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Biomedical subjects

I A Paul

Publications and source records attributed to I A Paul.

15 recordsLinked to original sources
PubMed1992

Differential effects of cytochrome P-450 induction on ligand binding to sigma receptors.

The identity of the sigma receptor as a form of cytochrome P-450 was investigated in rats treated with 3-methylcholanthrene or phenobarbital. The density of [3H]N,N'-di(o-tolyl)guanidine (DTG) binding to sigma 2 receptors in hepatic subcellular fractions increased following both treatments, while [3H](+)-pentazocine binding to sigma 1 receptors was unchanged. Furthermore, proadifen and piperonyl butoxide inhibited [3H](+)-pentazocine and [3H]DTG binding with low potency. The low affinity of cytochrome P-450 inhibitors for sigma receptors, the similar degree of enhancement of [3H]DTG binding by agents with disparate cytochrome P-450 induction profiles and the lack of change in [3H](+)-pentazocine binding are inconsistent with the identity of the sigma receptor as a cytochrome P-450.

Animals↗
PubMed1992

Down-regulation of cortical beta-adrenoceptors by chronic treatment with functional NMDA antagonists.

Down-regulation of cortical beta-adrenoceptors is observed in laboratory animals following chronic treatment with many clinically effective antidepressant therapies. [3H]Dihydroalprenolol (DHA) binding to cortical beta-adrenoceptors was examined in mice treated with the functional NMDA antagonists 1-aminocyclopropane-carboxylic acid (ACPC) and MK-801. ACPC and MK-801 reduced [3H]DHA binding by 19 (P less than 0.05) and 21% (P less than 0.05), respectively, while imipramine produced a 23% (P less than 0.05) reduction. No corresponding changes in the KD of [3H]DHA were observed. These findings are consistent with the observation that functional NMDA antagonists are active in animal models commonly used to evaluate antidepressants and may represent a novel approach to the treatment of depression.

Amino Acids↗
PubMed1992

Spatial learning impairment in a murine model of AIDS.

Mice infected with an immunosuppressive murine leukemia virus (MuLV) mixture, LP-BM5, displayed profound and selective deficits in spatial learning in a modified Morris water maze. These deficits appeared before the appearance of gross neurological impairment or histopathological changes in the central nervous system. Thus, LP-BM5-infected mice displayed deficits in several aspects of trained performance compared to controls. Furthermore, a failure to exhibit any evidence of task acquisition in this maze was observed almost twice as frequently (P less than 0.0005) in infected mice as in uninfected controls. Moreover, in the absence of gross visual, motoric, or motivational impairment, LP-BM5 MuLV-infected animals exhibited neither the target directed search pattern nor the spatial preference characteristic of controls. The spatial learning and memory deficit described here is the first report of cognitive impairment accompanying viral-induced immunosuppression in a nonprimate species.

Animals↗
PubMed1992

Modulation of (+)-[3H]pentazocine binding to guinea pig cerebellum by divalent cations.

The ability of cations to modulate the binding of the sigma 1 receptor-selective ligand (+)-[3H]pentazocine to guinea pig cerebellum was investigated. Di- and trivalent cations biphasically inhibited (+)-[3H]pentazocine binding, revealing multiple affinity states. The rank order of potency of these cations (based on the high affinity component of inhibition) was Zn2+ > Co2+ >> La3+ = Ni2+ = Cd2+ = Mn2+ = Gd2+ > Ba2+ = Sr2+ >> Mg2+ > Ca2+. The inhibition of 1,3-[3H]di(2-tolyl)guanidine binding to the sigma 2 receptor by these cations differed qualitatively and quantitatively from their effects on (+)-[3H]pentazocine binding. Although monovalent cations decreased the Kd for (+)-[3H]pentazocine binding, divalent cations split (+)-[3H]pentazocine binding into low and high affinity components. The Bmax of the high affinity component decreased with increasing divalent cation concentrations. Both mono- and divalent cations significantly reduced the rate of association of (+)-[3H]pentazocine with the sigma 1 receptor without altering the dissociation rate. (+)-[3H]Pentazocine binding was not altered by guanine nucleotides or by treatment with cholera or pertussis toxins. However, nonselective cation channel blockers (cinnarizine, hydroxyzine, prenylamine, amiodarone, and proadifen) potently inhibited (+)-[3H]pentazocine binding. These results indicate that physiologically relevant concentrations of divalent cations allosterically modulate (+)-[3H]pentazocine binding to the sigma 1 receptor, to reveal multiple affinity states. These sites do not represent sigma 1 to sigma 2 subtype interconversion or ternary complex formation with guanine nucleotide-binding proteins. However, the rank order of cation potency and the inhibition of binding by cation channel blockers is consistent with a potential role for sigma receptors as constituents of cation channels.

Animals↗
PubMed1991

Neural adaptation in response to chronic imipramine and electroconvulsive shock: evidence for separate mechanisms.

The effects of chronic imipramine and electroconvulsive shock alone or combined were assessed on rat brain beta-adrenoceptors and serotonin2 (5-HT2) receptors and on dynorphin and thyrotropin releasing hormone (TRH) levels. These treatments resulted in regionally discrete and treatment-specific patterns of change in beta-adrenoceptor and 5-HT2 receptor density and in TRH and dynorphin levels. Electroconvulsive shock eliminated the serotonergic component of hippocampal DHA binding, suggesting an effect of this treatment on 5-HT1 receptors. The effects of combined electroconvulsive shock and imipramine treatments on cortical 5-HT2 and beta-adrenoceptor density appeared to be the additive sum of the individual treatment effects. No treatment interaction was observed on hippocampal 5-HT2 and beta-adrenoceptors, except after day 2. No treatment interaction on peptide content was observed at any time. These results demonstrate independent anatomical specificity for the effects of electroconvulsive shock and imipramine and provide evidence that the mechanisms responsible for their antidepressant actions differ.

Animals↗
PubMed1991

Autoradiographic analysis of the in vivo distribution of 3H-imipramine and 3H-desipramine in brain: comparison to in vitro binding patterns.

Using high resolution autoradiographic techniques, the distribution of radioactivity in forebrain and brainstem was assessed after IV injection of 3H-impramine or 3H-desipramine. Results were compared with regional binding of the drugs to brain sections in vitro. Similar topographic binding of 3H-imipramine and 3H-desipramine was observed in vitro among brain regions, except in the paraventricular nucleus of the hypothalamus and locus coeruleus, where binding was greater for 3H-desipramine. For both 3H-desipramine and 3H-imipramine, some brain regions that exhibited high binding in vitro also showed high accumulation after in vivo injection. However, certain regions that contained high densities of binding sites for the antidepressant drugs as measured by in vitro binding showed very low accumulation of radioactivity after in vivo treatment. Such regions included the dentate gyrus of the hippocampus, layer 1 of piriform cortex, caudate-putamen, pontine and midbrain central gray, and cerebellar granular layer. Compared to in vitro binding of the drugs, the distribution of imipramine and desipramine in vivo appears more anatomically selective. For imipramine, primary sites of action in vivo, as indicated by the topographic distribution in brain, appear to be the locus coeruleus, hippocampus, lateral septal nucleus, and amygdala. For desipramine, the greatest accumulation in vivo was found in the locus coeruleus, paraventricular nucleus of the hypothalamus, and anterior thalamic nuclei.

Animals↗
PubMed1991

Down-regulation of dopamine1 (D1) receptors by chronic imipramine is species-specific.

Chronic treatment with imipramine (15 mg/kg, twice daily for 14 days) induces a down-regulation of limbic D1 receptors in rats but not in mice. In this mouse strain, both chronic and acute imipramine treatment have been shown to produce clear behavioral effects in the forced swim test. While the data presented here are consistent with previously reported findings in rats, they demonstrate that the down-regulation of D1 receptors by chronic antidepressant treatment is species-specific. This phenomenon indicates that D1 receptor down-regulation is not critical to the therapeutic mechanism of action of antidepressants.

Animals↗
PubMed1990

Neural adaptation in imipramine-treated rats processed in forced swim test: assessment of time course, handling, rat strain and amine uptake.

The intent of the present series of experiments was to better understand the events that produce a rapid adaptation of beta adrenergic and serotonin-2 (5-HT2) receptors when imipramine treatment and forced swim are combined in Sprague-Dawley rats. Beta adrenergic and 5-HT2 receptors were evaluated at specific stages of the forced swim test with and without imipramine treatment. Rapid changes in receptor binding were observed in saline-treated rats during specific stages of the test. The changes observed during forced swim could not be attributed to the transport-novelty that occurs during forced swim. Binding for both monoamine receptors was reduced in hippocampus and frontal cortex before the test swim in imipramine-treated rats as they were 10 min, 3 hr and 24 hr after the test swim. The increase in corticosterone induced by the second forced swim was not altered by imipramine, indicating that imipramine was not interfering with this measure of the stress response. In the Fisher-344 rat strain, imipramine did not produce a behavioral change during the test swim. In contrast to this lack of a behavioral change in the Fischer-344 rats, beta adrenergic and 5-HT2 receptor down-regulation was facilitated in this rat strain, similar to that found in imipramine-treated Sprague-Dawley rats subjected to swim. This latter finding suggests that beta adrenergic or 5-HT2 receptor adaptation alone is insufficient to cause an imipramine-induced behavioral change in the swim test. Studies with specific norepinephrine- and serotonin-uptake inhibitors, nisoxetine and fluoxetine, respectively, indicate that the behavioral effects of imipramine in the forced swim test are dependent upon norepinephrine uptake inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)

Adaptation, Physiological↗
PubMed1989

Neuroanatomically selective down-regulation of beta adrenergic receptors by chronic imipramine treatment: relationships to the topography of [3H]imipramine and [3H] desipramine binding sites.

The down-regulation of beta adrenergic receptors by chronic imipramine treatment was investigated with high resolution autoradiography of [125I]pindolol binding to brain sections. Neuroanatomically selective down-regulation of [125I]pindolol binding was found after chronic imipramine treatment. Subdivisions of the amygdala and hippocampus and discrete cortical regions were differentially affected. In the hippocampus, reduction of [125I]pindolol binding was observed in imipramine-treated rats in the CA-1 stratum radiatum and dentate molecular layer, but not in the CA-3 stratum radiatum. In the amygdala, the basolateral nucleus exhibited reduced [125I]pindolol binding after imipramine treatment but the central and medial nuclei were not affected. Chronic imipramine treatment was also associated with reduced [125I]pindolol binding in layer 1 of the cingulate cortex and layer 3 of the piriform cortex. In contrast, no effect on [125I]pindolol binding was apparent in the ventrolateral thalamic nucleus, caudate-putamen, lateral hypothalamus or layers 2 and 3 of the somatosensory cortex. In order to determine if regional variation in binding sites for imipramine, or its pharmacologically active metabolite desipramine, was responsible for the observed neuroanatomically selective reduction in [125I]pindolol binding, the binding of [3H]imipramine and [3H]desipramine was investigated. In some brain regions that exhibited high densities of [3H]imipramine and [3H]desipramine binding sites, [125I]pindolol binding was reduced after chronic treatment with imipramine. However, other regions that contained high densities of binding sites for antidepressant drugs did not show a reduction in [125I]pindolol binding after chronic imipramine treatment. Thus, regional binding of [3H]imipramine or [3H]desipramine cannot fully explain the neuroanatomical specificity of imipramine-induced beta adrenergic receptor down-regulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Regionally specific neural adaptation of beta adrenergic and 5-hydroxytryptamine2 receptors after antidepressant administration in the forced swim test and after chronic antidepressant drug treatment.

In the present investigation, experiments were performed in order to determine whether antidepressants are capable of inducing regionally specific adaptation of beta adrenergic and 5-hydroxytryptamine2 (5-HT2) receptors after chronic administration or when combined with the forced swim test. The drugs tested were imipramine, amitriptyline, pargyline and nomifensine. The regional pattern of beta adrenergic or 5-HT2 receptor binding changes induced after chronic treatment with these antidepressants was not uniform. All of the drugs reduced [3H]dihydroalprenolol binding to cortical membranes after chronic treatment but only two, imipramine and pargyline, did so in hippocampus. All of the antidepressants reduced cortical, but not hippocampal, beta adrenergic receptor binding after 2 days of treatment, indicating that the rate of antidepressant-induced neural adaptation is regionally specific. All of the drugs, except nomifensine, induced down regulation of both cortical and hippocampal 5-HT2 receptors after chronic treatment, as measured by [3H]ketanserin binding. The forced swim test accelerated the reduction of [3H] dihydroalprenolol binding in hippocampus induced by imipramine and pargyline while producing no further effect on cortical beta adrenergic receptors. The down-regulation of hippocampal, but not cortical 5-HT2 receptors by imipramine and pargyline was also facilitated in rats processed in the forced swim test. These results provide further support for the view that the forced swim antidepressant drug screen may be of heuristic value as a model of the adaptive neural mechanisms that accompany chronic antidepressant drug treatment. Furthermore, these data provide evidence that multiple neural mechanisms may be involved in the adaptive changes after antidepressant drug treatment.

Amitriptyline↗
PubMed1987

Behavioral and neurochemical responses to haloperidol and SCH-23390 in rats treated neonatally or as adults with 6-hydroxydopamine.

Behavioral and neurochemical effects of haloperidol (D2-dopamine antagonist) and SCH-23390 (D1-dopamine antagonist) were examined in unlesioned rats and in rats lesioned with 6-hydroxy-dopamine (6-OHDA) as adults or as neonates. In unlesioned rats, chronic haloperidol treatment (15 days) resulted in an increase in D2-dopamine receptor density, as measured with [3H]spiperone, in the nucleus accumbens and in the caudate-putamen. Rats treated as adults with 6-OHDA responded to chronic haloperidol similarly to controls. However, adult rats treated with 6-OHDA as neonates did not exhibit an increase in [3H]spiperone binding in response to chronic haloperidol treatment. Control and adult 6-OHDA-treated rats given haloperidol exhibited a profound akinesia. In contrast, rats that received 6-OHDA as neonates and were tested as adults did not display a significant behavioral response to haloperidol at doses as high as 2 mg/kg. Results similar to those for haloperidol were also found for SCH-23390. Chronic treatment (15 days) with this D1-dopamine antagonist increased [3H]SCH-23390 binding in the nucleus accumbens and caudate-putamen in unlesioned rats as well as in adult 6-OHDA-treated rats. However, after neonatal 6-OHDA treatment, an elevation in [3H]SCH-23390 binding did not occur after chronic SCH-23390 treatment. SCH-23390 produced akinesia similar to that produced by haloperidol in unlesioned and in adult 6-OHDA-treated rats. In contrast, rats lesioned with 6-OHDA as neonates and tested as adults did not exhibit a significant behavioral response to SCH-23390 under our test conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1985

Rapid down regulation of beta adrenergic receptors by combining antidepressant drugs with forced swim: a model of antidepressant-induced neural adaptation.

The hypothesis that behavioral responses to antidepressant drugs in the forced swim test are related to a rapid neural adaptation produced by the combination of drug treatment and swim stress was explored. As a measure of adaptation, brain beta adrenergic receptors were assayed using [3H]dihydroalprenolol [( 3H]DHA) binding to brain membranes from rats that were processed in the forced swim test. The combination of swim stress and imipramine treatment antagonized immobility induced by forced swimming and resulted in a reduction in [3H] DHA binding to membranes from forebrain preparations which did not include the corpus striatum. Administration of antidepressant drugs from other chemical classes, including pargyline, iprindole and nomifensine, also reduced immobility induced by the forced swim and produced a reduction in [3H]DHA binding to forebrain membranes. In homogenates of the corpus striatum, [3H]DHA binding was not altered by swim stress combined with antidepressant drug treatment. Chlordiazepoxide was without an effect on immobility or beta receptor binding when combined with forced swim. Even though atropine and amphetamine exhibited a positive activity in the forced swim test, they did not reduce [3H]DHA binding. Therefore, by combining behavioral and neurochemical analysis of animals processed in the forced swim test, it may be possible to differentiate, with greater confidence, potential antidepressant drugs from "false positives." The present studies support the hypothesis that antidepressant drug action in the forced swim test involves a rapid neural adaptation as reflected by the down regulation of beta adrenergic receptors. Thus, this behavioral paradigm may serve as a model of adaptive mechanisms induced by antidepressant drugs.

Adaptation, Physiological↗