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Biomedical subjects

R B Mailman

Publications and source records attributed to R B Mailman.

At least 91 records · Page 5Linked to original sources
PubMed1986

Motor effects of calcitonin administered intracerebroventricularly in the rat.

In rats treated with salmon calcitonin (CT) administered intracerebroventricularly (i.c.v., 85 or 8.5 pmol), spasmodic body movements, hopping and tail jerks, collectively termed dyskinesia, appeared within 1 h of administration and persisted for at least 24 h. In addition, spontaneous grooming, rearing and locomotion occurred less often in CT-treated rats than in vehicle-injected animals, while the incidence of both sniffing and nose poking remained essentially unchanged. The CT failed to displace either [3H]dopamine or [3H]spiperone from striatal membranes, and the behavioral effects were not blocked by haloperidol or SCH 23390, suggesting that the peptide did not directly affect dopamine receptors. The dyskinesia was not blocked by scopolamine, atropine, muscimol, diazepam or ketanserin. These data are consistent with the hypothesis that a compound with recognition characteristics similar to those of salmon CT may function as a neurotransmitter-modulator in the central nervous system.

Animals↗
PubMed1986

S(-)DP-5,6-ADTN as an in vivo dopamine receptor ligand: relation between displacement by dopamine agonists and their pharmacological effects.

The use of (-)DP-5,6-ADTN as a non-radioactively labeled ligand for an in vivo DA receptor assay is described and compared with racemic DP-5,6-ADTN, previously used for that purpose. The effects of four DA agonists (NPA, bromocriptine, DP-7-OH-ATN and 3-PPP) on the specific (-)DP-5,6-ADTN binding are related to their potencies to decrease striatal HVA concentrations and to induce stereotypy in rats. NPA and DP-7-OH-ATN caused a maximal decrease in HVA levels, when only a fraction of the receptors were occupied, while the occurrence of stereotypy was associated with a high receptor occupation, reflecting the higher affinity of these agonists for presynaptic than for postsynaptic receptors. Bromocriptine did not show this effect, as the dose-response relationships for HVA decrease, for induction of stereotypy and for the decrease in specific (-)DP-5,6-ADTN binding were all virtually equal to each other. While NPA and bromocriptine behaved as full postsynaptic agonists, in that maximal stereotyped behavior was observed after high doses, DP-7-OH-ATN was found to be a partial postsynaptic agonist, as it did not induce maximal stereotypy at a maximal receptor occupation. Racemic 3-PPP only caused a state of hypoactivity, but did neither affect specific (-)DP-5,6-ADTN binding nor striatal HVA levels. Our results are discussed in view of theories on the relation between receptor occupation and pharmacological effects and it is concluded that the in vivo receptor binding method using (-)DP-5,6-ADTN is a very useful tool for such investigations.

Animals↗
PubMed1986

Antagonistic behavioral effects of calcitonin and amphetamine in the rat.

Using an automated testing apparatus, the hypermotility induced by amphetamine had previously been found to be inhibited by intracerebroventricular (ICV) administration of salmon calcitonin (CT). The present study used a computer-supported direct observational method to characterize further the interactions of CT and amphetamine. After treatment with amphetamine (1.5 mg/kg, IP), the incidence of rearing, nose poking, and locomotion was reduced in rats that were pretreated with 85 pmol salmon CT ICV; the incidence of sniffing and grooming remained unchanged. CT-induced dyskinesia, a unique consequence of central CT treatment, was attenuated but not abolished by administration of amphetamine. These results support the premise that a compound with receptor recognition characteristics similar to those of salmon CT may act as a neurotransmitter-modulator in the central nervous system.

Amphetamine↗
PubMed1986

SCH23390 effects on apomorphine-induced responses of nigral dopaminergic neurons.

SCH23390 is a dopamine antagonist which has a high affinity for D1-like dopaminergic receptors. Receptor binding studies demonstrated significant levels of specific SCH23390 binding within nigral tissue. Therefore, electrophysiological experiments were conducted to determine if this antagonist influenced apomorphine-induced suppressions of unit firing recorded from dopaminergic cells of the substantia nigra zona compacta. Results presented in this report indicate that the autoreceptors located on dendrites and cell bodies of dopamine-containing neurons are not directly acted upon by SCH23390. This conclusion is drawn because: doses of SCH23390 known to block behaviors caused by dopamine agonists were ineffective in blocking rate reductions produced by apomorphine and pretreatment with 0.1 mg/kg of SCH23390 did not change the apomorphine dose-response curve for inhibition of dopaminergic neurons. Consistent with this finding, microinjections of SCH23390 into the zona compacta did not alter apomorphine-induced behaviors which are known to be blocked by haloperidol (a D2-like antagonist) intranigral injections. However, when only the larger apomorphine doses (64 and 128 micrograms/kg i.v.) are considered, SCH23390 pretreatment did attenuate the maximum response to apomorphine in some nigral cells. Because larger apomorphine concentrations alter striatal activity, such results may be reflective of alterations in a subpopulation of nigral neurons which are postsynaptic to neurons containing D1-like receptors and located elsewhere in the brain (e.g., in striatum). Collectively, these results agree with previous studies which suggest that dopamine receptors located on dopamine-containing neurons of the substantia nigra zona compacta are likely not of the D1-type.

Analysis of Variance↗
PubMed1985

SCH23390 causes persistent antidopaminergic effects in vivo: evidence for longterm occupation of receptors.

SCH23390 has neurochemical properties characteristic of a specific D1 dopamine receptor antagonist. However, it is a potent inhibitor of dopamine-mediated behaviors which previously had been thought to be linked to D2 receptors. The metabolism of SCH23390 following parenteral administration to rats was much more rapid in the periphery than in brain, and SCH23390 had behavioral effects long after its circulating concentration had declined below detectable levels. Furthermore, the stimulation of adenylate cyclase by dopamine was attenuated in striatal homogenates taken from rats treated with SCH23390 as much as twelve hours before sacrifice. Pretreatment with cis-flupenthixol, a compound with equivalent D1 potency in vitro, failed to inhibit dopamine-stimulated adenylate cyclase activity one or four hours following injection, despite the fact that this dose produced significant behavioral effects. These data indicate that SCH23390 may act with unusual tenacity at certain sites in the central nervous system.

Adenylyl Cyclases↗
PubMed1985

A computer-supported method for analyzing behavioral observations: studies with stereotypy.

The present report describes an observational method for quantifying behavior including drug-induced stereotypy, and employs an electronic data-collecting device with microcomputer hardware and software support. This method generates interval scale data, thus permitting the application of powerful parametric statistics, and also allows examination of discrete response topographies. For example, the method permits parametric comparisons among drug doses, treatment groups, as well as over time. The effects of the atypical antipsychotic drug thioridazine on apomorphine-induced stereotypy were used to illustrate the utility of the method. Thioridazine was found, among other effects, to potentiate apomorphine-induced gnawing and licking, while blocking sniffing.

Animals↗
PubMed1985

Binding of [3H]SCH23390 in rat brain: regional distribution and effects of assay conditions and GTP suggest interactions at a D1-like dopamine receptor.

The compound [9-3H]SCH23390 [R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7- ol] was synthesized, and the binding of this purportedly selective antagonist of D1 3,4-dihydroxyphenylethylamine (dopamine) receptors was characterized. The regional distribution of high-affinity, specific [3H]SCH23390 binding sites in the rat brain correlated well with levels of endogenous dopamine. Receptor densities were greatest in corpus striatum, nucleus accumbens, and olfactory tubercle; intermediate levels were found in several limbic and cortical areas, whereas few sites were detectable in cerebellum, brainstem, and ol-factory bulb. Specific binding in caudate-putamen was found to be both temperature- and pH-dependent, with optima at 25-30 degrees C and pH 7.8-8.0. Scatchard or Woolf analyses of binding in caudate-putamen suggest that most of the sites are either of a single class or of classes with similar characteristics (KD = 0.7 +/- 0.1 nM; Bmax = 347 +/- 35 fmol/mg of protein). Both dopamine and cis-flupenthixol altered the slope but not the intercept of lines generated by Scatchard analysis, suggesting a competitive mode of inhibition of [3H]SCH23390 binding. Competition for binding by dopamine or the D1 agonist SKF38393 was inhibited by guanine nucleotides, whereas GTP had little effect on the competition for binding by the antagonist cis-flupenthixol. The competition for [3H]SCH23390 binding sites by dopamine was much more sensitive to GTP than was competition for [3H]spiperone binding. These data support the hypotheses that [3H]SCH23390 binds to recognition sites that differ from those previously described using other radiolabeled dopamine antagonists and that these sites have the characteristics expected of dopamine receptors.

Animals↗
PubMed1985

Analytical considerations for quantitative determination of serotonin and its metabolically related products in biological matrices.

We discuss the use of "high-performance" liquid chromatography with electrochemical detection for the quantification fo serotonin (5-hydroxytryptamine) and metabolically related products (i. e., 5-hydroxyindoleacetic acid and 5-hydroxytryptophan) in biological matrices. Two methods are described: one for routine quantification of nanogram amounts or more; the other a two-column purification-separation ("trace enrichment") technique for determining subnanogram amounts of these compounds. Various factors affecting the liquid-chromatographic separation and quantification of 5-hydroxy-indoles are detailed, including selection of appropriate internal standard, sample purification, and effects of changes in mobile phase composition, e.g., ion-pair reagent, organic modifier content, and pH. We describe in detail the trace-enrichment method for determinations in the range of 25 pg to 25 ng, and discuss the general factors to consider when developing or modifying an assay for specific applications.

5-Hydroxytryptophan↗
PubMed1984

AF64A, a cholinergic neurotoxin, selectively depletes acetylcholine in hippocampus and cortex, and produces long-term passive avoidance and radial-arm maze deficits in the rat.

The behavioral and biochemical effects of AF64A, a presynaptic cholinergic neurotoxin, were investigated. Bilateral administration of this compound into the lateral cerebral ventricles produced transient and dose-related effects on sensorimotor function and long-term impairments of cognitive behavior. Male Fischer-F344 rats dosed with either 15 or 30 nmol of AF64A reacted 29-62% faster than CSF-injected controls in a hot-plate test 14 (but not 1, 7, 21 or 28) days following dosing. The group administered 15 nmol of AF64A was also significantly more active (41%) than controls 28 days following dosing. The activity level of this group was comparable to that of controls at other times and hyperactivity was never observed in the 30 nmol group. Retention of a step-through passive avoidance task, assessed 35 days after dosing, was impaired in both the 15 and the 30 nmol groups. Their step-through latencies were significantly shorter than the control latencies, and they exhibited more partial entries during the 24-h retention test. Radial-arm maze performance, measured 60-80 days following treatment, was markedly impaired in the treated groups. Animals treated with AF64A made fewer correct responses in their first 8 choices, required more total selections to complete the task, and had an altered pattern of spatial responding in the maze. The neurochemical changes produced by AF64A, determined 120 days after dosing, were specific to the cholinergic system and consisted of decreases of ACh in both the hippocampus (15 and 30 nmol groups) and the frontal cortex (30 nmol group). The concentrations of catecholamines, indoleamines, their metabolites and choline in various brain regions were not affected by AF64A. Furthermore, histological analysis revealed that the doses of AF64A used in the present study did not damage the hippocampus, the fimbria-fornix, the septum or the caudate nucleus. These data support the contention that cholinergic processes in the hippocampus and/or frontal cortex play an important role in learning and memory processes. Furthermore, based upon the behavioral and biochemical data presented, it is suggested that AF64A could be a useful pharmacological tool for examining the neurobiological substrates of putative cholinergic disorders such as senile dementia of the Alzheimer's type.

Acetylcholine↗
PubMed1984

Effects of trimethyltin on dopaminergic and serotonergic function in the central nervous system.

The effects of trimethyltin (TMT) administration on regional concentrations of dopamine (DA), serotonin (5-HT), and their metabolites were determined. Acute administration of 3 or 7 mg/kg TMT (as the chloride) to adult male Long-Evans rats caused alterations in both dopaminergic and serotonergic function in brain at 7 days posttreatment. Dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) concentrations were decreased in the nucleus accumbens of rats treated with 7 mg/kg, with a trend occurring with the 3-mg/kg dose group. Conversely, concentrations of DA or DOPAC were not altered in striatum, olfactory tubercle, septum, or amygdala/pyriform cortex. Administration of 3 mg/kg TMT decreased the concentration of serotonin in striatum and nucleus accumbens, and increased the concentration of 5-hydroxyindoleacetic acid (5-HIAA) in hippocampus. The 7-mg/kg dose resulted in increased concentrations of 5-HIAA in striatum, nucleus accumbens, septum, amygdala/pyriform cortex, and hippocampus, and also decreased the concentration of 5-HT only in amygdala/pyriform cortex. The ratio of 5-HIAA to 5-HT (an indirect estimate of serotonin turnover) was increased in all brain regions of rats treated with 7 mg/kg, and in nucleus accumbens and amygdala/pyriform cortex of rats treated with 3 mg/kg. Conversely, no alteration in the DOPAC to DA ratio was found in any region of brain in rats killed at 7 days, nor was there a change in dopamine receptors (as measured by [3H]spiperone binding) in rats treated with 7 mg/kg TMT and killed 7 days following exposure. Thus, the acute sequelae of TMT neurotoxicity appears to involve primarily serotonergic systems, and these effects may be related to the behavioral effects resulting from TMT administration.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1984

The effects of lead administration during development on lithium-induced polydipsia and dopaminergic function.

Previous studies have demonstrated that postnatal (days 2-29 of life) administration of lead (200 mg/kg/day by gavage) to Long-Evans rats caused permanent increases in lithium-induced polydipsia (LIP). These lead-induced increases in LIP were apparently not of renal origin, did not occur in animals treated with lead after day 30, and persisted for at least 6 months. The present studies have narrowed the dose-time window for lead-induced increases in LIP. The first study showed that continuous administration of lead (200 mg/kg/day, p.o.) in the form of lead acetate during days 2-9 of life caused increases in LIP (P = 0.022). Although lead-induced increases in LIP were not statistically significant (P = 0.084) for the group administered lead from days 9 to 19, the lack of a significant difference between the 2-9- and 9-19-day groups suggested that lead treatment during either of these time periods would result in LIP increases. Lead administration between days 19 and 29 of life was not effective in increasing LIP (P = 0.8). In the second study, a single dose of lead (200 mg/kg/day) was administered either on day 5 or 15 of life. Concentrations of lead in the blood on day 30 of life averaged 23.2 micrograms/100 ml for treated rats versus 4.8 micrograms/100 ml for controls. When tested at approximately 90 days of age, both groups showed significant increases in LIP (P = 0.028). The rats from this second study were also examined for changes in nigrostriatal dopamine function, since this pathway is known to be essential for LIP.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1984

Serum effects confound the neuroleptic radioreceptor assay.

The neuroleptic radioreceptor assay (NRRA) is used widely to monitor total neuroleptic-like activity (NLA) in patients taking one or more antipsychotic drugs. The original report of Creese and Snyder (1) stated that serum alone caused a small effect on binding which was negligible compared to normal daily variations in the assay. Conversely, in studies with striata from rat or cow brain, we found that sera from healthy, drug free volunteers, when used at 50 microL/1 mL assay volume, caused marked inhibition of binding. Although any sample of serum causes reproducible inhibition with a given preparation of bovine or rat striatal membranes, the effects of various serum samples may differ markedly when several striatal membrane preparations are compared. Moreover, samples taken from people at different times may also vary, although less than the interindividual differences. Despite this variance, the slopes of log-logit plots were equal to 1 either in the presence or absence of serum. Because of the differences in the interaction of individual sera with different membrane preparations, it is difficult to compensate accurately for this serum effect by simply including control serum in the standard curve. Thus, the use of the NRRA as a quantitative tool in the clinical pharmacology of neuroleptics may be limited by this non-specific effect of serum, and this finding may offer one explanation for some of the inconsistencies found in comparing the NRRA with direct analytical methods.

Animals↗
PubMed1984

An improved, automated adenylate cyclase assay utilizing preparative HPLC: effects of phosphodiesterase inhibitors.

Analysis of adenylate cyclase (ACase) activity in broken cell preparations usually involves conversion of [alpha-32P]ATP to [32P]cyclic AMP (cAMP) followed by purification of cAMP by liquid chromatographic methods. An automated, preparative reverse-phase HPLC procedure was developed that purifies cAMP rapidly and decreases variability and background. It permits the separation procedure to be validated rapidly prior to use with actual samples, and is readily adaptable for assaying guanylate cyclase, phosphodiesterases (PDE), or a variety of other related nucleotide-metabolizing enzymes. For ACase assays, 4.5% ZnSO4-10% Ba(OH)2 is added to the incubation mixture, and following centrifugation, the supernatant is injected on an HPLC apparatus fitted with a Waters Z-Module containing a 10-microns C18 reverse-phase cartridge. Using a mobile phase of 0.15 M sodium acetate-20% methanol (pH 5.0) at a flow rate of 4 ml/min, cAMP is eluted at k' greater than 1.25, whereas k' less than 0.5 for all other adenine nucleotides, permitting collection of the cAMP fraction after running the other nucleotides to waste. The method was validated by characterizing dopamine-sensitive ACase in homogenates of striatum from Sprague-Dawley rats. Basal activity (177 +/- 16 pmol/mg protein/min), the stimulation by dopamine (186 +/- 19 pmol/mg/min), the apparent Km for dopamine (5.0 +/- 1.5 microM), and expected effects of varying magnesium, EGTA, and GTP were similar to available data. However, it was found that isobutylmethylxanthine (IBMX) or theophylline, usually included in the incubation mixture as PDE inhibitors, markedly inhibited the synthesis of cAMP in both the presence and absence of dopamine. A consequence of this inhibition was a marked change in the apparent Km of dopamine calculated from a Lineweaver-Burk plot. The use of IBMX to inhibit PDEs was compared with an alternate strategy, the addition of excess exogenous cAMP. Simultaneous analysis of PDE and ACase activity was accomplished by including [3H]cAMP in the incubation and quantifying the amounts of [3H]cAMP hydrolyzed and [32P]cAMP synthesized. Without IBMX, a concentration of 1 mM exogenous cAMP was sufficient to prevent significant loss of [3H]cAMP. In the absence of exogenous cAMP, 0.5 mM IBMX did not completely prevent the breakdown of [3H]cAMP, whereas 2.5 mM IBMX did. Although there was 25% less [3H]cAMP recovered in the presence of 0.5 mM IBMX than with 2.5 mM IBMX, there was no difference in the amount of [32P]cAMP formed (either with or without dopamine).(ABSTRACT TRUNCATED AT 400 WORDS)

3',5'-Cyclic-AMP Phosphodiesterases↗