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Biomedical subjects

F J White

Publications and source records attributed to F J White.

At least 91 records · Page 5Linked to original sources
PubMed1989

Clearance of atrial natriuretic factor by lung, liver, and kidney in human subjects and the dog.

We determined human and canine plasma clearance of atrial natriuretic factor (ANF) by lung, liver, and kidney from arteriovenous differences in plasma ANF and measured organ plasma flow. Human subjects had lower plasma ANF concentrations in the pulmonary vein or the pulmonary capillary wedge position when compared with the pulmonary artery, and both sites yielded pulmonary ANF extraction ratios of 24%. Canine lung ANF extraction was 19 +/- 3% and pulmonary ANF clearance was 328 +/- 78 ml/min per m2 vs. 357 +/- 53 ml/min per m2 in man. Hepatic plasma ANF clearance was 216 +/- 26 ml/min with an extraction ratio of 30 +/- 3% in humans and 199 +/- 89 ml/min and 36 +/- 6% in the dog. Renal plasma ANF clearance in human subjects was 78 +/- 12 ml/min per kidney and correlated well with each kidney's creatinine clearance (r = 0.58, P less than 0.05). The mean renal ANF extraction ratio was 35 +/- 4% in human subjects and 42 +/- 6% in the dog. These data quantitate the specific organ ANF clearances by lung, liver, and kidney in human subjects and in dogs and provide a rationale for elevated plasma ANF levels in cirrhosis, renal failure, and diseases accompanied by reduced perfusion of these organs. These findings support the conclusion that plasma ANF concentrations are dependent upon both the stimuli for ANF secretion as well as the specific organ clearances of ANF.

Adolescent↗
PubMed1989

Electrophysiological effects of cocaine in the mesoaccumbens dopamine system: repeated administration.

Behavioral evidence indicates that the potent rewarding effects of cocaine are mediated, in part, by the mesoaccumbens dopamine (DA) system projecting from A10 DA cells in the ventral tegmental area (VTA) to the nucleus accumbens (NAc). Previous electrophysiological studies from our laboratory have indicated that cocaine (i.v.) exerts inhibitory effects on A10 DA neurons, due to enhanced stimulation by DA at DA autoreceptors are well as by activation of NAc-VTA feedback pathways. In the present experiments, extracellular single-unit recording and microiontophoretic techniques were used to determine the possible alterations in the mesoaccumbens DA system after repeated cocaine administration. Twice daily injections of cocaine (10 mg/kg i.p., 14 days) caused significant subsensitivity to the inhibitory effects of low i.v. doses of the DA agonist apomorphine in comparison to rats receiving similar treatments with saline or procaine. Iontophoretic application of DA to A10 DA neurons in rats treated repeatedly with cocaine (2X10 mg/kg, 14 days) also produced significantly less inhibition as compared to control rats. Cell population analysis of the VTA revealed that autoreceptor subsensitivity in cocaine-treated rats resulted in a significantly greater number of spontaneously active A10 DA neurons, and a significantly higher firing rate as compared to A10 DA neurons in control rats. In striking contrast to A10 DA cells, recordings from NAc neurons in cocaine-treated rats (2X10 mg/kg, 14 days) indicated that these cells were supersensitive to the inhibitory effects of iontophoretic DA. Although the mechanism underlying such supersensitivity remains unclear, the increased sensitivity of postsynaptic NAc DA receptors combined with the subsensitivity of A10 DA autoreceptors could lead to greatly enhanced DA transmission and may help to explain some aspects of cocaine-induced behavioral sensitization.

Animals↗
PubMed1988

B-HT 920 stimulates postsynaptic D2 dopamine receptors in the normal rat: electrophysiological and behavioral evidence.

The putative autoreceptor-selective dopamine (DA) agonist B-HT 920 was tested using electrophysiological and behavioral models thought to reflect actions at postsynaptic D2 DA receptors. Direct iontophoretic application of B-HT 920 onto nucleus accumbens neurons caused a current-dependent inhibition of firing which could be attenuated by pretreatment with alpha-methyl-p-tyrosine (to deplete DA) and reinstated (enabled) by concurrent administration of the selective D1 DA receptor agonist SKF 38393. These findings suggest that, like other selective D2 DA receptor agonists, the postsynaptic effects of B-HT 920 require concurrent stimulation of D1 DA receptors. Behavioral indices of postsynaptic D2 DA receptor stimulation (stereotyped sniffing and rearing) were also evident following combined treatment with B-HT 920 and SKF 38393. Moreover, similar "low-level" stereotyped behaviors were also observed when B-HT 920 was administered alone following pretreatment with the alpha-2 adrenoceptor antagonists idazoxane and piperoxane, suggesting that alpha-2 agonist actions of B-HT 920, in some way, mask the expression of D2 receptor-mediated stereotyped responses. When B-HT 920 was combined with SKF 38393 following pretreatment with idazoxane, both the intensity and form (continual licking and gnawing) of stereotyped behavior was enhanced. Taken together, these electrophysiological and behavioral findings indicate that B-HT 920 possesses the properties of a selective D2 DA receptor agonist and cannot be considered as a DA autoreceptor-selective compound.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1988

Is stimulation of both D1 and D2 receptors necessary for the expression of dopamine-mediated behaviors?

Recent electrophysiological findings have indicated that D1 dopamine (DA) receptor stimulation by SKF 38393 enables the inhibitory effects of the D2 receptor agonist quinpirole on nucleus accumbens neurons. In the present study, a similar interaction was shown for quinpirole-induced stereotyped behaviors. In control rats, SKF 38393 enhanced the stereotyped responses induced by quinpirole, converting lower-level stereotypies (sniffing and rearing) to more intense oral behaviors (licking and gnawing). In rats depleted of DA (79% reduction) by the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (AMPT), the behavioral effects of quinpirole were abolished. However, quinpirole-induced stereotyped responses were reinstated by SKF 38393 suggesting that D1 receptor stimulation by endogenous DA is necessary for D2 receptor-mediated stereotyped responses (sniffing, rearing). In support of this suggestion, stereotyped behaviors produced by the non-selective D1/D2 agonist apomorphine were not affected by AMPT pretreatment. In contrast to the effects of quinpirole, the ability of SKF 38393 to induce grooming responses was not abolished by AMPT pretreatment or by combined pretreatment with AMPT and reserpine (greater than 99% DA depletion). These results indicate that D1 receptor stimulation enables D2 receptor-mediated stereotyped responses, but that this relationship is not reciprocal since D2 receptor stimulation is not necessary for the grooming response elicited by SKF 38393.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1988

Electrophysiological effects of BMY 14802, a new potential antipsychotic drug, on midbrain dopamine neurons in the rat: acute and chronic studies.

The present experiments compared the ability of a new potential antipsychotic drug, BMY 14802 (alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine- butanol), to alter the electrophysiological activity of midbrain dopamine (DA) neurons in the rat substantia nigra (A9) and ventral tegmental area (A10). Intravenous administration of BMY 14802 reversed the rate-suppressant effects of the DA agonist apomorphine on both A9 and A10 DA neurons; however, this reversal occurred at significantly lower doses in A10 than in A9. These effects of BMY 14802 appeared not to be mediated by DA receptors because, unlike the established antipsychotic drugs haloperidol and clozapine, BMY 14802 pretreatment failed to block apomorphine-induced suppression of A10 DA cells. Repeated s.c. administration (28 days) of BMY 14802 (2.5-10.0 mg/kg) reduced the number of spontaneously active A10 DA cells recorded per electrode track without affecting the number of A9 DA cells. This inactivation of A10 DA neurons was only partially reversed by the administration of apomorphine. Thus, it is uncertain as to whether this effect was produced by depolarization block as occurs during repeated administration of known antipsychotic drugs. These findings indicate that BMY 14802 influences DA neurotransmission by a nondopaminergic (perhaps sigma opioid) mechanism. The more potent effect of BMY 14802 on A10 DA neurons suggests that this novel compound may exert antipsychotic effects without producing significant extrapyramidal side effects.

Animals↗
PubMed1988

Electrophysiological effects of cocaine in the mesoaccumbens dopamine system: studies in the ventral tegmental area.

Extracellular single-cell recording and microiontophoretic techniques were used to characterize the effects of cocaine on the activity of mesoaccumbens A10 dopamine (DA) neurons in the rat ventral tegmental area (VTA), which have been implicated in the rewarding effects of this and other drugs of abuse. Because cocaine inhibits the reuptake of DA, norepinephrine (NE), and serotonin (5-HT), and exerts local anesthetic actions, the possible involvement of each of these various mechanisms in the effects of cocaine on A10 DA neurons was investigated. Intravenous administration of cocaine caused a significant, dose-dependent, partial inhibition (50-70%) of the firing of antidromically identified mesoaccumbens DA neurons. Similar partial inhibition of A10 neurons was observed following intravenous administration of nomifensine, GBR-12909, and norcocaine, all of which inhibit DA reuptake. Neither the selective 5-HT uptake inhibitor fluoxetine nor the selective NE uptake inhibitor desmethylimipramine (DMI) inhibited the firing of A10 DA neurons. The local anesthetic agent procaine, which lacks DA uptake blocking efficacy, caused a slight, transient increase in firing rate. These results suggest that the effects of cocaine on A10 DA neurons are due to inhibition of DA reuptake, a conclusion that has been supported by several other findings. Pretreatment with reserpine to deplete vesicular stores of DA significantly reduced the ability of intravenous cocaine to suppress A10 DA neuronal activity. Microiontophoretic administration of cocaine caused only a weak (15-20%) inhibition of the activity of A10 DA neurons, but significantly increased and prolonged the inhibition produced by iontophoretic DA. This effect was not observed with iontophoretically administered procaine iontophoresis of cocaine also significantly potentiated the inhibition of A10 DA activity caused by electrical stimulation of the nucleus accumbens (NAc). Both unilateral ibotenic acid lesions of the NAc and hemitransections of the brain rostral to the VTA significantly reduced the inhibitory effects of intravenous cocaine on A10 DA neurons, suggesting that both somatodendritic impulse-regulating DA autoreceptors and inhibitory NAc-VTA feedback processes are involved in the effects of intravenous cocaine on A10 DA neurons. Therefore, it is hypothesized that the relatively weak inhibitory effects of cocaine on A10 DA neurons may represent a poor compensatory response to enhanced DA neurotransmission within the NAc, and may help to explain the extremely potent rewarding effects of this important drug of abuse.

Animals↗
PubMed1987

Inhibition of non-dopamine cells in the ventral tegmental area by benzodiazepines: relationship to A10 dopamine cell activity.

Previous electrophysiological studies have demonstrated that non-dopaminergic (non-DA) neurons within the substantia nigra pars reticulata (SNR) are extremely sensitive to the inhibitory effects of GABA and GABA-mimetic drugs, including benzodiazepines, whereas dopaminergic (DA) neurons in the substantia nigra pars compacta (SNC) are less sensitive to these compounds and may be influenced indirectly by SNR neurons. The interactions between A10 DA and non-DA neurons within the adjacent ventral tegmental area (VTA) are not as well characterized. In the present experiments, single unit recording and microiontophoretic techniques were used to determine the effects of benzodiazepines on DA and non-DA neurons in the VTA of chloral hydrate anesthetized rats. Diazepam, administered intravenously (i.v.), potently inhibited non-DA, SNR-like cells within the VTA. The effects of diazepam on A10 DA cells were more variable than those observed on non-DA, SNR-like cells in this region, but 77% of such cells showed moderate to marked excitation. Both of these effects were reversed by the benzodiazepine antagonist Ro 15-1788; on many cells, this agent produced marked rebound effects beyond the original basal firing rates. However, when administered alone, Ro 15-1788 exerted no effect on either cell population. Microiontophoretic administration of the benzodiazepines chlordiazepoxide and flurazepam resulted in marked inhibition of non-DA SNR-like cells, but produced either mild inhibition or no effect on A10 DA cells; excitation of DA cells was never observed even though the same neuron was excited by i.v. diazepam. These findings suggest that benzodiazepines act directly upon non-DA, SNR-like cells in the VTA to produce inhibition of activity and a disinhibition of A10 DA cells. This relationship makes it unlikely that benzodiazepines would enhance feedback inhibition of DA cells following neuroleptic administration. In fact, when administered following haloperidol, i.v. diazepam failed to reverse haloperidol-induced increases of A10 DA cell firing; if anything, diazepam further depolarized the cell. If antipsychotic drugs produce their clinical effects, in part, by inducing depolarization inactivation of DA cells, then benzodiazepines might be a useful adjunctive therapy in the treatment of schizophrenia.

Animals↗
PubMed1987

D-1 dopamine receptor stimulation enables the inhibition of nucleus accumbens neurons by a D-2 receptor agonist.

Depletion of catecholamines by pretreatment with the tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine attenuated the ability of the selective D-2 dopamine receptor agonist quinpirole to inhibit rat nucleus accumbens neurons when applied directly by microiontophoresis. Concurrent iontophoretic administration of the D-1 selective agonist SKF 38393, at currents which alone produced little inhibition, reinstated the inhibitory effect of quinpirole. These findings suggest that D-1 receptor stimulation may play a necessary 'enabling' role for D-2 receptor-mediated functional responses.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1987

D1 dopamine receptor--the search for a function: a critical evaluation of the D1/D2 dopamine receptor classification and its functional implications.

The present review focuses on the hypothesized D1/D2 dopamine (DA) receptor classification, originally based on the form of receptor coupling to adenylate cyclase activity. The pharmacological effects of compounds exhibiting putative selective agonist or antagonist profiles at those DA receptors positively coupled to adenylate cyclase activity (D1 DA receptors) are extensively reviewed. Comparisons are made with the effects of putative selective D2 DA receptor agonists and antagonists, and on the basis of this work, the DA receptor classification is critically evaluated. A variety of biochemical, behavioral, and electrophysiological evidence is presented which supports the view that D1 and D2 DA receptors can interact in both an opposing and synergistic fashion. Particular attention is focused on the possibility that D1 receptor stimulation is required to enable the expression of certain D2 receptor-mediated effects, and the functional consequences of this form of interaction are considered. A hypothetical model is presented which considers how both the opposing and enabling forms of interaction between D1 and D2 DA receptors can control behavioral expression. Finally, the clinical relevance of this work is discussed and the potential use of selective D1 receptor agonists and antagonists in the treatment of psychotic states and Parkinson's disease is considered.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1986

Effects of tiaspirone (BMY-13859) and a chemical congener (BMY-13980) on A9 and A10 dopamine neurons in the rat.

Two new potential antipsychotic drugs, BMY-13980 and BMY-13859 were compared for the ability to influence the electrophysiological activity of dopaminergic neurons in the substantia nigra zona compacta (A9 DA cells) and ventral tegmental area (A10 DA cells) in the brain of the rat. Both drugs reversed the rate-suppressant effects of the DA agonist apomorphine on DA cells in A10 to a greater extent than DA cells in A9; BMY-13980 was particularly selective in this regard. These results indicate that both drugs may exert DA antagonist effects which are suggestive of antipsychotic potential. In other experiments, the effects of chronic (28 days) treatment with BMY-13980 and BMY-13859 on the neuronal activity of DA were evaluated. Both compounds caused a significant decrease in the number of spontaneously active DA neurons in A10 recorded per electrode track, an effect previously demonstrated to be associated with antipsychotic efficacy. The drug BMY-13859, but not BMY-13980, also significantly decreased the number of spontaneously active DA cells/track in A9, an effect which may predict the liability of potential antipsychotic drugs for causing extrapyramidal motor dysfunction, including tardive dyskinesia. Thus, these experiments indicate that both BMY-13980 and BMY-13859 exert effects which may predict potential antipsychotic efficacy in clinical trials and that BMY-13980 may be less likely to cause extrapyramidal side effects.

Animals↗
PubMed1986

Comparative effects of LSD and lisuride: clues to specific hallucinogenic drug actions.

This review compares the effects of LSD and its nonhallucinogenic congener lisuride hydrogen maleate (LHM) on various biochemical, behavioral and electrophysiological indices of neuronal function. The underlying rationale is that any differences between the effects of LSD and LHM might be relevant to neuronal actions which are unique and specific to hallucinogenic drugs and thereby provide clues to the neurobiological substrates of hallucinogenesis. In biochemical studies, LHM appears to be very similar to LSD with respect to its actions on monoaminergic (5-HT, DA, NE) systems. The major difference between the two ergots appears quantitative in nature since LHM is more potent than LSD, especially on DA neurochemistry. Needed at the present time are additional comparative studies of LSD and LHM with respect to other biochemical measures, for example on the release of 5-HT and DA and comparisons at more molecular levels such as subcellular compartmentation. Also necessary are more intensive regional analyses on specific subpopulations of 5-HT and DA systems (mesolimbic, mesostriatal and mesocortical). Behavioral studies are relatively uniform in their characterization of the greater DA-ergic activity of LHM as compared to LSD. In particular, the drug discrimination (DD) procedure has indicated a more specific interaction of LSD with 5-HT neuronal systems as compared to LHM and has successfully differentiated the relative roles of 5-HT and DA systems in the behavioral effects of LSD and LHM. Electrophysiological studies have been consistent with both biochemical and behavioral findings with respect to the much greater effect of LHM on DA receptors. In fact, the effects of LSD on DA-containing neurons are both weak and heterogeneous, again indicating a need for more detailed analyses of specific DA projection systems. The greater potency of LHM than LSD on 5-HT containing dorsal raphe neurons has lessened the attractiveness of the once popular theory that hallucinogenic efficacy is related to diminution of impulse flow in 5-HT systems but has also spawned greater interest in the possible role of postsynaptic 5-HT receptors in hallucinogenic drug action. Thus far, the most interesting finding is the ability of LSD and other hallucinogens, but not LHM, to potentiate an excitomodulatory effect of 5-HT in the facial motor nucleus. If such a phenomenon occurs more generally in the CNS, the importance of this finding will be greatly enhanced. Preliminary data is presented which suggests that LSD may also induce such an effect in a limbic forebrain structure, the nucleus accumbens.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenylyl Cyclases↗
PubMed1986

Electrophysiological evidence for the existence of both D-1 and D-2 dopamine receptors in the rat nucleus accumbens.

Extracellular single-unit recording and microiontophoretic techniques were used to characterize the pharmacological properties of dopamine (DA) receptors within the rat nucleus accumbens (NAc), a forebrain structure that receives a dense innervation from mesolimbic DA-containing neurons (A10 DA neurons) located in the ventral tegmental area (VTA). Of the NAc neurons tested, 75% were inhibited by microiontophoretic administration of the selective D-2 receptor agonist, LY-141865, whereas 38% were inhibited by microiontophoretic administration of the selective D-1 receptor agonist, SKF-38393. Of the 30 NAc neurons that were tested with both of these agonists, nine were inhibited by both agonists, 11 were inhibited only by LY-141865, five were inhibited only by SKF-38393, and five were not affected by either of these compounds. The inhibitory effects of LY-141865 were blocked and reversed by either intravenous or iontophoretic administration of the selective D-2 antagonist (-)-sulpiride, which, however, failed to alter the inhibitory effects of SKF-38393. In contrast, the purportedly selective D-1 antagonist, SCH-23390, selectively blocked and reversed the inhibitory effects of SKF-38393, suggesting that the two agonists were producing their inhibitory effects via distinct DA receptors. Additional experiments indicated that intravenous administration of LY-141865 caused a biphasic increase/decrease in the activity of NAc neurons. The initial rate increase was apparently due to disinhibition since it was also shown that D-2 DA receptors located on A10 DA neurons exhibited a 3-10-fold greater sensitivity to LY-141865 and DA as compared to the NAc D-2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1985

Beneficial short-term effects of unprocessed wheat bran on lipid and glucose metabolism in man.

Supplementation of the normal diets of seven healthy 18-22-year old male and female volunteers with 0.15 g unprocessed wheat bran/kg body weight/d for 6 weeks increased fibre consumption by 35 per cent without noticeably affecting the intake of other major nutrients. Fasting concentrations of plasma total cholesterol, triglyceride and glucose were unchanged by wheat bran supplementation, whereas HDL-cholesterol was increased and LDL-cholesterol decreased by 46 per cent and 25 per cent respectively after 6 weeks. Glycosylated haemoglobin was decreased by 18 per cent, 27 per cent and 45 per cent after 2, 4 and 6 weeks. The results illustrate the potential value of consuming relatively small amounts of unprocessed wheat bran for the promotion of health and treatment of certain metabolic diseases in man.

Adolescent↗
PubMed1985

Electrophysiological effects of cholecystokinin: central dopaminergic systems.

The coexisting cholecystokinin (CCK)/dopamine (DA) neurons are located predominantly in the ventral tegmental area of the rat and project to the medial part of the nucleus accumbens (NAc). Iontophoretically applied CCK consistently activated presumed CCK/DA cells as well as those cells receiving CCK/DA projections in the medial NAc. Unsulfated CCK had little or no effect. The putative CCK antagonist proglumide selectively blocked the activation produced by CCK but not glutamate. DA also reversed CCK-induced excitation, presumably by its hyperpolarizing actions. These results suggest that CCK and DA may interact to influence the CCK/DA system.

Animals↗