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Biomedical subjects

R B Rothman

Publications and source records attributed to R B Rothman.

At least 109 records · Page 6Linked to original sources
PubMed1996

Pharmacological screen for activities of 12-hydroxyibogamine: a primary metabolite of the indole alkaloid ibogaine.

The purported efficacy of ibogaine for the treatment of drug dependence may be due in part to an active metabolite. Ibogaine undergoes first pass metabolism and is O-demethylated to 12-hydroxyibogamine (12-OH ibogamine). Radioligand binding assays were conducted to identify the potency and selectivity profiles for ibogaine and 12-OH ibogamine. A comparison of 12-OH ibogamine to the primary molecular targets identified previously for ibogaine demonstrates that the metabolite has a binding profile that is similar, but not identical to the parent drug. Both ibogaine and 12-OH ibogamine demonstrated the highest potency values at the cocaine recognition site on the 5-HT transporter. The same rank order (12-OH ibogamine > ibogaine), but lower potencies were observed for the [3H]paroxetine binding sites on the 5-HT transporter. Ibogaine and 12-OH ibogamine were equipotent at vesicular monoamine and dopamine transporters. The metabolite demonstrated higher affinity at the kappa-1 receptor and lower affinity at the NMDA receptor complex compared to the parent drug. Quantitation of the regional brain levels of ibogaine and 12-OH ibogamine demonstrated micromolar concentrations of both the parent drug and metabolite in rat brain. Drug dependence results from distinct, but inter-related neurochemical adaptations, which underlie tolerance, sensitization and withdrawal. Ibogaine's ability to alter drug-seeking behavior may be due to combined actions of the parent drug and metabolite at key pharmacological targets that modulate the activity of drug reward circuits.

Binding Sites↗
PubMed1996

Chronic cocaine exposure potentiates prolactin and head shake responses to 5-HT2 receptor stimulation in rats.

The effect of repeated cocaine administration on serotonin2 (5-HT2) receptor function was examined in male rats. Rats were fitted with indwelling jugular catheters and subsequently received cocaine (15 mg/kg, i.p., b.i.d.) or saline for 7 days. Rats were challenged with the 5-HT2 agonist DOI (25, 100, 400 micrograms/kg, i.v.) or saline 42 hr and 8 days after cessation of chronic treatment. Serial blood samples were collected at various times after DOI challenge and analyzed for prolactin levels. DOI-induced head shakes and skin jerks were examined concurrently in the same subjects. After 42 hr of withdrawal, the stimulatory effects of DOI on prolactin release and shaking behavior were significantly enhanced in cocaine-treated rats. Conversely, the skin jerk response to DOI was not altered by prior cocaine exposure. After 8 days of withdrawal, the prolactin and head shake responses to DOI were still potentiated in cocaine-treated rats, but this effect was no longer statistically significant. The data indicate that chronic cocaine enhances the sensitivity of 5-HT2 receptor mechanisms. Our findings further suggest the possibility that altered 5-HT2 receptor function may be involved in the mood disturbances experienced by abstinent cocaine addicts.

Amphetamines↗
PubMed1996

Acute sensitivity vs. context-specific sensitization to cocaine as a function of genotype.

Individual variability in the acute and chronic effects of psychomotor stimulants is due, in part, to genetic factors. The purpose of this series of studies was to utilize a behavioral model of sensitization, namely increased locomotor activity, to assess individual variability in sensitization to the chronic effects of cocaine and its relationship to the acute stimulant effects of cocaine. Because the degree of sensitization is proportional to the training dose, genetic differences in acute sensitivity to cocaine were assessed and incorporated into the sensitization paradigm. Acute sensitivity and context-dependent sensitization were determined in six inbred mouse strains. Large quantitative and qualitative differences were found in the acute potency and efficacy of cocaine to stimulate locomotor activity. The ED50 was higher in the strains in which cocaine was most efficacious. Context-specific sensitization was determined via chronic administration of equiactive doses of cocaine (ED50) specifically paired with the test apparatus or with the home colony. Sensitization was time, environment, and genotype dependent. The differences in the number of trials required to show sensitization were unrelated to the acute locomotor stimulant effects of cocaine. These findings suggest that acute cocaine-induced locomotor activity and context-specific sensitization reflect different pharmacological properties of cocaine.

Animals↗
PubMed1996

Cocaine cross-sensitization to dopamine uptake inhibitors: unique effects of GBR12909.

Repeated administration of cocaine will cross-sensitize the locomotor response to a variety of psychomotor stimulants. The ability of cocaine to cross-sensitize the locomotor effects of other psychomotor stimulants provides information relevant to the pharmacological mechanisms underlying the sensitization process. The purpose of the current experiment was to investigate the ability of cocaine to cross-sensitize the locomotor effects of several dopamine uptake blockers with unique pharmacological profiles. Cocaine (40 mg/kg, IP) or saline was administered prior to a locomotor session on day one. On day 2, a full dose-effect curve was established for the locomotor effects of cocaine, RTI-55, mazindol, and GBR12909. Previous exposure to cocaine significantly affected locomotor activity and stereotopy-like behavior produced by cocaine, mazindol, RTI-55, and GBR12909. However, GBR12909 was unique in that the maximal stimulant effect and slope of the dose-effect curve was significantly depressed and the stereotopy-like behavior was unchanged. Thus, despite the similarity of these compounds in their ability to inhibit dopamine uptake, cocaine-induced sensitization did not generalize to GBR12909. This study further demonstrates the unique pharmacology of GBR12909 and supports the further study of this compound as a potential treatment medication for cocaine abuse.

Animals↗
PubMed1996

Downregulation of mu-opioid binding sites following chronic administration of neuropeptide FF (NPFF) and morphine.

The effect of continuous ICV infusion of NPFF (10 micrograms/microliter) and morphine (40 micrograms/microliter) on mu-opioid binding sites was examined in rats using the in vitro radiolabeled techniques of whole-brain homogenate receptor binding and quantitative autoradiography. Mu receptors were labeled with [3H][D-Ala2-MePhe4,Glyol5] enkephalin in the homogenate binding experiments and with [125I][D-Ala2-MePhe4,Gly-ol5]enkephalin in autoradiographic studies. In homogenate binding studies, chronic administration of NPFF or morphine significantly downregulated mu receptors by 20% and 44%, respectively. Quantitative autoradiographic experiments demonstrated downregulation of mu opioid receptors in specific brain nuclei for both NPFF- and morphine-treated animals. Within the striatum and several nuclei of the thalamus, the mu receptors of the NPFF- and morphine-treated animals were decreased by 20-30% and 38-73%, respectively. These results suggest that NPFF may modulate opioid-mediated responses in part by altering the density of mu-opioid receptors.

Analgesics, Opioid↗
PubMed1996

Effects of phentermine and cocaine on fenfluramine-induced depletion of serotonin in mouse brain.

The combined administration of phentermine and fenfluramine (PHEN/FEN) has been used as a treatment for obesity. Recent evidence suggests that this drug mixture may also be an effective medication for substance abuse disorders, including cocaine dependence. It is well-established that repeated high-dose fenfluramine causes serotonin (5-HT) terminal degeneration in laboratory animals, and no studies have addressed possible interactions between phentermine and fenfluramine. The purpose of the present work was to examine the effect of phentermine coadministration on fenfluramine-induced depletion of 5-HT in mouse forebrain. In addition, because of the potential for cocaine abuse in drug addicts taking PHEN/FEN as a medication, we examined the effects of PHEN/FEN on forebrain 5-HT levels in the presence or absence of cocaine. Fenfluramine (0, 3, 10, 30 mg/kg, s.c. twice daily for 4 days) caused a dose-dependent reduction in forebrain 5-HT without affecting dopamine or norepinephrine. Phentermine coadministration (7 mg/kg, s.c. twice daily for 4 days) did not significantly alter the 5-HT-depleting effect of fenfluramine. Likewise, cocaine (10 mg/kg, i.p.), administered 60 min prior to or 60 min after PHEN/FEN, had no effect on the PHEN/FEN-induced decrease in central 5-HT. The present results indicate that doses of phentermine far above those typically administered to humans do not potentiate the 5-HT-depleting effect of repeated high-dose fenfluramine. Moreover, exposure to cocaine does not significantly alter the long-term neurochemical actions of the PHEN/FEN mixture.

Animals↗
PubMed1996

Evaluation of phentermine and fenfluramine, alone and in combination, in normal, healthy volunteers.

Recent clinical reports indicate that combined administration of phentermine and fenfluramine may have useful effects in the treatment of drug abuse. The present study was designed to evaluate the subjective and mood-altering effects of these drugs, alone and in combination, in normal healthy volunteers. Seven male and five female volunteers participated in an eight-session, double-blind study in which each subject received each of the following drug conditions: d-amphetamine (10 and 20 mg), phentermine (30 mg), fenfluramine (40 and 80 mg), phentermine (30 mg) with fenfluramine (40 mg), phentermine (30 mg) with fenfluramine (80 mg), and placebo. Sessions were conducted in a laboratory setting two or three days a week. Subjects completed standardized self-report questionnaires and psychomotor tests before and at regular intervals after each drug administration. Phentermine produced effects that were similar to those of d-amphetamine, whereas fenfluramine produced different and apparently aversive effects (e.g., it increased measures of anxiety and confusion). Phentermine reduced the apparently aversive effects of fenfluramine when the two drugs were given together. These results suggest that the combination of phentermine and fenfluramine would have a low potential for abuse.

Adult↗
PubMed1996

Endocrine responses during acute nicotine withdrawal.

Acute administration of nicotine increases cortisol and prolactin but the endocrine effects of tobacco withdrawal are unknown. In a residential, double-blind, placebo-controlled, crossover study, volunteers smoked ad lib for 4 days and underwent monitored tobacco abstinence for 3 days. On no-smoking days, patches delivering 0, 10, 20, or 30 mg nicotine were applied for 16 h. Daily plasma samples were analyzed for ACTH, cortisol, and prolactin. During nicotine abstinence (0 mg patch), circulating levels of ACTH, cortisol, and prolactin did not significantly change from ad lib smoking levels. Over all the patch conditions there was a significant effect of day, with modest but significant elevations of cortisol and ACTH levels on the second no-smoking day (Wed, 37 h abstinent). Prolactin levels increased during nicotine abstinence, but this effect was not significant. The observed endocrine changes did not correlate with physiologic, performance, or subjective measures of tobacco withdrawal. Our data indicate endocrine changes during acute tobacco withdrawal are transient and small. Thus, the present results do not support the use of ACTH as a treatment for tobacco cessation.

Administration, Cutaneous↗
PubMed1996

Characterization of antinociception to opioid receptor selective agonists after antisense oligodeoxynucleotide-mediated "knock-down" of opioid receptor in vivo.

Pharmacological studies in vivo and in vitro have suggested the existence of subtypes of the delta opioid receptor termed delta1 and delta2 (delta1 and delta2). The hypothesis of subtypes of delta receptors was further explored by assessing the effects of administration of antisense or mismatch oligodeoxynucleotides (ODN) in vivo to the cloned DOR, or to a conserved region of the cloned opioid receptors, on the antinociceptive responses elicited by selective mu, ku and delta opioid receptor agonists in mice. Additionally, the density of opioid delta receptors in brain after delta opioid receptor (DOR) ODN treatment was investigated. Repeated twice daily intracerebroventricular (i.c.v.) administration of DOR antisense, but not mismatch, ODN, produced a dose- and time-related blockade of i.c.v. [D-Ala2, Glu4]deltorphin (delta2 agonist), but not [D-Pen2, D-Pen5]enkephalin (delta1 agonist), antinociception. The antinociceptive responses to selective mu and kappa opioid agonists were unaffected by DOR antisense or mismatch ODN treatments. The antinociceptive effect of an A90 dose of [D-Ala2, Glu4]deltorphin was significantly reduced by the third day of DOR antisense ODN administration and persisted over a treatment period of 6 days with recovery by the third posttreatment day. Saturation studies in mouse whole brain preparations with the selective delta-radioligand [3H]naltrindole showed that DOR antisense, but not mismatch, ODN treatment produced a significant time-related reduction in Bmax values of approximately 30 to 40% by day 6, without changing the Kd value. The reduction in DOR density was reversible and returned to control levels within 3 days after cessation of antisense ODN treatment. The i.c.v. administration of an antisense, but not mismatch, ODN directed to a conserved region of the cloned opioid receptors, termed common opioid receptor antisense ODN, inhibited the antinociceptive effects of i.c.v. mu, kappa and delta agonists, including [D-Pen2, D-Pen5]enkephalin. These data further support the hypothesis of subtypes of opioid delta receptors.

Analgesics↗
PubMed1996

Structure-activity relationships for SNC80 and related compounds at cloned human delta and mu opioid receptors.

The racemic compound (+/-)-BW373U86 ¿(+/-)-4-((alpha R*)- alpha-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxy- benzyl)-N,N-diethylbenzamide dihydrochloride} is a potent delta opioid receptor agonist in the mouse vas deferens assay with little mu or kappa opioid receptor activity in the guinea pig ileum tissue preparation. In contrast, radioligand binding studies show that (+/-)-BW373U86 is only about 10-fold selective for delta over mu opioid receptors. Studies of the enantiomeric forms of (+/-)-BW373U86 and derivatives (SNC80 and related compounds) show that some of these isomers are significantly better in both receptor binding and pharmacological selectivity than (+/-)-BW373U86. In this study we have determined the binding affinities of 10 different SNC80-related compounds at cloned human delta and mu opioid receptors and measured the potency of SNC80 for the inhibition of forskolin-stimulated adenylyl cyclase. The most selective delta receptor ligand (SNC162) differed from SNC80 by the absence of the 3-methoxy substitution of the benzyl ring. The Ki for SNC162 at the delta receptor (0.625 nM) was over 8700-fold lower than that at the mu receptor (5500 nM), making this the most selective delta receptor ligand available. Reduction of the allyl side chain of SNC80 to produce radiolabeled [3H]SNC121 allowed direct measurement of the association and dissociation rate constants. SNC80 was 26-fold less potent than [D-Pen2, pCI-Phe4, D-Pen5]enkephalin in the delta receptor adenylyl cyclase inhibition assay, but showed full agonist activity with an EC50 value of 9.2 nM. The regulation of SNC80 binding affinity to the delta receptor by GTP analogs is undetectable in [3H]naltrindole binding inhibition studies, but direct binding studies with [3H]SNC121 in the presence of 100 microM 5'-guanylylimidotriphosphate show a 55% reduction in maximum binding site density consistent with a lower affinity for a part of the receptor population. Addition of 120 mM sodium chloride reduces SNC80 affinity nearly 40-fold in [3H]naltrindole binding inhibition studies. The results of these studies define specific structural features of these compounds responsible for opioid receptor interactions and suggest a possibly novel mechanism for delta receptor activation.

Animals↗
PubMed1995

Effects of intravenous cocaine on plasma cortisol and prolactin in human cocaine abusers.

The aim of the present work was to examine the cortisol and prolactin responses to acute cocaine administration in human cocaine users. Each subject served as his own control during intravenous saline placebo and cocaine (40 mg) infusion sessions. Cocaine significantly elevated plasma cortisol but did not affect prolactin. The rise in cortisol coincided with an increase in heart rate and blood pressure after cocaine. In agreement with studies in animals, our data suggest that cocaine activates the hypothalamic-pituitary-adrenal axis in humans. However, based on the well-known importance of dopamine as a prolactin-inhibiting factor, the failure of cocaine to suppress prolactin in the present study raises questions concerning the role of dopamine in the mechanism of acute cocaine action in humans.

Adult↗
PubMed1995

(E)-8-benzylidene derivatives of 2-methyl-5-(3-hydroxyphenyl)morphans: highly selective ligands for the sigma 2 receptor subtype.

The determination of the structure and function of the sigma receptor subtypes and their physiological role(s) has been impeded by the unavailability of selective ligands. We have developed a new class of sigma subtype selective receptor ligands that are (E)-8-benzylidene derivatives of the synthetic opioid (+/-)-, (+)-, and (-)-2-methyl-5-(3-hydroxyphenyl)morphan-7-one (1). The derivatives can be prepared by reaction of 1, (+)-1, and (-)-1 with the appropriate benzaldehyde under Claisen-Schmidt conditions. Incorporation of substituted (E)-8-benzylidene moieties onto the 7-keto precursor of (+)-2-methyl-5-(3-hydroxyphenyl)morphan, (+)-1, produces compounds (-)-2 through (-)-7 (5.8-32.0 nM, sigma 1), which have between a 25- and 131-fold increase in affinity for the sigma 1 receptor subtype relative to the keto precursor (+)-1 (Ki = 762 nM, sigma 1). Compound (-)-2 is the most selective of this group (16-fold) for the sigma 1 subtype versus sigma 2. Substitution of an (E)-8-benzylidene moiety onto the 7-keto precursor of (-)-2-methyl-5-(3-hydroxyphenyl)morphan, (-)-1, produces compounds (+)-2-(+)-9 (6.4-52.6 nM, sigma 2), which have at least a 475-3906-fold increase in affinity for the sigma 2 receptor subtype relative to the keto precursor (-)-1 (Ki = 25 x 10(3) nM). This enhancement of sigma 2 receptor affinity is accompanied by substantial selectivity of all of these dextrorotatory products for the sigma 2 relative to the sigma 1 subtype (32-238-fold), and thus, they are among the most sigma 2 selective compounds currently known. Furthermore, the sigma 1 subtype is highly enantioselective for the levorotatory isomers, (-)-2-(-)-7 (41-1034-fold), whereas the sigma 2 subtype is only somewhat enantioselective for the dextrorotatory isomers, (+)-2-(+)-7 (2.6-9.3-fold). All of these derivatives retain substantial affinity for the mu opioid receptor. Despite the high affinity of the dextrorotatory derivatives for the mu opioid receptor, the high affinity and selectivity for sigma 2 over sigma 1 sites will surely prove beneficial as tools for the delineation of the function and physiological role of sigma 2 receptors.

Animals↗
PubMed1995

Opioid peptide receptor studies. 4. Antisense oligodeoxynucleotide to the delta opioid receptor delineates opioid receptor subtypes.

Prior work in our laboratory has identified putative subtypes of delta (delta cx-1, delta cx-2, delta ncx-1, delta ncx-2) and kappa 2 (kappa 2a and kappa 2b) receptors. Previous studies showed that chronic (three day) i.c.v. administration of antisense oligodeoxynucleotide to the cloned delta opioid receptor selectively decreased [3H][D-Ala2,D-Leu5]enkephalin binding to the delta ncx site, not the delta cx-2 site. The present study extends this work by demonstrating that delta antisense DNA selectively affects the delta ncx-2 site sparing the other putative delta receptor subtypes and kappa 2 receptor subtypes. This selectivity is not due to anatomically specific effects of delta antisense DNA since autoradiograms show that delta binding is reduced in all regions of the brain after chronic i.c.v. administration of delta antisense DNA. These data strongly suggest that the delta cx-1, delta cx-2, delta ncx-1, kappa 2a and kappa 2b binding sites are different proteins than the delta ncx-2 binding site, which, based on its sensitivity to delta antisense DNA, is synonymous to the cloned delta opioid receptor. Viewed collectively, these data suggest that administration of delta antisense DNA, and by extension other receptor-selective antisense DNA, is a powerful approach to distinguishing between postulated receptor subtypes.

Animals↗
PubMed1995

Evidence for alterations in presynaptic serotonergic function during withdrawal from chronic cocaine in rats.

The effects of repeated cocaine administration on serotonin (5-hydroxytryptamine, 5-HT) function were investigated by comparing the corticosterone response to 5-HT receptor agonists in cocaine-treated and vehicle-treated rats. Male rats were fitted with indwelling jugular catheters and received cocaine (15 mg/kg i.p., b.i.d.) or saline for 7 days. Rats were challenged with either saline, the 5-HT releaser fenfluramine (1.2 mg/kg i.v.), the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 50 micrograms/kg i.v.), or the 5-HT2A/2C receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI; 100 micrograms/kg i.v.) 42 h and 8 days after the final chronic treatment. Repeated blood samples were withdrawn immediately before and at 15, 30 and 60 min after acute challenge injections. All 5-HT receptor agonists increased plasma corticosterone, but the fenfluramine-induced rise in corticosterone was significantly attenuated in cocaine-treated rats withdrawn for 42 h. This blunted response to fenfluramine exhibited only partial recovery when examined at 8 days postchronic treatment. Corticosterone responses to 8-OH-DPAT and DOI were not affected by cocaine exposure. Our data suggest that chronic cocaine produces deficits in presynaptic 5-HT function, and alterations in 5-HT neurotransmission may underlie the dysphoria experienced by abstinent cocaine users. Neuroendocrine challenge tests should be performed in human addicts to evaluate potential 5-HT dysfunction associated with cocaine abuse.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1995

Repeated cocaine administration reduces 5-HT1A-mediated prolactin secretion in rats.

The prolactin and behavioral responses elicited by the 5-HT1A agonist 8-OH-DPAT (8-hydroxy-2-[di-n-propylamino]tetralin) were examined in male rats previously exposed to chronic cocaine (15 mg/kg, i.p., b.i.d., 7 days) or saline. After 42 h of withdrawal, cocaine-treated rats exhibited a reduced prolactin response to 8-OH-DPAT challenge (50 micrograms/kg, i.v.). A 5-fold higher dose of 8-OH-DPAT stimulated maximal prolactin secretion that was similar in cocaine- and saline-treated rats. Prior cocaine treatment had no effect on the 5-HT syndrome induced by 8-OH-DPAT. Our data agree with the findings of others and suggest that 5-HT1A receptors mediating neuroendocrine secretion become subsensitive after repeated cocaine administration.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1995

High-performance liquid chromatographic resolution of synthetic opiate and "anti-opiate" peptides from human plasma.

An assay system using reversed-phase high-performance liquid chromatographic (HPLC) resolution of synthetic anti-opioid peptides (AOPs) and opioid peptides (OPs) was developed. Samples were diluted with trifluoroacetic acid, loaded onto Sep-Pak C18 cartridges, eluted, dried, and redissolved in ethanol-acetic acid-water. Retention-time consistency was established, and high levels of synthetic AOP and OP recovery, generally higher than 80%, were achieved. In a single HPLC run synthetic enkephalins, dynorphins, and beta-endorphins were separated even when extracted from human plasma using a volatile mobile phase which yielded fractions totally compatible with quantitation by radioimmunoassay. Combining the resolution of HPLC with the sensitivity of radioimmunoassay (RIA) may facilitate simultaneous measurement of numerous neuropeptides in body fluids such as plasma and cerebrospinal fluid.

Chromatography, High Pressure Liquid↗