Biomedical subjects
Publications and source records attributed to P Skolnick.
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Several estrogenic compounds were examined for their abilities to stimulate the formation of adenosine 3',5'-monophosphate (cyclic AMP) in incubated hypothalami from immature (27-28 day old) female rats. 17-beta estradiol (E2) and diethylstilbestrol (DES) significantly increased the formation of cyclic AMP while estrone and estriol elicited small but not statistically significant increases in cyclic AMP formation. 17-alpha estradiol was ineffective in increasing cyclic AMP formation. The anti-estrogenic agent clomiphene was found to effectively antagonize the formation of cyclic AMP elicited by E2 and DES, while having no stimulatory effects on cyclic AMP formation itself. These data indicate that the binding of estrogenic compounds to cytoplasmic sites (receptors) in the hypothalamus is required for subsequent stimulation of cyclic AMP formations.
Diethylstilbestrol (DES) and 17beta-estradiol elicit significant increases in levels of endogenous and [14C]cyclic AMP in [14C]adeninelabeled hypothalami from immature female rats, but only after incubation of the hypothalami with these estrogenic agents for 40-50 min. Estriol has no effect. The 2-fold accumulation of cyclic AMP elicited by low concentrations (20 muM) of DES appears dependent on catecholamine-related mechanisms, since it is prevented by either alpha- or beta-adrenergic antagonists. Higher concentrations (100 muM) of DES elicit a 3-fold accumulation of [14C]cyclic AMP which is only partially blocked by adrenergic antagonists, haloperidol, or the adenosine antagonist, theophylline. These phenomena appear to be specific for the hypothalamus since incubation of cerebral cortical slabs with estrogens resulted in no significant increases in the levels of cyclic AMP. The slow time course in whole hypothalami and the complete lack of effects of low concentrations of estrogenic agents in chopped hypothalami suggest an indirect mechanism of action. Interaction of estrogens with receptors in cell bodies may result, after a latent period of 40-50 min, in enhanced release of catecholamines from distal synaptic terminals and in stimulation of catecholamine-sensitive adenylate cyclases at post-synaptic sites.
Methoxamine elicits a rapid accumulation of adenosine 3',5'-monophosphate (cyclic AMP) in rat cerebral cortical slices with maximal effects at 100 muM. The accumulations of cyclic AMP elicited by this amine are completely blocked by the alpha adrenergic antagonists, phenoxybenzamine and dihydroergokryptine, partially blocked by the alpha antagonist, phentolamine, and unaffected by the beta blocking agent, propranolol, or by the local anesthetic, tetracaine. The magnitude of the accumulations of cyclic AMP elicited by methoxamine in cerebral cortical slices of four rat strains (F-344, ACI, BUF, and Sprague-Dawley) exhibit a strong negative correlation with spontaneous motor activity and a positive correlation with the magnitude of norepinephrine-elicited accumulations of cyclic AMP. The stimulatory interaction of methoxamine with alpha adrenergically regulated cyclic AMP-generating systems differs from the interaction of norepinephrine with alpha receptors as evidenced by the following observations: 1) the stimulatory effects of methoxamine and norepinephrine are nearly additive; 2) the stimulatory effects of methoxamine and adenosine are nearly additive, whereas the effects of norepinephrine and adenosine are much more than additive. Methoxamine, however, does not increase further the magnitude of accumulation of cyclic AMP elicited by a combination of norepinephrine and adenosine. The results are consonant with the interaction of methoxamine with alpha adrenergic receptors which are normally activated by norepinephrine only to a marginal extent. However, in the presence of adenosine, these receptors are now sensitive to activation by norepinephrine.
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Responses of norepiniephrine sensitive adeniosinie 3',5'-monophosphate (cyclic AMP)-generating systems in combined midbrain-striatal slices of four rat strains correlate positively with spontaneous behavioral activity and negatively with levels of midbrain and striatal tyrosine hydroxylase. Responses of cerebral cortical norepinephrine-sensitive cyclic AMP systems correlate negatively with spontaneous behavioral activity antd positively with midbrain and striatal tyrosine hydroxylase. Such correlations were not found with responses of the cyclic AMP- generatinlg systems to isoproterenol, adenosine. veratridine or of an adenosne and norepinephrine combination.
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Buspirone is an azaspirodecanedione that has anxiolytic actions in man and anticonflict actions in experimental animals. In contrast to many commonly used anxiolytic agents, buspirone does not appear to have significant sedative, muscle relaxant or anticonvulsant actions. Consequently, it has been termed an "anxioselective" agent. The effects of buspirone and related compounds have been examined in a number of neurotransmitter systems that have been linked to the actions of other anxiolytic agents. Buspirone has been shown to affect dopaminergic, serotonergic and noradrenergic pathways, as well as the GABA-benzodiazepine receptor chloride ionophore complex. Nonetheless, the doses (in vivo) and/or concentrations (in vitro) of buspirone (and related compounds) needed to affect these systems are not consistent with a causal relationship between the anxiolytic actions of buspirone and any of these systems. The neurochemical mechanism by which buspirone and related compounds exert both anticonflict and anxiolytic actions remains unknown.
A dose-dependent (12.5-100 mg/kg) suppression of cytotoxic T lymphocyte (CTL) activity was observed in mice after administration of the benzodiazepine receptor 'inverse agonist' FG 7142 (N-methyl-beta-carboline-3-carboxamide). This compound produces a syndrome resembling stress or anxiety in both animals and man. Addition of FG 7142 (1-1000 nM) to either a 4-hour 51Chromium-release assay or 5-day in vitro CTL generation system did not affect CTL activity. Pretreatment with the benzodiazepine receptor antagonist Ro 15-1788 (10 mg/kg) attenuated FG 7142-induced suppression of CTL activity, but had no effect when administered alone. Time-course studies indicated that FG 7142-induced suppression of CTL activity was long-lasting. The suppression of CTL activity by FG 7142 provides further evidence that the central nervous system pathways subserved by the benzodiazepine/GABA receptor chloride channel complex may play an important role in the modulation of immune function.
In the present studies, base line and drug-induced performance of two mouse strains (C57Bl/6 and NIH-Swiss) was evaluated in the forced swim test (FST) and tail suspension test (TST). Intra- and interstrain comparisons indicate that the biological substrates mediating performance in these behavioral procedures are not identical. For example, in NIH-Swiss mice, a sevenfold difference in base line immobility was observed between the FST and TST. By contrast, the base line immobility in C57Bl/6 mice was similar in both procedures. Further, in C57Bl/6 mice, imipramine produced a "U-shaped" dose-response curve in the FST, whilst no evidence of a biphasic response was present in the TST at doses up to 45 mg/kg. In the FST, the AMPA receptor potentiator LY451646 produced a similar dose-response relationship in C57Bl/6 and NIH-Swiss mice, but the minimum effect dose (MED) was fivefold higher in NIH-Swiss mice. This potency difference appears due to both pharmacokinetic and pharmacodynamic factors. These intra- and interstrain differences in performance indicate that despite a face value similarity, the neurochemical pathways involved in mediating performance in these two widely used tests are not identical.
A cDNA for the human "peripheral-type" benzodiazepine receptor (PBR) was isolated from a liver cDNA library. The 851-nucleotide probe hybridized with a approximately 1 kb mRNA in Northern blots of RNA extracted from various human tissues and cell lines. The human PBR probe was hybridized to DNA from a somatic cell hybrid mapping panel to determine that the gene maps to chromosome 22. With a regional mapping panel for chromosome 22, we localized the gene within band 22q13.31. The ligand-binding properties of the receptor expressed from the cDNA were examined in transient expression experiments and compared to the endogenous human PBR. The PBR ligand [3H]PK 11195 had high affinity for the expressed receptor in COS-1 cells, but the affinities of a pair of isoquinoline propanamide enantiomers differed remarkably in expressed and endogenous human PBR. These findings reveal that the host cell and/or post-translational modification may have an important influence on PBR function.
Strain differences in both immune function and behavior were observed following exposure of mice to the death of cage-cohorts. AKR/J, BALB/cN, and C3H/HeJ mice were exposed to a dead cohort for two hours at 48 hour intervals for 30 days. During this two hour period, AKR/J mice displayed intense fighting and mounting behavior. In addition, these mice attacked, cannibalized, and buried carcasses. Neither C3H/HeJ nor BALB/cN mice exhibited the complete repertoire of behaviors directed at either carcasses or cage-cohorts observed in AKR/J mice. After 15 exposures to the death of cage-cohorts, allogeneic cytotoxic T-lymphocyte (CTL) response was suppressed in AKR/J mice, but was enhanced or unchanged in C3H/HeJ and BALB/cN mice, respectively. Other immune parameters including natural killer (NK) cell activity, and lipopolysaccharide-stimulated B cell proliferation were unchanged in AKR/J mice but increased in BALB/cN mice exposed to the death of cage-cohorts for thirty days. These results suggest: 1) that both suppression of the CTL response and behaviors indicative of defensive burying in AKR/J mice may specifically be due to the loss of cage-cohorts, since they were not observed following exposure of these mice to the death of contraspecific animals; and 2) that both the behavioral repertoire and immune responses following exposure to the death of cage-cohorts may be strain dependent. This strain dependence may reflect differences in the ability to cope with the intermittent presentation of a stressor, and may explain, at least in part, variability in stress-induced changes in immune functions.