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Biomedical subjects

F J White

Publications and source records attributed to F J White.

At least 109 records · Page 6Linked to original sources
PubMed1984

Electrophysiological evidence for A10 dopamine autoreceptor subsensitivity following chronic D-amphetamine treatment.

Extracellular single unit recording techniques were used to determine whether chronic treatment with D-amphetamine (AMP) causes a subsensitivity of dopamine (DA) autoreceptors on A10 DA neurons in the rat ventral tegmental area. Either once daily or twice daily intraperitoneal (i.p.) administration of 5.0 mg/kg AMP for 1 week significantly reduced the ability of intravenous (i.v.) AMP and apomorphine (APO) to suppress the firing of A10 DA neurons when tested 24-32 h after the final administration of i.p. AMP. For both of these treatment regimens, the dose-response curves for AMP and APO induced suppression were shifted approximately 4-fold to the right of control. Following an 8 day abstinence period, only the rats that received twice daily AMP injections exhibited subsensitivity to i.v. AMP and APO; the degree of subsensitivity was reduced by 50% as compared to that observed 24-32 h post-treatment. These results were not due to acute tolerance phenomena since a single i.p. injection of AMP 24-32 h before testing failed to alter sensitivity to i.v. AMP and APO. Rather, the results indicate that chronic AMP treatment reduces the sensitivity of A10 DA neurons to DA agonists. DA autoreceptor subsensitivity was demonstrated further by the finding that the ability of microiontophoretically applied DA to suppress A10 DA neuronal activity was markedly reduced (5.8-fold shift of the dose-response curve) by chronic AMP treatment (2 X 5 mg/kg/day). In contrast, there was no alteration in the ability of iontophoretic gamma-amino butyric acid (GABA) to suppress A10 DA activity in chronic AMP rats. Chronic AMP-treatment also increased the number of spontaneously active A10 DA neurons as well as their basal firing rate. It is suggested that the ability of chronic AMP treatment to decrease the auto-regulatory ability of A10 DA neurons may be related to the phenomena of behavioral sensitization and AMP psychosis.

Animals↗
PubMed1984

Interactions of cholecystokinin octapeptide and dopamine on nucleus accumbens neurons.

Local microiontophoretic administration of cholecystokinin octapeptide (CCK) increased the firing rates of neurons in the dorsomedial nucleus accumbens (NAc), but exerted little to no effect on lateral NAc neurons. This regionally defined CCK-effect corresponds to the topographical distribution of CCK-like immunoreactive nerve terminal fiber networks and CCK receptors within the NAc. The excitatory effects of CCK were selectively antagonized by the CCK antagonist proglumide. Dopamine (DA) decreased the firing of NAc cells and reversed CCK-induced excitation. These results suggest that CCK and DA may interact to influence the activity of neurons within the dorsomedial NAc.

Animals↗
PubMed1984

A10 dopamine neurons: role of autoreceptors in determining firing rate and sensitivity to dopamine agonists.

The present experiments investigated the relationship between the spontaneous basal firing rate of A10 dopamine (DA) neurons and their sensitivity to the rate-suppressant effects of intravenously administered apomorphine (APO) and d-amphetamine (AMP) as well as microiontophoretically ejected DA. The results indicated highly significant inverse relationships between basal neuronal activity and sensitivity to DA and DA agonists, i.e. the faster the spontaneous rate of an A10 DA neuron, the less sensitive that cell was to agonist-induced suppression. This relationship was not found for the rate suppressant effects of iontophoretic gamma-aminobutyric acid. There were no significant differences between the effects of iontophoretic DA on pre-glutamate and glutamate-driven activity of the same A10 DA neurons indicating that faster firing rates, per se, did not determine the sensitivity of these cells to DA agonists. Rather, these results suggest that both spontaneous activity and sensitivity to DA agonists may be determined by the density (or sensitivity) of DA autoreceptors on A10 DA neurons. This hypothesis was supported by the finding that antidromically identified mesocortical DA neurons, which were significantly less responsive to DA, APO and AMP exhibited significantly faster firing rates than other A10 DA neurons. Thus, this subpopulation of A10 DA neurons is primarily made up of cells with low autoreceptor density (or sensitivity).

Action Potentials↗
PubMed1984

Pharmacological characterization of dopamine autoreceptors in the rat ventral tegmental area: microiontophoretic studies.

Extracellular single-cell recording and microiontophoretic techniques were used to characterize the presynaptic dopamine (DA) receptors (autoreceptors) on A10 DA neurons in the rat ventral tegmental area. Thus, the ability of various agonists to inhibit the activity of A10 DA neurons was compared. DA and the DA agonists N-n-propylnorapomorphine (NPA), apomorphine, lisuride, pergolide, LY141865 and bromocriptine all suppressed the activity of A10DA neurons. NPA was the most potent exogenous agonist, exerting effects that were similar to an equimolar concentration of DA (0.01 M). When ejected at equimolar concentrations (0.01 M) and equivalent ejection currents, the rank order of potency for these agonists was DA = NPA greater than LY141865 greater than pergolide = lisuride = apomorphine greater than norepinephrine greater than bromocriptine. The alpha-2 adrenoceptor agonist clonidine, the beta adrenoceptor agonist isoproterenol, the D-1 specific DA agonist SKF 38393 and the hallucinogenic ergot lysergic acid diethylamide exerted only weak effects or were inactive. The D-2 specific DA antagonist sulpiride completely blocked the rate-suppressant effects of DA and DA agonists but not those of gamma-aminobutyric acid. The purported D-1 specific DA antagonist SCH 23390 failed to block the effects of either DA or the D-2 specific DA agonist LY141865. These results indicate that DA agonists suppress the activity of the majority of A10 DA neurons by acting directly on somatodendritic DA autoreceptors which exhibit the pharmacological characteristics of D-2 receptors.

Animals↗
PubMed1983

Differential effects of classical and atypical antipsychotic drugs on A9 and A10 dopamine neurons.

Prolonged treatment with classical antipsychotic drugs decreased the number of spontaneously active dopamine neurons in both the substantia nigra (A9) and the ventral tegmental area (A10) of the rat brain. In contrast, treatment with atypical antipsychotic drugs selectively decreased the number of A10 dopamine neurons. Related drugs lacking antipsychotic efficacy failed to decrease dopamine activity. These findings suggest that the inability of atypical antipsychotic drugs to decrease A9 dopamine neuronal activity may be related to their lower potential for causing tardive dyskinesia and that the inactivation of A10 neurons may be involved in the delayed onset of therapeutic effects during treatment.

Animals↗
PubMed1983

Comparison of the effects of chronic haloperidol treatment on A9 and A10 dopamine neurons in the rat.

The effects of chronic haloperidol (CHAL) treatment on A9 and A10 dopamine (DA) neurons were compared using extracellular single cell recording techniques. CHAL caused a time-dependent reduction in the number of spontaneously active A9 and A10 DA cells and induced an irregular firing pattern in many of the DA cells that remained active. Both of these effects occurred earlier and to a greater extent in A10 than in A9. Intravenous injection of the DA agonist apomorphine reversed both the reduction of active DA neurons and the irregular discharge pattern, suggesting that both effects were due to the process of depolarization inactivation. Lesions of the nucleus accumbens (NAc) produced by ibotenic acid prevented the development of depolarization inactivation of A10 DA neurons, indicating that this process is mediated primarily by NAc-A10 feedback pathways. The results suggest that the slow development of depolarization inactivation of DA cells produced by CHAL may contribute to the delayed onset of the clinical effects of long-term treatment with antipsychotic drugs.

Animals↗
PubMed1983

Antagonism of a behavioral effect of LSD and lisuride in the cat.

These experiments investigated the role of serotonin 5-HT) and dopamine (DA) receptors in the limb-flick (LF) response elicited by the hallucinogenic ergot LSD and its nonhallucinogenic structural congener lisuride. Pretreatment with either the 5-HT antagonist pizotifen (BC-105) or the DA antagonist haloperidol significantly attenuated LF elicited by either LSD or lisuride. Thus, the LF model failed to differentiate the neuropharmacological actions of LSD and lisuride. Cocaine also prevented LSD- and lisuride-elicited LF simply by reducing the activity of cats (response competition) suggesting the need for caution in interpreting 'antagonism' of the LF response.

Animals↗
PubMed1982

Behavioral and biochemical evidence for serotonergic actions of tetrahydro-beta-carbolines.

In two groups of rats trained to discriminate LSD (0.1 mg/kg or 0.24 mg/kg) from saline, tetrahydro-beta-carboline (THBC; 1-12 mg/kg as free base) and its derivative 6-methoxy-THBC (1-12 mg/kg as free base) substituted partially for LSD. The substitution of THBC for 0.1 mg/kg of LSD was analyzed further with antagonism tests in 16 animals and was attenuated by the serotonin (5-HT) antagonist BC-105 (pizotifen; 3 mg/kg) but not by the dopamine (DA) antagonist haloperidol (0.1 mg/kg). It was abolished by pretreatment with the 5-HT synthesis inhibitor p-chlorophenylalanine (100 mg/kg/day for 3 days). In addition, THBC was found to inhibit 3H-LSD binding to homogenates of rat frontal cortex with an IC50 value of 4 microM which is similar to that previously reported for other 5-HT agonists. These data indicate that THBCs exert potent 5-HT agonist actions. Since THBCs have recently been found in mammalian brain and other tissues, the present results are of interest in relation to a possible role of these substances in endogenous psychosis.

Animals↗
PubMed1982

Dopaminergic and serotonergic mediation of the discriminable effects of ergot alkaloids.

The involvement of dopamine (DA) and serotonin (5-HT) neuronal systems in the discriminative stimulus effects of various ergot derivatives was assessed by administering four ergots to 36 rats which had been trained to discriminate either apomorphine (APO) or d-lysergic acid diethylamide (LSD) from saline. Lergotrile, lisuride and LSD substituted for APO (0.25 mg/kg) while bromocriptine and ergonovine (ergometrine) did not; only lisuride mimicked LSD (0.08 mg/kg). Antagonism tests showed that the DA antagonist haloperidol but not the 5-HT antagonist BC-105 (pizotifen) blocked the APO cue; both the LSD cue and the substitution of LSD for APO were blocked by BC-105 but not by haloperidol. It was concluded that DA receptor activation plays a prominent role in the discriminative stimulus effects of lergotrile and lisuride as well as APO and a secondary role in the LSD cue; 5-HT seems to be of major importance in the mediation of the effects of LSD and, to a lesser extent, lisuride. The functions of the two monoamines in the discriminable effects of bromocriptine and, particularly, ergonovine are less clear.

Animals↗
PubMed1982

Lysergic acid diethylamide (LSD) and lisuride: differentiation of their neuropharmacological actions.

The nonhallucinogenic ergot derivative lisuride exerts many pharmacological effects that are similar to those of its hallucinogenic congener, lysergic acid diethylamide (LSD). Animals trained to discriminate between the presence of one drug and the other can be used to differentiate the actions of these compounds on a neuronal level. The discriminative stimulus effect of LSD (the LSD cue) is similar to that of the serotonin agonist quipazine, whereas the lisuride cue is similar to that of the dopamine agonist apomorphine. These data support the hypothesis that serotonin is intricately involved in the hallucinogenic effects of LSD.

Animals↗
PubMed1982

Training dose as a factor in LSD-saline discrimination.

To assess the effects of training dose on the discriminative stimulus properties of LSD, groups of rats (eight/group) were trained to discriminate each of three doses of LSD (0.02, 0.08 or 0.32 mg/kg) from saline. This was accomplished by using a method of progressively altering dose ("fading"). Dose-response tests revealed that the three LSD cues were specific to the dose used during training and that, as the training dose declined, the slope of the LSD dose-response curve became less steep. Substitution tests with direct serotonin (5-HT) agonists (quipazine, MK-212, 5-methoxy-N,N-dimethyltryptamine) and antagonism tests with central 5-HT antagonists (methiothepin and cyproheptadine) indicated that 5-HT is involved in mediating the in vivo effects of LSD and that training dose co-determines (along with the dose of the test compound) the extent of substitution or antagonism. In addition, substitution tests with the peripherally-active 5-HT agonist 5-methoxytryptamine and 5-HT antagonist xylamidine suggested that the peripheral serotonergic actions of LSD may be involved (in part) in the low dose (0.02 mg/kg) LSD cue. In contrast to 5-HT, dopamine (DA) did not appear to be involved in the discriminative stimulus properties of LSD, because no significant dose or group effects were seen during tests with the DA agonists apomorphine and d-amphetamine or the DA antagonist haloperidol.

Animals↗
PubMed1982

Progesterone-binding globulin and progesterone in guinea-pigs after ovariectomy, abortion and parturition.

The level of progesterone in the serum of pregnant guinea-pigs which continued their pregnancies after ovariectomy on Day 30 fell and then rose again. In contrast, progesterone-binding globulin (PBG) was apparently not affected. PBG did however fall in guinea-pigs which aborted and also after parturition. It is apparent therefore that high PBG levels were associated with continued pregnancy. The half life of PBG was found to be approximately 2 days.

Abortion, Spontaneous↗
PubMed1982

Analyzing mechanism(s) of hallucinogenic drug action with drug discrimination procedures.

Some of the advantages of using drug discrimination (DD) procedure to analyze the mechanisms of action of hallucinogenic and related drugs were illustrated by reviewing research with lysergic acid diethylamide (LSD). Because they ensure that drug-induced alterations in interoceptive "state" become biologically meaningful "cues," these procedures are reliable, robust, sensitive and specific. With reference to LSD, many DD experiments suggest: (1) that while hallucinogens substitute for (mimic) LSD (in rats), such substitution does not predict hallucinogenic potency (in humans) but does predict similarities in mechanism(s) of action; (2) the behavioral (in vivo) effects of LSD, unlike those of some of its congeners, are mediated primarily by central, serotonergic (5-HT) neuronal mechanism although LSD may also have (secondary) dopamine (DA) agonist properties; (3) both the locus and the nature of these LSD-5-HT interactions are unclear: cells arising from B-7, B-8 and B-9 regions of the dorsal-medial raphe may be involved; pretreatment with agents that deplete 5-HT and increase the stereospecific binding of 3H-LSD in vitro (p-chlorophenylalanine; 5,7-dihydroxytryptamine) enhance sensitivity to LSD in vivo.

Animals↗
PubMed1982

The role of dopamine and serotonin in the discriminative stimulus effects of lisuride.

The discriminative stimulus properties of the clinically important ergot derivative lisuride hydrogen maleate (LHM) were investigated by training groups of rats (13 per group) to discriminate either of three training doses of LHM (0.02, 0.08 or 0.32 mg/kg) from saline. Dose-response tests showed that the three LHM cues were specific to the dose used during training and the dose-response curve became more steep as the training dose increased. In substitution tests, the direct dopamine (DA) agonists apomorphine and lergotrile substituted for LHM and the potency order of the LHM-like effect (LHM greater than apomorphine greater than lergotrile) corresponded to previous electrophysiological and biochemical results. The indirect DA agonist d-amphetamine did not substitute for LHM. The direct serotonin (5-HT) agonists quipazine, MK-212 and 5-methoxy-N,N-dimethyltryptamine produced dose-dependent, but incomplete, substitution for LHM which covaried with LHM training dose. In antagonism tests, only drug capable of blocking DA receptors, haloperidol and methiothepin, attenuated the LHM cues; the 5-HT antagonists cyproheptadine, BC-105 and xylamidine were ineffective. These data indicate that the primary neuronal action mediating the discriminative stimulus effects of a wide range of LHM doses was direct activation of central DA receptors. The 5-HT agonist actions of LHM proved to be secondary in that 5-HT agonists substituted only partially for LHM and 5-HT antagonists failed to attenuate LHM cues.

Animals↗
PubMed1981

A neuropharmacological analysis of the discriminative stimulus properties of fenfluramine.

Rats were trained to discriminate fenfluramine (1.0 mg/kg) from saline in a two-lever drug discrimination task. The dose-response curve for this discrimination was orderly with an ED50 of about one-half of the training dose (0.52 mg/kg). In substitution tests, indirect (p-chloroamphetamine) and direct (quipazine, MK-212, lisuride) serotonin (5-HT) agonists substituted for fenfluramine. Since none of these compounds have been reported to be hallucinogenic and the potent hallucinogen LSD did not substitute completely, it was suggested that the discriminative stimulus properties of fenfluramine are not related to its ability to produce hallucinations in humans. The fenfluramine cue, like the quipazine cue, was antagonized by the 5-HT antagonists cyproheptadine and methiothepin. Unlike quipazine, fenfluramine was also partially antagonized by the 5-HT uptake inhibitor, fluoxetine, and the 5-HT synthesis inhibitor, p-chlorophenylalanine. Thus, the fenfluramine cue differs from that of quipazine in that it is mediated via indirect actions on 5-HT receptors. Since the indirect dopamine (DA) agonist d-amphetamine failed to substitute and the DA antagonist haloperidol failed to block the fenfluramine cue, a mediating role for DA was not indicated. Another indirect DA agonist, cocaine, substituted partially for fenfluramine, a result which paralleled that seen with fluoxetine. Both of these partial substitutions were reduced by cyproheptadine; therefore, it was concluded that these effects may be due to the common ability of cocaine, fluoxetine, and fenfluramine to inhibit 5-HT uptake.

Animals↗
PubMed1981

Lack of specificity of an animal behavior model for hallucinogenic drug action.

It has been proposed recently that the occurrence of drug-induced limb-flicking (LF) and abortive grooming (AG) in cats can serve as a viable animal behavior model for the actions of hallucinogens in humans. If this is the case, such behaviors should occur reliably following the administration of drugs that produce hallucinations in humans and should not occur after administration of other, non-hallucinogenic drugs--a hypothesis that was examined in the present experiment. The frequency of LF and AG were observed in 12 cats which were given a wide range of doses of the potent hallucinogen, d-LSD (0.01-0.16 mg/kg), as well as several other compounds. The results showed that three non-hallucinogenic agents which are related to LSD in various ways, the ergot derivative lisuride, the serotonin agonist, quipazine, and the dopamine agonist, apomorphine, significantly increased LF frequency. Lisuride and quipazine also caused AG. Cocaine did not elicit either behavior. Thus, it was concluded that the proposed model cannot be regarded as specific to hallucinogenic drugs. In addition, the frequency of these behaviors, as well as their reliability and robustness, were shown to be party dependent on the environment in which observation occurs.

Animals↗
PubMed1981

Concentration and relationship to progesterone of progesterone-binding globulin in pregnant guinea-pigs: measurement by progesterone tracer binding assay.

A single-point progesterone tracer binding assay (TBA) was developed to measure the concentration of progesterone-binding globulin (PBG) in the serum of pregnant guinea-pigs. Tritiated progesterone was added to dilutions of a reference serum, the percentage bound calculated and a standard curve constructed. The amount of progesterone tracer bound to serum samples was determined, and the concentration of binding protein in the sample relative to the reference was calculated. The molar concentration in the reference serum was determined by Scatchard analysis. The TBA could readily process 30 samples per day. There was a rapid rise in PBG concentrations between days 15 and 20 of gestation, in parallel with progesterone concentrations. The molar ratio of PBG: progesterone was approximately 10:1 after this time, until about day 45 when there was an increase in ratio.

Alpha-Globulins↗