N6-phenylisopropyladenosine (PIA) being approximately 12 times more active than S-PIA. The A-1-selective agonist CPA was a weak inhibitor of [3H]NECA binding (Ki = 251 nM). The rank order of activity of adenosine agonists in displacing specific [3H]NECA binding was NECA greater than or equal to 2-chloroadenosine greater than CHA greater than or equal to 5'-N-methylcarboxamido adenosine greater than or equal to R-PIA greater than CPA greater than S-PIA. Binding was also displaced by the marine adenosine agonist 1-methylisoguanosine and by a series of xanthine antagonists with the activity order being 1,3-dipropyl-8-(2-amino-4-chloro)phenylxanthine greater than 8-phenyltheophylline greater than 8-p-sulfophenyltheophylline.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1986

L-dopa reverses the effects of MPP+ toxicity.

The behavioral and neurochemical consequences of the intrastriatal administration of 1-methyl-4-phenylpyridinium ion (MPP+), the toxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), were evaluated using the shuttlebox avoidance paradigm. MPP+ caused a significant depletion of striatal dopamine and significant disruption of shuttlebox performance. L-Dopa administration reversed both the dopamine depletion and the behavioral deficits. These observations are discussed in reference to the rodent-MPTP model of Parkinson's disease.

1-Methyl-4-phenylpyridinium↗
PubMed1986

Ascorbic acid reduces the dopamine depletion induced by methamphetamine and the 1-methyl-4-phenyl pyridinium ion.

The neurotoxic actions of methamphetamine and the 1-methyl-4-phenyl pyridinium ion (MPP+) have been ascribed, at least in part, to the generation of free radicals. This hypothesis was evaluated by attempting to reduce the toxic actions of these compounds by pretreatment with an antioxidant, ascorbic acid. The intrastriatal administration of methamphetamine caused a 37% depletion of dopamine. Treatment with 100 or 1000 mg/kg of ascorbic acid significantly reduced the methamphetamine-induced dopamine depletion (by 21 and 27%, respectively). The intrastriatal administration of MPP+ caused an 88% depletion of dopamine. Treatment with 100 or 1000 mg/kg of ascorbic acid significantly reduced the MPP+-induced dopamine depletion (by 22 and 45%, respectively). Thus, free radicals may mediate the toxic actions of these compounds.

1-Methyl-4-phenylpyridinium↗
PubMed1986

The effects of prenatal morphine on the responsiveness to morphine and amphetamine.

The effects of morphine administered to pregnant Sprague-Dawley rats on the schedule-controlled behavior of the offspring were examined. It was observed that both male and female adult rats exposed prenatally to morphine were tolerant to the disruptive effects of morphine on fixed-interval responding compared to age-matched controls. These morphine-treated rats, however, were neither tolerant nor supersensitive to the disruptive effects of the catecholaminergic agonist, amphetamine, and did not exhibit any alteration in their steady state levels of central monoamines. These observations are discussed in relation to the effects of prenatal morphine exposure on unconditioned behaviors.

Amphetamine↗
PubMed1985

Neurochemical and functional consequences following 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) and methamphetamine.

The neurochemical and functional consequences following MPTP administration to the rat were evaluated and compared to similar effects following methamphetamine administration. It was observed that MPTP induced long lasting depletions of striatal dopamine concentrations and this neurotoxic effect could be prevented by pargyline pretreatment. The MPTP-induced neuronal damage produced a tolerance to the disruptive effects of amphetamine and a supersensitivity to the disruptive effects of apomorphine in rats responding in a schedule controlled paradigm. Methamphetamine, like MPTP, produced depletions of striatal dopamine but these actions were potentiated by pargyline pretreatment. These observations are discussed in reference to possible deleterious effects following the administration of pargyline to patients with Parkinson's Disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1985

Age-dependent effects of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP).

The neurotoxic effects of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) have been shown to be dependent upon its conversion to 1-methyl-4-phenyl pyridine ion (MPP+) by monoamine oxidase. Since central monoamine oxidase activity increases with age, the neurotoxic effects of MPTP should be age-dependent. This hypothesis was evaluated by administering MPTP to three groups of rats differing in age. It was observed that both the lethality and neurotoxicity of MPTP were age-dependent.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1985

Ascorbic acid reduces the dopamine depletion induced by MPTP.

The administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to mice was found to cause a long-lasting depletion of striatal dopamine concentrations, but did not alter striatal serotonin concentrations. The concomitant administration of ascorbic acid attenuated this MPTP-induced dopamine depletion. These observations are discussed in reference to the possible mechanisms through which MPTP exerts its neurotoxic actions on dopaminergic neurons.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1985

Cocaine blocks the dopamine depletion induced by MPTP.

The administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to mice causes a long-lasting depletion of striatal dopamine. The concomitant administration of a dopamine uptake blocker, cocaine, protected the mice from this MPTP-induced dopamine depletion. These observations are discussed in reference to the mechanism through which MPTP enters dopaminergic neurons as well as species differences in the sensitivity of the serotonergic system to the toxic effects of MPTP.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1985

Pretreatment with ascorbic acid attenuates the neurotoxic effects of methamphetamine in rats.

The toxic effects of methamphetamine on dopamine and serotonergic neurons have recently been linked to the endogenous formation of 6-hydroxydopamine and 5,7-dihydroxytryptamine, respectively. It has been speculated that the ability of methamphetamine to both release dopamine and serotonin as well as to inhibit monoamine oxidase activity leads to the non-enzymatic oxidation of dopamine and serotonin to the neurotoxins. This hypothesis was evaluated by pretreating rats with high doses of an antioxidant (ascorbic acid) prior to the administration of methamphetamine. It was observed that the administration of 25.0 mg/kg of methamphetamine at 12 hour intervals for a four day period caused a long-lasting depletion of dopamine and serotonin. Pretreatment with 100.0 mg/kg of ascorbic acid 30 minutes before each methamphetamine injection significantly (but not completely) attenuated this neurotoxic action of methamphetamine. These observations are discussed in reference to animal models of Parkinson's disease.

Animals↗
PubMed1984

Medial and lateral amygdalectomy differentially influences consummatory negative contrast.

Rats shifted from a 32% to 4% sucrose solution consume substantially less 4% sucrose than unshifted animals that experience only the 4% solution. This negative contrast effect was found to be attenuated by lesions of the lateral aspects of the amygdala (basolateral, lateral, and basomedial nuclei) and eliminated by lesions of the medial aspects of the amygdala (corticomedial and central nuclei). The results are discussed in terms of the possible role the amygdala may play in some of the proposed determining factors mediating consummatory negative contrast (e.g., emotionality, neophobia, memory).

Amygdala↗
PubMed1983

The effects of naloxone and interstimulation interval on post-ictal depression in kindled seizures.

Two experiments were conducted to investigate the effects of naloxone hydrochloride on seizure thresholds seizure afterdischarges (thresholds and durations) and on post-ictal depression. Experiment 1 examined the effects of naloxone dosage and interstimulation interval (ISI) on kindled seizures. Eight male hooded rats were exposed to a factorial combination of two ISIs (30 and 60 s) and 3 naloxone doses (2, 10 mg/kg and a saline control) during a threshold testing procedure. Naloxone was found to significantly shorten motor seizure duration and post-ictal depression. Experiment 2 examined the effects of naloxone on a subsequent suprathreshold-stimulation-induced seizure following an initial suprathreshold stimulation. A factorial combination of 3 naloxone doses (2, 5 and 10 mg/kg) and a saline control and two ISIs (2 and 6 min) separating the two stimulations was employed. While no main effects for either naloxone or ISI were found in the subsequent seizure activity, there was a significant interaction between naloxone and ISI for the subsequent motor seizure duration. It was concluded from the results of the present experiments that the direction and consistency of naloxone's effects on kindled seizures were present but not very strong. However, the effects of ISI on seizure activity were found to be consistent with the previous literature.

Animals↗
PubMed1982

Phencyclidine raises kindled seizure thresholds.

Phencyclidine (PCP) has been reported to have both anesthetic and seizure-inducing properties. In the present experiment the effect of PCP on previously established seizures, kindled in the amygdala, was examined, using rats as subjects. In a repeated measures design three doses of PCP (1, 2 and 5 mg/kg) were compared with a saline control condition. The high dose of PCP was found to significantly increase seizural afterdischarge thresholds, while not affecting seizure durations.

Amygdala↗