Biomedical subjects

K C Rice

Publications and source records attributed to K C Rice.

At least 55 records · Page 3Linked to original sources

PubMed2000

Effects of phentermine and fenfluramine on extracellular dopamine and serotonin in rat nucleus accumbens: therapeutic implications.

Combined administration of the amphetamine analogs phentermine and fenfluramine (PHEN/FEN) has been used in the treatment of obesity. While these medications are thought to modulate monoamine transmission, the precise neurochemical effects of the PHEN/FEN mixture have not been extensively studied. To assess the mechanism of PHEN/FEN action, in vivo microdialysis studies were performed in the nucleus accumbens of conscious freely moving rats. A series of amphetamine derivatives including phentermine, chlorphentermine, fenfluramine, and PHEN/FEN (1:1 ratio), were infused locally into the accumbens via reverse-dialysis (1, 10, 100 microM) or injected systemically (1 mg/kg, ip). Dialysate samples were assayed for dopamine (DA) and serotonin (5-HT) by high-performance liquid chromatography with electrochemical detection. When infused locally, phentermine preferentially increased extracellular DA, whereas fenfluramine selectively increased extracellular 5-HT. Local administration of chlorphentermine or the PHEN/FEN mixture caused parallel elevations of both transmitters. Analogous results were obtained when the drugs were injected systemically. Phentermine stimulated robust locomotor activity in mice, whereas chlorphentermine and fenfluramine did not. PHEN/FEN caused modest locomotor stimulation after a low dose, but had no effect at the highest dose. Accumulating evidence suggests that chronic drug and alcohol abuse is associated with deficits in both DA and 5-HT neuronal function. Thus, dual activation of DA and 5-HT neurotransmission with monoamine releasing agents may be an effective treatment strategy for substance use disorders, as well as for obesity. Synapse 36:102-113, 2000. Published 2000 Wiley-Liss, Inc.

Amphetamine↗

PubMed2000

Assessment of SNC 80 and naltrindole within a conditioned taste aversion design.

Although compounds with relative selectivity for the mu and kappa opiate receptors subtypes have been reported to condition taste aversions, it is not known whether systemically administered delta compounds have the ability to produce aversions. To that end, female Long-Evans rats were adapted to water deprivation and were given pairings of a novel saccharin solution and various doses of the selective delta agonist SNC 80 (0.32-10.0 mg/kg; Experiment 1) or the selective delta antagonist naltrindole (1.0-18.0 mg/kg; Experiment 2). For comparison, the relatively selective mu agonist morphine (Experiment 1) and mu antagonist naloxone (Experiment 2) were assessed under identical conditions. Both SNC 80 (Experiment 1) and naltrindole (Experiment 2) were effective as unconditioned stimuli within this design, inducing dose-dependent taste aversions with repeated conditioning trials. Although at no dose did animals injected with SNC 80 differ from those injected with morphine, aversions induced by SNC 80 were acquired at a faster rate than those induced by morphine. Subjects injected with naloxone drank significantly less than those injected with naltrindole at the 10 mg/kg dose, and aversions induced by naloxone at 5.6 and 10 mg/kg were acquired at a faster rate than those induced by naltrindole. Although the basis for opioid agonist- and antagonist-induced taste aversions is not known, the differences between aversions induced by SNC 80 and naltrindole and those induced by morphine and naloxone, respectively, may be a function of their relative selectivity for specific opiate receptor subtypes.

Animals↗

PubMed2000

Morphine discriminative control is mediated by the mu opioid receptor: assessment of delta opioid substitution and antagonism.

Morphine is an effective training drug in drug discrimination procedures. In subsequent generalization tests in which other opioids are administered, mu opioid agonists selectively substitute for the training drug. Given the relative selectivity of morphine for the mu receptor, such substitution patterns suggest that the mu opioid receptor is mediating the discriminative control of this compound. The present study assessed this selective mediation by examining the ability of the delta opioid agonist SNC80 to substitute for (and the delta opioid antagonist naltrindole to antagonize) morphine stimulus effects in rats trained to discriminate morphine from its vehicle in the conditioned taste aversion baseline of drug discrimination learning. Although morphine and methadone produced dose-related substitution for morphine (10 mg/kg), there was no evidence of substitution for morphine by SNC80 at any dose tested. Further, although naloxone (3.2 mg/kg) completely blocked the discriminative effects of morphine, naltrindole (3.2-10 mg/kg) did not significantly affect the morphine stimulus. These data suggest that the discriminative control established to morphine is mediated by its activity at the mu, but not the delta, receptor.

Animals↗

PubMed2000

Peripheral administration of CRF and urocortin: effects on food intake and the HPA axis in the marsupial Sminthopsis crassicaudata.

The hypothalamic peptides corticotrophin releasing factor (CRF) and urocortin (UCN) decrease food intake and increase energy expenditure when administered either centrally or peripherally to rodents. The effects of CRF and UCN on food intake in other mammals (for example marsupials), however, are not known. Peripherally administered CRF induced cortisol release in the marsupial Sminthopsis crassicaudata via the CRF1 receptor, and central CRF administration potently decreased food intake, as in rodents. When peripherally administered, both CRF and UCN decreased food intake in S. crassicaudata, but UCN was considerably more potent ( approximately 50 fold) in this regard. The anorectic effects of CRF and UCN were not blocked by the CRF1 receptor antagonist antalarmin, suggesting that the peripheral effects of CRF and UCN on food intake are mediated primarily by the CRF2 receptor.

Adrenal Glands↗

PubMed2000

Neurochemical neutralization of amphetamine-type stimulants in rat brain by the indatraline analog (-)-HY038.

Amphetamine-type stimulants are substrates for the proteins that serve as transporters for the biogenic amines dopamine (DA), serotonin (5HT), and norepinephrine (NE) and release these neurotransmitters from neurons located in the peripheral and central nervous system. Using indatraline as a lead compound, we sought to develop a long-acting depot medication that would neutralize the deleterious effects of amphetamine-type stimulants. Our first efforts produced (+/-)-HY038, and its two stereoisomers, which are hydroxy-substituted analog of indatraline. The K(i) values for [(3)H]DA reuptake inhibition by (-)-HY038 and (+)-HY038 were 3.2 +/- 0.1 and 32 +/- 1 nM. Similar results were obtained for [(3)H]5HT reuptake inhibition. (-)-HY038 and (+)-HY038 were slightly less potent at inhibiting [(3)H]NE reuptake (K(i) values of 20 +/- 2 and 159 +/- 12 nM). Low doses of (-)-HY038 blunted the ability of AMPH to release [(3)H]DA by shifting the AMPH dose-response curve to the right in a dose-dependent manner. (-)-HY038 also inhibited the ability of (+)-methamphetamine and (+/-)-3,4-methylenedioxymethamphetamine ((+/-)-MDMA) to release [(3)H]DA. Low doses of (-)-HY038 blunted the ability of these stimulants to release [(3)H]NE and [(3)H]5HT by shifting their dose-response curves to the right in a manner similar to that seen for inhibition of [(3)H]DA release. These data indicate that (-)-HY038 inhibits the ability of AMPH, (+)-methamphetamine and (+/-)-MDMA to release DA, NE, and 5HT and therefore might have the potential to neutralize the neurotoxic and cardiovascular side-effects of substrate-type stimulants.

Amphetamine-Related Disorders↗

PubMed2000

Effects of corticotropin-releasing factor on neuronal activity in the serotonergic dorsal raphe nucleus.

The present study examined the regional localization of corticotropin-releasing factor (CRF)- and 5-hydroxytryptamine (5-HT)-immunoreactive (IR) fibers within the rat dorsal raphe nucleus (DRN) using immunohistochemistry. Additionally, the effects of CRF, administered intracerebroventricularly (0.1-3.0 micrograms) or intraraphe (0.3-30 ng), on discharge rates of putative 5-HT DRN neurons were quantified using in vivo single unit recording in halothane-anesthetized rats. CRF-IR fibers were present at all rostrocaudal levels of the DRN and exhibited a topographical distribution. CRF produced predominantly inhibitory effects on DRN discharge at lower doses and these effects diminished or became excitatory at higher doses. Inhibition of DRN discharge by CRF was attenuated by the nonselective CRF antagonist, DPheCRF12-41 and the CRF-R1-selective antagonist, antalarmin, implicating the CRF-R1 receptor subtype in these electrophysiological effects. The present findings provide anatomical and physiological evidence for an impact of CRF on the DRN-5HT system.

Animals↗

PubMed2000

A practical synthesis of the serotonin 5-HT2A receptor antagonist MDL 100907, its enantiomer and their 3-phenolic derivatives as precursors for [11C]labeled PET ligands.

A practical synthesis of the 3-phenolic precursor of MDL 100907, a selective 5-HT2A receptor antagonist, is described. The route was also applied to the enantiomeric series, thus affording the direct precursors of both 3-[11C]MDL 100907 and its enantiomer as ligands for positron emission tomography. Similar methodology was developed for the direct synthesis of MDL 100907 and its enantiomer, MDL 100009. The routes utilized classical optical resolution of the N-nor intermediates in at least 98% enantiomeric excess and easily afforded multigram amounts of the chiral precursors of a variety of N- and 3-O-substituted enantiomers.

Carbon Radioisotopes↗

PubMed2000

Uptake and release effects of diethylpropion and its metabolites with biogenic amine transporters.

Three metabolites of diethylpropion (1), (+/-)-2-ethylamino-1-phenyl-propan-1-one (2), (1R,2S)-(-)-N,N-diethylnorephedrine (3a) and (1S,2R)-(-)-N,N-diethylnorephedrine (3b) were synthesized. Their uptake and release effects with biogenic amine transporters were evaluated. A major finding of this study is that the in vivo activity of diethylpropion on biogenic amine transporters is most likely due to metabolite 2 as diethylpropion (1) and the metabolites 3a and 3b showed little or no effect in the assays studied. These studies also revealed that 2 acted as a substrate at the norepinephrine (IC50 = 99 nM) and serotonin transporters (IC50 = 2118 nM) and an uptake inhibitor at the dopamine transporter (IC50 = 1014 nM). The potent action of 2 at the NE transporter supports the hypothesis that amphetamine-type subjective effects may be mediated in part by brain norepinephrine.

Animals↗

PubMed2000

Response requirements and unit dose modify the effects of GBR 12909 on cocaine-maintained behavior.

Previous studies found that GBR 12909 can decrease cocaine-maintained responding at doses that do not affect food-maintained responding. In this study, the effects of GBR 12909 (0.3-3.0 mg/kg) were further examined by varying the response requirement and unit dose of cocaine. Rhesus monkeys earned food or cocaine under a multiple fixed-ratio (FR) schedule. The FR for food was always 30, but the FR for cocaine was varied from 10-130 and the unit dose was varied from 5.6-56.0 microg/kg per injection. Doses of GBR 12909 were tested in an ascending order, for 5 consecutive sessions each. GBR 12909 selectively decreased cocaine-maintained responding in all monkeys in at least 1 condition. These effects were enhanced with large response requirements and/or small unit doses. The results demonstrate that environmental variables can influence the selectivity of GBR 12909's effects and contribute to a growing debate concerning the evaluation of potential pharmacotherapies for drug abuse.

Animals↗

PubMed2000

Methamphetamine dependence: medication development efforts based on the dual deficit model of stimulant addiction.

Converging lines of evidence indicate that withdrawal from prolonged exposure to stimulants and alcohol results in synaptic deficits of both dopamine (DA) and serotonin (5-HT). According to the dual deficit model proposed by the authors, DA dysfunction during cocaine or alcohol withdrawal underlies anhedonia and psychomotor retardation, whereas 5-HT dysfunction gives rise to depressed mood, obsessional thoughts, and lack of impulse control. This model predicts that pharmacotherapies which correct only one of the two neurochemical deficits will not be effective. On the other hand, pharmacotherapies which "correct" both of the proposed DA and 5-HT abnormalities should be effective in treating stimulant and alcohol dependence. This paper reviews two approaches, based on the dual deficit model, taken by our laboratory to develop medications to treat stimulant abuse.

Animals↗

PubMed2000

Development of a novel class of monocyclic and bicyclic alkyl amides that exhibit CB1 and CB2 cannabinoid receptor affinity and receptor activation.

CB1 and CB2 cannabinoid receptors can be activated by several different classes of agonists, including cannabinoids such as delta9-tetrahydrocannabinol and 9-nor-9beta-hydroxyhexahydrocannabinol, and eicosanoids such as arachidonylethanolamide. Structure-activity relationship studies have identified potential pharmacophoric elements for binding to cannabinoid receptors by both cannabinoids and eicosanoids. Molecular models have hypothesized conformational, spatial, and pharmacophoric distance requirements based upon radioligand binding data whereby overlap of pharmacophoric elements of the two classes disclose a low energy conformation of arachidonylethanolamide that can occupy the same receptor space as cannabinoid ligands. To test this model, we have developed a novel class of monocyclic and bicyclic alkyl amide cannabinoid receptor ligands. Further, we predicted a spatial conformation for these compounds in a molecular model based on the pharmacophoric and structural requirements for binding to the CB1 cannabinoid receptor.

Adenylyl Cyclase Inhibitors↗

PubMed2000

Opioid receptor imaging with positron emission tomography and [(18)F]cyclofoxy in long-term, methadone-treated former heroin addicts.

Stabilized methadone-maintained former heroin addicts (MTPs) treated with effective doses of methadone have markedly reduced drug craving; reduction or elimination of heroin use; normalized stress-responsive hypothalamic-pituitary-adrenal, reproductive, and gastrointestinal function; and marked improvement in immune function and normal responses to pain, all of which are physiological indices modulated in part by endogenous and exogenous opioids directed at the mu and, in some cases, the kappa-opioid systems. This study was performed to explore opioid receptor binding in MTPs. Fourteen normal, healthy volunteers and 14 long-term MTPs in treatment for 2 to 27 years and receiving 30 to 90 mg/day of methadone were studied with positron emission tomography using tracer amounts of [(18)F]cyclofoxy, an opioid antagonist that labels mu and kappa opioid receptors. Imaging was performed in the morning, 22 h after the last dose of methadone in patients, and concurrent plasma levels of methadone were determined. Five brain regions of specific interest for addiction and pain research (thalamus, amygdala, caudate, anterior cingulate cortex, and putamen) were among the six regions of highest [(18)F]cyclofoxy binding. Specific binding of [(18)F]cyclofoxy was lower by 19 to 32% in these regions in MTPs compared with those in normal volunteers. The degree to which specific binding was lower in caudate and putamen correlated with methadone plasma levels (P <.01 and P <.05, respectively), suggesting that these lower levels of binding may be related to receptor occupancy with methadone and that significant numbers of opioid receptors may be available to function in their normal physiological roles.

Adult↗

PubMed2000

Role of delta-opioid receptors in biological processes.

Agonists at the delta-opioid receptor were initially investigated as potential analgesic agents that may lack the undesired effects (respiratory depression, constipation, dependence) of mu-opioid agonists such as morphine. These studies have, however, uncovered that the delta-opioid system is involved in many biological processes, and thus delta-opioid-based medications have great therapeutic potential for the treatment of a wide variety of disorders.

Journal Article↗

PubMed1999

Probes for narcotic receptor mediated phenomena. 26. Synthesis and biological evaluation of diarylmethylpiperazines and diarylmethylpiperidines as novel, nonpeptidic delta opioid receptor ligands.

We recently reported (+)-4-¿(alphaR)-alpha-¿(2S,5R)-4-allyl-2, 5-dimethyl-1-piperazinyl¿-3-methoxybenzyl-N,N-diethylbenzamide (1b, SNC80) as a novel nonpeptidic delta receptor agonist and explored the structure-activity relationships (SAR) of a series of related derivatives. We have found that delta binding activities and selectivity showed little change when the 3-methoxy group in 1b was removed or replaced by the other substituents, whereas the N, N-diethylbenzamide group is important for interaction with the delta receptor. Extensive modification of the piperazine nucleus led to the synthesis of a new series of N, N-diethyl(alpha-piperazinylbenzyl)benzamides (2, 3a-e), N, N-diethyl(alpha-piperidinyl or piperidinylidenebenzyl)benzamides (4a, 5a-c, 6a-b), and related derivatives (4b, 7a-c). Several compounds (2, 3a, 3e, 6a) strongly bound to the delta receptor with K(i) values in the low nanomolar range. On the other hand, the binding affinities of these compounds for the mu and kappa receptors were negligible, indicating excellent delta opioid receptor subtype selectivity. The two nitrogen atoms on the piperazine nucleus showed different SAR in the interaction of this series of compounds at the delta receptor. Nitrogen N(4) appears to be an important structural element and is essential for electrostatic interaction, while N(1) seems to be unnecessary for recognition at the delta receptor.

Animals↗

PubMed1999

Delta opioid binding selectivity of 3-ether analogs of naltrindole.

Masking of the 3-phenol of naltrindole as a range of ethers caused a decrease in binding affinity at all three opiate receptors (mu, kappa, delta), however for the methyl ether, the reduction in affinity at both mu and kappa was greater than at delta, thereby increasing delta binding selectivity.

Naltrexone↗

PubMed1999

Opioid peptide receptor studies. 10. Nor-BNI differentially inhibits kappa receptor agonist-induced G-protein activation in the guinea pig caudate: further evidence of kappa receptor heterogeneity.

There is strong evidence supporting the existence of multiple kappa receptors. Previous studies proposed that U69,593 and (+)-tifluadom act on different kappa receptor subtypes, kappa(1) (kappa(1)) and kappa(2) (kappa(2)), respectively. In this study, we investigated the effects of the kappa selective antagonist nor-binaltorphimine (Nor-BNI) on U69,593- and (+)-tifluadom-induced receptor-mediated stimulation of [(35)S]-GTP-gamma-S binding in the guinea pig caudate. The IC(50) value of Nor-BNI in the presence of a stimulating concentration of U69,593 (1 microM) was 0.19+/-0.02; while the IC(50) for Nor-BNI in the presence of (+)-tifluadom (1 microM) was 13.9+/- 1.62 nM. The mu-opioid receptor antagonist CTAP (10,000 nM) significantly reduced (+)-tifluadom-stimulated [(35)S]-GTP-gamma-S binding in rat brain sections and guinea pig brain membranes, indicating that (+)-tifluadom has mu agonist activity. Under conditions in which the mu agonist activity of (+)-tifluadom was blocked by 1000 nM CTAP the Ki value for Nor-BNI for inhibition of U69,593-stimulated [(35)S]-GTP-gamma-S binding was 0.036+/-.004 nM, whereas, its Ki value for the (+)-tifluadom-stimulated [(35)S]-GTP-gamma-S binding was 0.27+/-.015 nM. These results suggest that (+)-tifluadom and U69,593 activate pharmacologically different receptors. This study provides functional evidence in support of kappa receptor heterogeneity.

Animals↗

PubMed1999

Oxygenated analogues of 1-[2-(Diphenylmethoxy)ethyl]- and 1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazines (GBR 12935 and GBR 12909) as potential extended-action cocaine-abuse therapeutic agents.

An investigation into the preparation of potential extended-release cocaine-abuse therapeutic agents afforded a series of compounds related to 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (1a) and 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (1b) (GBR 12935 and GBR 12909, respectively), which were designed, synthesized, and evaluated for their ability to bind to the dopamine transporter (DAT) and to inhibit the uptake of [(3)H]-labeled dopamine (DA). The addition of hydroxy and methoxy substituents to the benzene ring on the phenylpropyl moiety of 1a-1d resulted in a series of potent and selective ligands for the DAT (analogues 5-28). The hydroxyl groups were included to incorporate a medium-chain carboxylic acid ester into the molecules, to form oil-soluble prodrugs, amenable to "depot" injection techniques. The introduction of an oxygen-containing functionality to the propyl side chain provided ketones 29 and 30, which demonstrated greatly reduced affinity for the DAT and decreased potency in inhibiting the uptake of [(3)H]DA, and benzylic alcohols 31-36, which were highly potent and selective at binding to the DAT and inhibiting [(3)H]DA uptake. The enantiomers of 32 (34 and 36) were practically identical in biological testing. Compounds 1b, 32, 34, and 36 all demonstrated the ability to decrease cocaine-maintained responding in monkeys without affecting behaviors maintained by food, with 34 and 36 equipotent to each other and both more potent in behavioral tests than the parent compound 1b. Intramuscular injections of compound 41 (the decanoate ester of racemate 32) eliminated cocaine-maintained behavior for about a month following one single injection, without affecting food-maintained behavior. The identification of analogues 32, 34, and 36, thus, provides three potential candidates for esterification and formulation as extended-release cocaine-abuse therapeutic agents.

Animals↗

PubMed1999

GBR12909 attenuates amphetamine-induced striatal dopamine release as measured by [(11)C]raclopride continuous infusion PET scans.

Major neurochemical effects of methamphetamine include release of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) via a carrier-mediated exchange mechanism. Preclinical research supports the hypothesis that elevations of mesolimbic DA mediate the addictive and reinforcing effects of methamphetamine and amphetamine. This hypothesis has not been adequately tested in humans. Previous in vivo rodent microdialysis demonstrated that the high affinity DA uptake inhibitor, GBR12909, attenuates cocaine- and amphetamine-induced increases in mesolimbic DA. The present study determined the ability of GBR12909 to attenuate amphetamine-induced increases in striatal DA as measured by [(11)C]raclopride continuous infusion positron emission tomography (PET) scans in two Papio anubis baboons. [(11)C]Raclopride was given in a continuous infusion paradigm resulting in a flat volume of distribution vs. time for up to 45 min postinjection. At that time, a 1.5 mg/kg amphetamine i.v. bolus was administered which caused a significant (30.3%) reduction in the volume of distribution (V(3)"). The percent reduction in the volume of distribution and, hence, a measure of the intrasynaptic DA release ranged between 22-41%. GBR12909 (1 mg/kg, slow i.v. infusion) was administered 90 min before the administration of the radiotracer. The comparison of the volume of distribution before and after administration of GBR12909 showed that GBR12909 inhibited amphetamine-induced DA release by 74%. These experiments suggest that GBR12909 is an important prototypical medication to test the hypothesis that stimulant-induced euphoria is mediated by DA and, if the DA hypothesis is correct, a potential treatment agent for cocaine and methamphetamine abuse. Furthermore, this quantitative approach demonstrates a way of testing various treatment medications, including other forms of GBR12909 such as a decanoate derivative.

Amphetamine↗