PubMed Health⌕ Search

Biomedical subjects

M F Piercey

Publications and source records attributed to M F Piercey.

At least 55 records · Page 3Linked to original sources
PubMed1992

Effects of cholinergic agonists on regional brain energy metabolism in the scopolamine-treated rat.

The effects of scopolamine, physostigmine, RS86 and U-80816B on regional energy metabolism were studied in rodents by means of the 2-deoxyglucose autoradiographic technique. Scopolamine depressed metabolism in an area of cerebral cortex, focused around the parietal region. Rats treated with cholinergic direct agonists (U-80816B, RS86) as well as with the indirect agonist (physostigmine) all showed decreases in cortical energy metabolism, similar to scopolamine. They also induced an increase in thalamic metabolism. When these drugs were given in conjunction with scopolamine, metabolism tended to change in the opposite direction from the values obtained with the drug alone. These results suggest that there are complex interactions between pre- and post-synaptic muscarinic receptors. Additionally, nicotinic receptors could also be involved in some of the effects of physostigmine.

Animals↗
PubMed1992

Intrinsic activity determinations at the dopamine D2 guanine nucleotide-binding protein-coupled receptor: utilization of receptor state binding affinities.

Guanine nucleotide-binding protein-coupled receptors have been shown to exist in both a high affinity agonist (HiAg) and a low affinity agonist (LowAg) state. The formation of the HiAg state is promoted by agonists, and the formation of this state of the receptor appears to be a critical factor in the generation of the effector-activating complex G alpha.GTP.Mg2+ and in the production of a stimulus. The magnitude of the difference in the affinity a compound has for the HiAg versus the LowAg state of the receptor has been related to the intrinsic activity of the compound. In this paper the HiAg and LowAg affinities (Ki) of full and partial dopamine agonists of varying levels of intrinsic activity were determined using membranes from Chinese hamster ovary cells stably transfected with the D2i receptor. The HiAg state was defined using the recently described dopamine agonist ligand [3H]U-86170, and the LowAg state was defined using [3H] raclopride plus 600 microM GTP. The LowAg/HiAg ratios for apomorphine (43), HW-165 (12.5), (-)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [(-)-3-PPP] (4.5), terguride (1.6), SDZ-208-911 (1.2), and SDZ-208-912 (0.3) were found to correlate well with their electrophysiologically derived intrinsic activities (r = 0.92). Using this relationship, the intrinsic activity for compounds such as (+)-3-PPP (112%), quinpirole (104%), U-68553B (102%), and U-86170 (95%) was predicted to be high (greater than 90%); (-)-apomorphine (73%) was of high/moderate intrinsic activity, HW-165 (52%), (+)-apomorphine (51%), and (-)-3-PPP (34%) were in the intermediate range, and terguride (16.5%), SDZ-208-911 (11.7%), and SDZ-208-912 (-12%) were at the lower end of the intrinsic activity spectrum. The receptor state binding-determined intrinsic activity values for quinpirole (100%), U-86170F (94.8%), HW-165 (52.1%), (-)-3-PPP (34.3%), SDZ-208-911 (11.7%), and SDZ-208-912 (-12%) were found to correlate well (r = 0.908) with their maximum response (intrinsic activity), as determined using ATP-mediated increases in arachidonic acid release from CHO-D2i cells. In addition, the maximal effect of several of these compounds on rat striatal homovanillic acid (HVA) levels was determined. The drug-induced changes in tissue HVA levels were found to be consistent with the affinity-derived intrinsic activities of the drugs.(ABSTRACT TRUNCATED AT 400 WORDS)

Aminoquinolines↗
PubMed1991

Regional cerebral glucose metabolism compared in rodents and humans.

In order to compare regional brain glucose metabolism in rats and humans, this parameter was measured using Sokoloff's deoxyglucose method in rats, and positron emission tomography with magnetic resonance imaging in humans. An atlas of cerebral regions of interest common to both species was developed to facilitate the evaluation of the relationship in regional values. We found among the regions studied a significant positive correlation in their metabolic values (r = 0.72, P less than 0.001) and coefficients of variation (r = 0.59, P less than 0.01) suggesting that regional brain glucose consumption is comparable between rat and human. Results of this study support the view that rat and human brain may be phylogenetically linked functionally as well as anatomically.

Aged↗
PubMed1991

The hypnotics triazolam and zolpidem have identical metabolic effects throughout the brain: implications for benzodiazepine receptor subtypes.

Using Sokoloff's 2-deoxyglucose autoradiography procedure, the effects of trizolam, a classical benzodiazepine (BZ) hypnotic, were compared to those of zolpidem, which preferentially binds to BZ1 receptor subtypes. Triazolam depressed metabolism in 40 of the more than 60 brain regions evaluated. Zolpidem depressed metabolism in all of these areas, including the spinal cord, an area where the BZ1 receptor subtype is not supposed to exist. Zolpidem and triazolam also depressed metabolism in the molecular layer of the dentate gyrus, an area low in BZ1 receptors. Neither drug affected metabolism in 21 areas, including the regions most specific for the BZ1 subtype (cerebellum, inferior colliculus, globus pallidus, and substantia nigra pars reticularis). It is concluded that: (i) zolpidem and triazolam depress energy metabolism of the same areas of the brain, (ii) zolpidem's effects may not be mediated solely through the BZ1 receptor subtype, and (iii) the BZ2 receptor may be functionally more significant than the BZ1 receptor.

Animals↗
PubMed1991

Effects of the partial dopamine receptor agonists SDZ 208-911, SDZ 208-912 and terguride on central monoamine receptors. A behavioral, biochemical and electrophysiological study.

The partial dopamine receptor agonists SDZ 208-911 (N-[(8-alpha)-2,6-dimethylergoline-8-yl]-2,2-dimethylpropanamid e), SDZ 208-912 (N-[8-alpha)-2-chloro-6-methylergoline-8-yl]-2,2- dimethylpropanamide) and terguride (transdihydrolisuride; TDHL) were tested in biochemical, behavioral (locomotor activity) and electrophysiological assays in male rats. In reserpine-pretreated rats, SDZ 208-911 and terguride dose-dependently reduced striatal DOPA formation (NSD 1015 treatment) with similar efficacy (-80%) and potency as the selective D2 receptor agonist quinpirole (LY 171555). SDZ 208-912 only produced a partial reduction (-32%) at the highest dose tested. SDZ 208-911 and terguride partially reversed (by approximately 50%) the gamma-butyrolactone (GBL)-induced increase in striatal DOPA accumulation. Quinpirole produced a 100% reversal while SDZ208-912, per se, was inactive. While quinpirole decreased DOPA accumulation, all three partial agonists elevated striatal DOPA accumulation in non-pretreated rats with SDZ 208-912 being as potent and efficacious as haloperidol. The three partial agonists displayed comparatively high affinities in vitro for the dopamine D2 (3H-spiperone) receptor site and somewhat lower affinity for the 5-HT1A (3H-8-OH-DPAT) receptor site. SDZ 208-911 and SDZ 208-912 also showed high affinities for central alpha 2 (3H-idazoxane) receptors. In line with these findings, the partial ergoline agonists dose-dependently elevated the DOPA accumulation in the noradrenaline-rich cortical brain region and decreased the 5-HT synthesis rate (5-HTP accumulation) in the limbic brain region. Furthermore, high doses of SDZ 208-911 and terguride produced weak signs of the 5-HT behavioral syndrome (flat body posture) in reserpinized rats. In the locomotor activity studies in non-pretreated rats, SDZ 208-911, SDZ 208-912 and terguride reduced the activity to 10-20% of controls with SDZ 208-912 being approximately ten times less potent than the other two compounds. Weak postsynaptic dopamine receptor agonist effects of the partial agonists were demonstrated only in reserpine-pretreated rats; all three partial agonists tested produced occasional forward locomotion and the so-called "jerking" behavior. Extracellular single unit recordings were carried out in chloral hydrate-anesthetized rats to investigate the effects on firing rates of dopamine neurons located in the substantia nigra pars compacta. Intravenous administration of SDZ 208-911 and terguride depressed the firing rate by 42 and 53%, respectively, while apomorphine completely inhibited the cells. SDZ 208-912 only reduced the firing by 16% and some cells displayed a biphasic response with a weak depression at low doses that disappeared at high doses.(ABSTRACT TRUNCATED AT 400 WORDS)

4-Butyrolactone↗
PubMed1991

5-HT1A agonists uncouple noradrenergic somatodendritic impulse flow and terminal release.

Both noradrenergic (NE) and serotonergic (5-HT) systems have been implicated in anxiety and depression, as well as in the therapeutic actions of drugs treating these conditions. We have used microelectrode recordings of nerve cell impulse frequencies and in vivo voltammetric recordings of monoamine release to evaluate effects of the arylpiperazine 5-HT1A anxiolytics, buspirone and ipsapirone. Both buspirone and ipsapirone significantly depressed 5-HT neuronal firing rates in dorsal raphe (DR), but significantly increased NE neuronal firing rates in locus coeruleus (LC). In CA1 region of hippocampus, both buspirone and ipsapirone significantly depressed NE release with potencies greater than those required for the significant depression of 5-HT release. It is concluded that, contrary to the belief that the 5-HT1A arylpiperazines act primarily through 5-HT mechanisms, alterations in NE function may be critically important for their therapeutic effects, just as is the case for the benzodiazepine anxiolytics and the tricyclic antidepressants.

Action Potentials↗
PubMed1990

Effects of MDMA ('ecstasy') on firing rates of serotonergic, dopaminergic, and noradrenergic neurons in the rat.

3,4-Methylenedioxymethamphetamine (MDMA), a non-hallucinogenic drug of abuse, potently depressed firing rates of a subpopulation of serotonin neurons in the dorsal and median raphe. High neurotoxic doses depressed those serotonin neurons unresponsive to low doses. Noradrenaline neurons in the locus coeruleus were also depressed by moderate doses. Dopamine neurons were unaffected. It is concluded that MDMA's unique psychological effects are mediated through a subpopulation of serotonergic and noradrenergic neurons, presumably through effects on release mechanisms.

3,4-Methylenedioxyamphetamine↗
PubMed1990

Electrophysiological effects of dopamine autoreceptor antagonists, (+)-AJ 76 and (+)-UH 232.

The weak aminotetralin stimulants, (+)-AJ 76, cis-(+)-5-methoxy-1-methyl-2-(n-propylamino)tetralin and (+)-UH 232, cis-(+)-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin, were tested for their effects on firing rates of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNPC). (+)-AJ 76 and (+)-UH 232 antagonized the depression of DA neuron firing rates following autoreceptor stimulation by apomorphine. Thus, just as they antagonize DA autoreceptors on presynaptic terminals, these aminotetralins also antagonize the somatodendritic DA autoreceptor. However, in contrast to terminal autoreceptors where (+)-AJ 76 is the most potent antagonist, (+)-UH 232 is the most potent on cell body autoreceptors. (+)-AJ 76 and (+)-UH 232 also reversed the depression of DA neurons arising from activation of negative feedback pathways by amphetamine-induced DA release in postynaptic areas. Based on potencies to reverse amphetamine and apomorphine, respectively, the postsynaptic/presynaptic potency ratios for (+)-AJ 76, (+)-UH 232, and haloperidol were all near unity. It is concluded that (+)-AJ 76 and (+)-UH 232 antagonize both postsynaptic and somatodendritic sites with equal potencies, and that their weak stimulant properties may be due to a preferential antagonism of nerve terminal autoreceptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1990

U-66444B and U-68553B, potent autoreceptor agonists at dopaminergic cell bodies and terminals.

U-66444B was evaluated for pre- and postsynaptic effects in dopaminergic (DA) cell body and nerve terminal regions of chloral hydrate anesthetized rats. U-66444B depressed DA neurons in substantia nigra pars compacta and ventral tegmental area with a potency three times that for apomorphine. With a sufficient dose, cells were completely silenced. Activity was found to reside principally in the (+)-stereoisomer, U-68553B. The effects of U-66444B and U-68553B were reversed by 0.1 mg/kg haloperidol. Apomorphine, but not U-66444B nor U-68553B, depressions were accompanied by rapid tachyphylaxis. After 2 wk of U-66444B 0.6 mg/kg/day, potency was not significantly affected. By using in vivo voltammetry, 100 micrograms/kg U-68553B produced a depression in DA release that was more dramatic and more prolonged than that for 500 micrograms/kg apomorphine. On DA postsynaptic receptors, iontophoretic U-66444B and apomorphine were approximately equipotent in depressing caudate neuron firing. It is concluded that U-66444B and its active enantiomer, U-68553B, are more potent, longer acting and possibly more selective as DA autoreceptor agonists than apomorphine. The propensity to produce tolerance appears weak.

Animals↗
PubMed1989

Autoradiographic identification of prolactin binding sites in rat median eminence.

Binding sites for prolactin were localized and quantified in the female rat brain by in vitro autoradiographic analysis with iodine-125-labeled ovine prolactin. Following incubation, labeled prolactin bound preferentially to the median eminence and choroid plexus of the lateral and third ventricles. The addition of excess unlabeled ovine prolactin blocked binding of the labeled hormone in the choroid plexus, and attenuated prolactin binding in the median eminence. These results provide evidence for median eminence. These results provide evidence for prolactin-specific recognition sites in the median eminence, a region intimately involved in the hypothalamic regulation of prolactin secretion.

Animals↗
PubMed1989

Spinal analgesic actions of kappa receptor agonists, U-50488H and spiradoline (U-62066).

Administered i.p. to mice, the selective kappa receptor agonists U-50488H and spiradoline (U-62066) were more potent on the tail-flick than on the hot-plate analgesic assay. Both were more potent after i.s. rather than i.c. administration, a result consistent with earlier demonstrations that tail-flick analgesia is generally dependent upon spinal mechanisms. Intraspinal U-50488H was not effective in elevating rat tail-flick latencies. Both drugs increased the thresholds for cat spinal cord nociceptive neurons to respond to a noxious heat stimulus. However, maximal responses of spinal cord neurons to nociceptive stimuli were not altered. It is concluded that although spinal cord sites may be critical to kappa receptor analgesic mechanisms, the effects are quite distinct from spinal cord effects observed previously with classical narcotic analgesics.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1989

Animal behavioral and neurochemical effects of the CNS toxic amino acid antitumor agent, acivicin.

The investigational amino acid antitumor agent, acivicin, has been reported to cause dose-related and reversible CNS toxicity in humans characterized by sedation, ataxia, hallucinations, personality changes, and other symptoms. In a series of studies aimed at characterizing this toxicity, we investigated several species as potential animal models, determined the effects of acivicin on neuronal action potentials, and measured drug effects on the brain content of several putative amino acid neurotransmitters. In mice, we were unable to demonstrate any effects of acivicin in a battery of tests used in identifying and classifying CNS-active agents of potential therapeutic utility. In rats, unlike phencyclidine and certain other psychotomimetic drugs, acivicin produced no impairment of shock avoidance or brightness discrimination in animals trained on an automated Y-maze. In contrast to the rodent species, acivicin effects were perceived as resembling those of cyclazocine by rhesus monkeys trained to discriminate between psychoactive drugs and saline by food reinforcement. Cats treated with acivicin exhibited dose-related symptoms of sedation, somnolence, and ataxia. Iontophoretically applied acivicin was shown to have no effect on the spontaneous firing rate of dorsal horn interneurones in spinal cats. At the time of peak CNS symptoms in cats treated with 100 mg/kg acivicin, content of gamma-aminobutyric acid (GABA; nmoles/mg protein) was elevated from 57-140% in cerebellum, diencephalon, midbrain, and corpus callosum compared to control animals. Brain contents of glutamate, glutamine, and aspartate were not altered in cats experiencing neurotoxicity. These studies have shown that some symptoms of acivicin CNS toxicity are shared by humans and higher non-human species such as the cat and the monkey but not by rodents. Acivicin itself is apparently not a CNS excitant or depressant, but metabolites of the drug could be. Acivicin may also cause increases in the GABA content of localized regions of brain.

Action Potentials↗
PubMed1988

Electrophysiological evidence that spiperone is an antagonist of 5-HT1A receptors in the dorsal raphe nucleus.

The neuroleptic spiperone, which binds to 5-HT1A, 5-HT2 and dopamine (DA) receptors, was studied for its effects on serotonin (5-HT) and DA neurons in dorsal raphe nucleus and substantia nigra pars compacta, respectively. We found that 1 mg/kg i.v. spiperone, but not LY53837 (a 5-HT2 antagonist), antagonized the inhibition induced by 5-HT1A agonists 8-hydroxy-dipropylaminotetralin (8-OH-DPAT) and buspirone in the dorsal raphe nucleus. Lower spiperone doses blocked DA receptors in substantia nigra pars compacta, but did not affect 5-HT neurons. Doses of 8-OH-DPAT completely silencing dorsal raphe neurons were ineffective in substantia nigra pars compacta. However, buspirone antagonized DA receptors in substantia nigra pars compacta with doses similar to those depressing dorsal raphe neurons. It is concluded that spiperone is an antagonist of 5-HT1A receptors in the dorsal raphe nucleus.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1988

Functional evidence for PCP-like effects of the anti-stroke candidate MK-801.

MK-801 is an indirect antagonist of the NMDA excitatory amino acid receptor which is being considered for possible clinical development for treatment of epilepsy and stroke. MK-801 was evaluated for its effects on regional brain energy metabolism by means of Sokoloff's 2-deoxyglucose (2-DG) autoradiography method. MK-801 produced dramatic alterations in regional energy metabolism, exciting Papez circuit and dopaminergic structures most intensely. The pattern of metabolic alterations was virtually indistinguishable from that previously described for the psychotomimetic drug of abuse, phencyclidine (PCP). It is concluded that MK-801 is at risk for possibly producing PCP-like psychotomimetic effects.

Animals↗
PubMed1988

Dramatic limbic and cortical effects mediated by high affinity PCP receptors.

Using Sokoloff's 2-deoxyglucose (2-DG) autoradiographic technique, the psychotomimetic drug, phencyclidine (PCP, "angel dust") dramatically increased metabolism in diencephalic and telencephalic brain regions known to be rich in high affinity PCP receptors. These effects were greatest in the limbic circuit described in 1937 by the neurologist James Papez (mammillary bodies, anterior thalamus, cingulate gyrus, entorhinal cortex, hippocampus, fornix) and the terminal zones of dopaminergic projections. Caudal to the prefrontal cortex, the cerebral cortex developed an anterior-posterior metabolic gradient somewhat similar to that reported in schizophrenia. Brainstem areas were generally unaffected. These data 1) provide functional data to support Papez' assertion that his central limbic circuit may be important in emotional expression, 2) reaffirm the potential importance of dopaminergic function in psychotic-like behaviors, 3) provide an animal model for schizophrenia, and 4) establish that PCP uses high affinity PCP receptor binding sites to express its psychobiological effects.

Animals↗
PubMed1987

Reversal of scopolamine-induced amnesia and alterations in energy metabolism by the nootropic piracetam: implications regarding identification of brain structures involved in consolidation of memory traces.

Pretreatment with scopolamine, 3 mg/kg, prevented the acquisition of a passive avoidance task in rats. These amnesic effects of scopolamine could largely be overcome by treatment with 100 mg/kg of the nootropic drug piracetam. In order to identify the brain structures involved, the effects of these drugs on regional energy metabolism were measured throughout the brain, utilizing Sokoloff's 2-deoxyglucose autoradiographic procedures. Scopolamine, 3 mg/kg, reduced glucose utilization in several areas of the cerebral cortex. These effects were largest in the parietal and temporal cortices. Other areas affected included the sensorimotor and cingulate cortices, the ventral and lateral thalamus, and the dendritic neuropil of the CA1, CA2, and CA3 regions of the hippocampus. The regional depressions in glucose metabolism observed following scopolamine treatment in the rat had some resemblance to depressions in glucose metabolism reported for Alzheimer's disease patients in positron emission tomography studies. Piracetam, 100 mg/kg, did not alter the energy metabolism of any of the 41 brain regions examined. However, this dose of piracetam completely reversed the scopolamine-induced depressions in the hippocampus. Piracetam partially but significantly reversed the scopolamine effects in the cingulate cortex. It is concluded that the data provide support for the hippocampal-cholinergic theory of memory as originally formulated by Meyers and Domino in 1964 and give insight into the mechanisms by which nootropics work.

Amnesia↗