Publications by authors named "Taline V Khroyan"

30 Publications

  • Page 1 of 1

Synthesis, Biological Evaluation, and SAR Studies of 14β-phenylacetyl Substituted 17-cyclopropylmethyl-7, 8-dihydronoroxymorphinones Derivatives: Ligands With Mixed NOP and Opioid Receptor Profile.

Front Psychiatry 2018 19;9:430. Epub 2018 Sep 19.

Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom.

A series of 14β-acyl substituted 17-cyclopropylmethyl-7,8-dihydronoroxymorphinone compounds has been synthesized and evaluated for affinity and efficacy for mu (MOP), kappa (KOP), and delta (DOP) opioid receptors and nociceptin/orphanin FQ peptide (NOP) receptors. The majority of the new ligands displayed high binding affinities for the three opioid receptors, and moderate affinity for NOP receptors. The affinities for NOP receptors are of particular interest as most classical opioid ligands do not bind to NOP receptors. The predominant activity in the [S]GTPγS assay was partial agonism at each receptor. The results are consistent with our prediction that an appropriate 14β side chain would access a binding site within the NOP receptor and result in substantially higher affinity than displayed by the parent compound naltrexone. Molecular modeling studies, utilizing the recently reported structure of the NOP receptor, are also consistent with this interpretation.
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http://dx.doi.org/10.3389/fpsyt.2018.00430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156383PMC
September 2018

and Profile of PPL-101 and PPL-103: Mixed Opioid Partial Agonist Analgesics with Low Abuse Potential.

Front Psychiatry 2017 12;8:52. Epub 2017 Apr 12.

Torrey Pines Institute for Molecular Studies, Port St. Lucie, FL, USA.

Opiates are still the most effective and widely used treatments for acute and chronic pain. However, the problems associated with morphine and other standard opioid analgesics severely limit their effectiveness in the clinic. PPL-101 and PPL-103 derived from morphine and morphinan ring systems contain a chiral N-substituent, which confers it with a unique combination of high-binding affinities and partial agonist activities at mu, delta, and kappa opioid receptors, leading to unique pharmacology compared to other conventional opioids. Acute antinociceptive and reward acquisition of PPL-101 and PPL-103 were assessed in mice using the tail flick assay and conditioned place preference (CPP) paradigm, respectively. The reinforcing effects of these compounds were assessed in rats using the self-administration paradigm. In mice, PPL-101 and PPL-103 produced antinociception reaching maximal effects that were equivalent to morphine at approximately 1/3 and 1/10 of morphine's dose, respectively. PPL-101-induced antinociception was attenuated following pretreatment with the kappa antagonist JDTic, but not the mu opioid antagonist beta-FNA. In mice, PPL-101 and PPL-103 produced dose-dependent decreases in activity, similar to other kappa agonists; however, they did not produce conditioned place aversion, and in fact elicited a trend toward CPP. In rats, neither PPL-101 nor PPL-103 were self-administered when substituted for morphine and PPL-101 attenuated morphine self-administration, when administered systemically prior to the self-administration session. Collectively, these results indicate that mixed opioid receptor partial agonists can produce potent antinociceptive activity with a lack of aversion in mice and without being self-administered in rats. Compounds with this profile could be superior analgesics with greatly reduced addiction liability and fewer side-effects compared to traditional opiates.
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http://dx.doi.org/10.3389/fpsyt.2017.00052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5388777PMC
April 2017

Cyclooxygenase inhibition targets neurons to prevent early behavioural decline in Alzheimer's disease model mice.

Brain 2016 07 13;139(Pt 7):2063-81. Epub 2016 May 13.

1 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA

Identifying preventive targets for Alzheimer's disease is a central challenge of modern medicine. Non-steroidal anti-inflammatory drugs, which inhibit the cyclooxygenase enzymes COX-1 and COX-2, reduce the risk of developing Alzheimer's disease in normal ageing populations. This preventive effect coincides with an extended preclinical phase that spans years to decades before onset of cognitive decline. In the brain, COX-2 is induced in neurons in response to excitatory synaptic activity and in glial cells in response to inflammation. To identify mechanisms underlying prevention of cognitive decline by anti-inflammatory drugs, we first identified an early object memory deficit in APPSwe-PS1ΔE9 mice that preceded previously identified spatial memory deficits in this model. We modelled prevention of this memory deficit with ibuprofen, and found that ibuprofen prevented memory impairment without producing any measurable changes in amyloid-β accumulation or glial inflammation. Instead, ibuprofen modulated hippocampal gene expression in pathways involved in neuronal plasticity and increased levels of norepinephrine and dopamine. The gene most highly downregulated by ibuprofen was neuronal tryptophan 2,3-dioxygenase (Tdo2), which encodes an enzyme that metabolizes tryptophan to kynurenine. TDO2 expression was increased by neuronal COX-2 activity, and overexpression of hippocampal TDO2 produced behavioural deficits. Moreover, pharmacological TDO2 inhibition prevented behavioural deficits in APPSwe-PS1ΔE9 mice. Taken together, these data demonstrate broad effects of cyclooxygenase inhibition on multiple neuronal pathways that counteract the neurotoxic effects of early accumulating amyloid-β oligomers.
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http://dx.doi.org/10.1093/brain/aww117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4939702PMC
July 2016

High affinity α3β4 nicotinic acetylcholine receptor ligands AT-1001 and AT-1012 attenuate cocaine-induced conditioned place preference and behavioral sensitization in mice.

Biochem Pharmacol 2015 Oct 7;97(4):531-541. Epub 2015 Aug 7.

Astraea Therapeutics, 320 Logue Avenue, Mountain View, CA, United States. Electronic address:

Cholinergic signaling via the nicotinic acetylcholine receptors (nAChRs) in the mesolimbic circuitry is involved in the rewarding effects of abused drugs such as cocaine and opioids. In mouse studies, nonselective nAChR antagonist mecamylamine blocks cocaine-induced conditioned place preference (CPP) and behavioral sensitization. Among subtype-selective nAChR antagonists, the β2-selective antagonist dihydrobetaerythroidine and α7 antagonist methyllycaconitine (MLA), but not MLA alone prevent behavioral sensitization to cocaine. Since the role of the α3β4 nAChR subtype in the rewarding and behavioral effects of cocaine is unknown, the present study investigated the effect of two potent and selective α3β4 nAChR ligands, AT-1001 and AT-1012, on the acquisition of cocaine-induced CPP and behavioral sensitization in mice. At 5-30mg/kg, cocaine produced robust CPP, whereas behavioral sensitization of locomotor activity was only observed at the higher doses (20-30mg/kg). Pretreatment with AT-1001 (1-10mg/kg) or AT-1012 (3-10mg/kg) blocked CPP induced by 5mg/kg cocaine, but not by 30mg/kg cocaine. Lower doses of AT-1001 (0.3-1mg/kg) and AT-1012 (1-3mg/kg) did not affect the increase in locomotor activity induced by 5 or 30mg/kg cocaine. But AT-1001, at these doses, blocked locomotor sensitization induced by 30mg/kg cocaine. These results indicate that the α3β4 nAChR play a role in the rewarding and behavioral effects of cocaine, and that selective α3β4 nAChR ligands can attenuate cocaine-induced behavioral phenomena. Since the selective α3β4 nAChR functional antagonist AT-1001 has also been shown to block nicotine self-administration in rats, the present results suggest that α3β4 nAChRs may be a target for the treatment of cocaine addiction as well as for cocaine-nicotine comorbid addiction.
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http://dx.doi.org/10.1016/j.bcp.2015.08.083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4600456PMC
October 2015

Varenicline enhances dopamine release facilitation more than nicotine after long-term nicotine treatment and withdrawal.

Pharmacol Res Perspect 2015 Feb 16;3(1):e00105. Epub 2014 Dec 16.

Center for Health Sciences, SRI International Menlo Park, California, 94025.

An important factor contributing to the high relapse rates among smokers is nicotine withdrawal symptoms. Multiple studies suggest that decreased dopamine release in nucleus accumbens plays a key role in withdrawal. However, recent reports showed that long-term nicotine exposure itself also decreases accumbal dopamine release, suggesting that additional mechanisms are involved in withdrawal. Here, we used real-time cyclic voltammetry in brain slices containing the nucleus accumbens to further elucidate the changes in dopamine release linked to nicotine withdrawal. Rats received vehicle or nicotine via the drinking water for 2-3 months. Studies assessing the expression of somatic signs in vehicle-treated, nicotine-treated, and 24-h nicotine withdrawn rats showed that nicotine withdrawal led to a significant increase in somatic signs. Subsequent voltammetry studies showed that long-term nicotine decreased single-pulse-stimulated dopamine release via an interaction at α6β2* receptors. Nicotine withdrawal led to a partial recovery in α6β2* receptor-mediated release. In addition, long-term nicotine treatment alone increased dopamine release paired-pulse ratios and this was partially reversed with nicotine removal. We then evaluated the effect of bath-applied nicotine and varenicline on dopamine release. Nicotine and varenicline both decreased single-pulse-stimulated release in vehicle-treated, nicotine-treated, and nicotine withdrawn rats. However, bath-applied varenicline increased paired-pulse ratios to a greater extent than nicotine during long-term nicotine treatment and after its withdrawal. Altogether these data suggest that nicotine withdrawal is associated with a partial restoration of dopamine release measures to control levels and that varenicline's differential modulation of dopamine release may contribute to its mechanism of action.
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http://dx.doi.org/10.1002/prp2.105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4317236PMC
February 2015

AT-1001: a high-affinity α3β4 nAChR ligand with novel nicotine-suppressive pharmacology.

Br J Pharmacol 2015 Apr 23;172(7):1834-45. Epub 2015 Jan 23.

Torrey Pines Institute for Molecular Studies, Port St. Lucie, FL, USA.

Background And Purpose: The α3β4 subtype of nicotinic acetylcholine receptors (nAChRs) has been implicated in mediating nicotine reinforcement processes. AT-1001 has been recently described as a high-affinity and selective α3β4 nAChR antagonist that blocks nicotine self-administration in rats. The aim of this study was to investigate the mechanism of action underlying the nicotine-suppressive effects of AT-1001.

Experimental Approach: Effects of AT-1001 were determined using in vitro assays and rat models of nicotine addiction, and compared with varenicline.

Key Results: AT-1001 and its analogue AT-1012 were functionally selective as antagonists for α3β4 over α4β2 nAChRs, but not to the same extent as the binding selectivity, and had partial agonist activity at α3β4 nAChRs. In contrast, varenicline was a partial agonist at α4β2, a weak agonist at α3β4 and inhibited α4β2 at a much lower concentration than it inhibited α3β4 nAChRs. AT-1001 and varenicline also had very different in vivo properties. Firstly, AT-1001 did not exhibit reinforcing properties per se while varenicline was self-administered. Secondly, systemic treatment with AT-1001 did not induce reinstatement of nicotine seeking but rather attenuated reinstatement induced by varenicline, as well as nicotine. Finally, unlike varenicline, AT-1001 selectively blocked nicotine self-administration without altering alcohol lever pressing as assessed in an operant co-administration paradigm.

Conclusions And Implications: These findings describe a more complex AT-1001 in vitro profile than previously appreciated and provide further support for the potential of AT-1001 and congeners as clinically useful compounds for smoking cessation, with a mechanism of action distinct from currently available medications.
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http://dx.doi.org/10.1111/bph.13034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376460PMC
April 2015

Designing bifunctional NOP receptor-mu opioid receptor ligands from NOP-receptor selective scaffolds. Part II.

Bioorg Med Chem 2014 Apr 5;22(8):2508-16. Epub 2014 Mar 5.

Astraea Therapeutics, LLC., 320 Logue Avenue, Mountain View, CA 94043, United States. Electronic address:

The nociceptin opioid receptor (NOP) and its endogenous peptide ligand nociceptin/orphanin FQ have been shown to modulate the pharmacological effects of the classical opioid receptor system. Suppression of opioid-induced reward associated with mu-opioid receptor (MOP)-mediated analgesia, without decreasing anti-nociceptive efficacy, can potentially be achieved with NOP agonists having bifunctional agonist activity at MOP, to afford 'non-addicting' analgesics. In Part II of this series, we describe a continuing structure-activity relationship (SAR) study of the NOP-selective piperidin-4-yl-1,3-dihydroindol-2-one scaffold, to obtain bifunctional activity at MOP, and a suitable ratio of NOP/MOP agonist activity that produces a non-addicting analgesic profile. The SAR reported here is focused on the influence of various piperidine nitrogen aromatic substituents on the ratio of binding affinity and intrinsic activity at both the NOP and MOP receptors.
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http://dx.doi.org/10.1016/j.bmc.2014.02.047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4033624PMC
April 2014

Retrodialysis of N/OFQ into the nucleus accumbens shell blocks cocaine-induced increases in extracellular dopamine and locomotor activity.

Eur J Pharmacol 2013 Jan 5;699(1-3):200-6. Epub 2012 Dec 5.

SRI International, Menlo Park, CA 94025, USA.

Nociceptin (N/OFQ) has been implicated in a variety of neurological disorders, most notably in reward processes and drug abuse. N/OFQ suppresses extracellular dopamine in the nucleus accumbens (NAc) after intracerebroventricular injection. This study sought to examine the effects of retrodialyzed N/OFQ on the cocaine-induced increase in extracellular dopamine levels in the NAc, as well as locomotor activity, in freely moving rats. 1.0μM, 10μM, and 1mM N/OFQ, in the NAc shell, significantly suppressed the cocaine-induced dopamine increase in the NAc, while N/OFQ alone had no significant effect on dopamine levels. Co-delivery of the selective NOP receptor antagonist SB612111 ([(-)-cis-1-Methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol] reversed the N/OFQ suppression of cocaine-induced dopamine in the NAc, suggesting that this is an NOP receptor-mediated effect. Using a novel system to assess locomotion, we measured various motor activities of the animals with simultaneous microdialysis from the home cage. Cocaine produced an expected increase in total activity, including horizontal movement and rearing behavior. Retrodialysis of N/OFQ with cocaine administration affected all motor activities, initially showing no effect on behavior, but over time inhibiting cocaine-induced motor behaviors. These results suggest that N/OFQ can act directly in the NAc shell to block cocaine-induced increases in extracellular dopamine levels. Extracellular dopamine and locomotor activity can be dissociated within the NAc and may reflect motor output differences in shell versus core regions of the NAc. These studies confirm the widespread involvement of NOP receptors in drug addiction and further validate the utility of an NOP receptor agonist as a medication for treatment of drug addiction.
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http://dx.doi.org/10.1016/j.ejphar.2012.11.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3570659PMC
January 2013

Rodent motor and neuropsychological behaviour measured in home cages using the integrated modular platform SmartCage™.

Clin Exp Pharmacol Physiol 2012 Jul;39(7):614-22

SRI International, Menlo Park, CA, USA.

1. To facilitate investigation of diverse rodent behaviours in rodents' home cages, we have developed an integrated modular platform, the SmartCage(™) system (AfaSci, Inc. Burlingame, CA, USA), which enables automated neurobehavioural phenotypic analysis and in vivo drug screening in a relatively higher-throughput and more objective manner. 2, The individual platform consists of an infrared array, a vibration floor sensor and a variety of modular devices. One computer can simultaneously operate up to 16 platforms via USB cables. 3. The SmartCage(™) detects drug-induced increases and decreases in activity levels, as well as changes in movement patterns. Wake and sleep states of mice can be detected using the vibration floor sensor. The arousal state classification achieved up to 98% accuracy compared with results obtained by electroencephalography and electromyography. More complex behaviours, including motor coordination, anxiety-related behaviours and social approach behaviour, can be assessed using appropriate modular devices and the results obtained are comparable with results obtained using conventional methods. 4. In conclusion, the SmartCage(™) system provides an automated and accurate tool to quantify various rodent behaviours in a 'stress-free' environment. This system, combined with the validated testing protocols, offers powerful a tool kit for transgenic phenotyping and in vivo drug screening.
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http://dx.doi.org/10.1111/j.1440-1681.2012.05719.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567678PMC
July 2012

AT-1001: a high affinity and selective α3β4 nicotinic acetylcholine receptor antagonist blocks nicotine self-administration in rats.

Neuropsychopharmacology 2012 May 25;37(6):1367-76. Epub 2012 Jan 25.

SRI International, Menlo Park, CA, USA.

Genomic and pharmacologic data have suggested the involvement of the α3β4 subtype of nicotinic acetylcholine receptors (nAChRs) in drug seeking to nicotine and other drugs of abuse. In order to better examine this receptor subtype, we have identified and characterized the first high affinity and selective α3β4 nAChR antagonist, AT-1001, both in vitro and in vivo. This is the first reported compound with a Ki below 10 nM at α3β4 nAChR and >90-fold selectivity over the other major subtypes, the α4β2 and α7 nAChR. AT-1001 competes with epibatidine, allowing for [³H]epibatidine binding to be used for structure-activity studies, however, both receptor binding and ligand-induced Ca²⁺ flux are not strictly competitive because increasing ligand concentration produces an apparent decrease in receptor number and maximal Ca²⁺ fluorescence. AT-1001 also potently and reversibly blocks epibatidine-induced inward currents in HEK cells transfected with α3β4 nAChR. Importantly, AT-1001 potently and dose-dependently blocks nicotine self-administration in rats, without affecting food responding. When tested in a nucleus accumbens (NAcs) synaptosomal preparation, AT-1001 inhibits nicotine-induced [³H]dopamine release poorly and at significantly higher concentrations compared with mecamylamine and conotoxin MII. These results suggest that its inhibition of nicotine self-administration in rats is not directly due to a decrease in dopamine release from the NAc, and most likely involves an indirect pathway requiring α3β4 nAChR. In conclusion, our studies provide further evidence for the involvement of α3β4 nAChR in nicotine self-administration. These findings suggest the utility of this receptor as a target for smoking cessation medications, and highlight the potential of AT-1001 and congeners as clinically useful compounds.
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http://dx.doi.org/10.1038/npp.2011.322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3327842PMC
May 2012

Peptides derived from the prohormone proNPQ/spexin are potent central modulators of cardiovascular and renal function and nociception.

FASEB J 2012 Feb 28;26(2):947-54. Epub 2011 Oct 28.

SRI International, Menlo Park, California, USA.

Computational methods have led two groups to predict the endogenous presence of a highly conserved, amidated, 14-aa neuropeptide called either spexin or NPQ. NPQ/spexin is part of a larger prohormone that contains 3 sets of RR residues, suggesting that it could yield more than one bioactive peptide; however, no in vivo activity has been demonstrated for any peptide processed from this precursor. Here we demonstrate biological activity for two peptides present within proNPQ/spexin. NPQ/spexin (NWTPQAMLYLKGAQ-NH(2)) and NPQ 53-70 (FISDQSRRKDLSDRPLPE) have differing renal and cardiovascular effects when administered intracerebroventricularly or intravenously into rats. Intracerebroventricular injection of NPQ/spexin produced a 13 ± 2 mmHg increase in mean arterial pressure, a 38 ± 8 bpm decrease in heart rate, and a profound decrease in urine flow rate. Intracerebroventricular administration of NPQ 53-70 produced a 26 ± 9 bpm decrease in heart rate with no change in mean arterial pressure, and a marked increase in urine flow rate. Intraventricular NPQ/spexin and NPQ 53-70 also produced antinociceptive activity in the warm water tail withdrawal assay in mice (ED(50)<30 and 10 nmol for NPQ/spexin and NPQ 53-70, respectively). We conclude that newly identified peptides derived from the NPQ/spexin precursor contribute to CNS-mediated control of arterial blood pressure and salt and water balance and modulate nociceptive responses.
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http://dx.doi.org/10.1096/fj.11-192831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3290442PMC
February 2012

Structural determinants of opioid and NOP receptor activity in derivatives of buprenorphine.

J Med Chem 2011 Oct 7;54(19):6531-7. Epub 2011 Sep 7.

Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, U.K.

The unique pharmacological profile of buprenorphine has led to its considerable success as an analgesic and as a treatment agent for drug abuse. Activation of nociceptin/orphanin FQ peptide (NOP) receptors has been postulated to account for certain aspects of buprenorphine's behavioral profile. In order to investigate the role of NOP activation further, a series of buprenorphine analogues has been synthesized with the aim of increasing affinity for the NOP receptor. Binding and functional assay data on these new compounds indicate that the area around C20 in the orvinols is key to NOP receptor activity, with several compounds displaying higher affinity than buprenorphine. One compound, 1b, was found to be a mu opioid receptor partial agonist of comparable efficacy to buprenorphine but with higher efficacy at NOP receptors.
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http://dx.doi.org/10.1021/jm2003238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188691PMC
October 2011

Differential effects of nociceptin/orphanin FQ (NOP) receptor agonists in acute versus chronic pain: studies with bifunctional NOP/μ receptor agonists in the sciatic nerve ligation chronic pain model in mice.

J Pharmacol Exp Ther 2011 Nov 22;339(2):687-93. Epub 2011 Aug 22.

SRI International, Menlo Park, California, USA.

1-(1-Cyclooctylpiperidin-4-yl)-indolin-2-one (SR14150) and 1-(1-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)piperidinl-4-yl)-indolin-2-one (SR16835) are moderately selective nociceptin/orphanin FQ (NOP) receptor agonists. In the [(35)S]guanosine 5'-O-(3-thiotriphosphate) assay in vitro, SR14150 is a partial agonist at both the NOP and μ-opioid receptors, whereas SR16835 is a full agonist at the NOP receptor and has low efficacy at μ receptors. These compounds were tested for antinociceptive and antiallodynic activity, using mice in chronic pain, subsequent to spinal nerve ligation (SNL) surgery. When administered subcutaneously to mice after SNL surgery, SR14150 but not SR16835 increased tail-flick latency, which was blocked by the opioid antagonist naloxone, but not by the NOP receptor antagonist (-)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB-612111). In contrast, both SR14150 and SR16835 had antiallodynic activity when mechanical allodynia was measured with von Frey monofilaments. This effect was completely blocked by SB-612111 but not by naloxone. On the other hand, morphine antinociception and antiallodynia were both blocked by naloxone and potentiated by SB-612111. These results indicate that, in mice, circuitry mediating antinociceptive activity in acute and chronic pain states is different. It is possible that during a chronic pain state, an up-regulated NOP system in the spinal cord leads to NOP receptor-mediated antiallodynia, which is blocked by NOP antagonists. However, supraspinal up-regulation could lead to an attenuation of morphine antinociception and antiallodynia, which can be alleviated by an NOP receptor antagonist. Thus, although neither NOP agonists nor antagonists are effective as analgesics in acute pain, they may have efficacy as analgesics, either alone or in combination with morphine, for treatment of chronic pain.
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http://dx.doi.org/10.1124/jpet.111.184663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3199991PMC
November 2011

The first universal opioid ligand, (2S)-2-[(5R,6R,7R,14S)-N-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylpentan-2-ol (BU08028): characterization of the in vitro profile and in vivo behavioral effects in mouse models of acute pain and cocaine-induced reward.

J Pharmacol Exp Ther 2011 Mar 21;336(3):952-61. Epub 2010 Dec 21.

SRI International, Menlo Park, CA 94025, USA.

Certain behavioral features of buprenorphine, including a bell-shaped curve for antinociception and attenuation of alcohol consumption, are thought to be mediated by activation of nociceptin/orphanin FQ peptide (NOP) receptors, despite moderate affinity and low efficacy at NOP receptors. We hypothesized that ligands with buprenorphine's physical properties, but possessing increased NOP receptor affinity and efficacy, would improve the profile as a drug abuse medication and reduce addiction liability. Using this strategy, we designed several compounds with universally high affinity, i.e., less than 10 nM at μ, δ, κ, and NOP receptors. Among these, (2S)-2-[(5R,6R,7R,14S)-N-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylpentan-2-ol (BU08028) has high affinity at all opioid receptors and increased NOP receptor efficacy in vitro in the [³⁵S]GTPγS binding assay, however, while still being a partial agonist. In vivo, BU08028 was evaluated in an acute thermal antinociception assay, for its ability to induce conditioned place preference (CPP), and for its effect on cocaine-induced CPP. BU08028 is a very potent long-lasting analgesic. It produces an increase in locomotor activity and a significant CPP. As a pretreatment to cocaine, BU08028 does not alter cocaine CPP but causes a further increase in cocaine-induced locomotor activity. The analgesic, rewarding, and stimulant effects are probably caused by μ receptor stimulation. It is likely that with BU08028, a partial agonist at both NOP and μ receptors, μ-mediated activity overpowers NOP-mediated effects. Thus, it is possible that a different buprenorphine analog that is a universal high-affinity opioid ligand but with "full agonist" activity at NOP may counteract traditional opioid-mediated effects such as antinociception and reward.
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http://dx.doi.org/10.1124/jpet.110.175620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3061529PMC
March 2011

Comparison of the antinociceptive and antirewarding profiles of novel bifunctional nociceptin receptor/mu-opioid receptor ligands: implications for therapeutic applications.

J Pharmacol Exp Ther 2009 Dec 22;331(3):954-64. Epub 2009 Sep 22.

Neuropharmacology Program, SRI International, Menlo Park, California, USA.

The nociceptin receptor (NOPr), a member of the opioid receptor family, is a target for the treatment of pain and drug abuse. Nociceptin/orphanin FQ (N/OFQ), the endogenous peptide for NOPr, not only modulates opioid antinociception, but also blocks the rewarding effects of several abused drugs, such as morphine, cocaine, and amphetamine. We hypothesized that NOPr agonists, with bifunctional activity at the mu-opioid receptor (MOPr), may function as nonaddicting analgesics or as drug abuse medications. Bifunctional small-molecule NOPr agonists possessing different selectivities and efficacies at MOPr were evaluated in an acute thermal antinociception assay, and for their ability to induce conditioned place preference (CPP) and their effect on morphine-induced CPP. 1-(1-Cyclooctylpiperidin-4-yl)-indolin-2-one) (SR14150), a high-affinity NOPr partial agonist, with low MOPr affinity and efficacy, produced analgesia that was naloxone-reversible. SR14150 did not induce CPP alone, nor did it attenuate morphine-induced CPP. 3-Ethyl-1-(1-(4-isopropylcyclohexyl)piperidin-4-yl)-indolin-2-one (SR16507), which has high affinity for both NOPr and MOPr, full agonist activity at NOPr, and partial agonist activity at MOPr, was also a potent analgesic and produced CPP alone, but also modestly attenuated morphine CPP. 1-(1-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)piperidinl-4-yl)-indolin-2-one (SR16835), a NOPr full agonist and low-affinity MOPr partial agonist, was not antinociceptive, did not produce CPP alone, but attenuated morphine CPP. Our results suggest that NOPr full-agonist activity is required to modulate opioid-induced reward, whereas a bifunctional NOPr/MOPr partial agonist profile may be suitable as a nonaddicting analgesic. The opioid-modulating effects of the NOPr ligands may be used effectively to produce better medications for treatment of drug abuse and pain.
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http://dx.doi.org/10.1124/jpet.109.157446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2784720PMC
December 2009

Nociceptin/orphanin FQ receptor activation attenuates antinociception induced by mixed nociceptin/orphanin FQ/mu-opioid receptor agonists.

J Pharmacol Exp Ther 2009 Dec 27;331(3):946-53. Epub 2009 Aug 27.

Policy Division, SRI International, Menlo Park, California 94025, USA.

Activation of brain nociceptin/orphanin FQ (NOP) receptors leads to attenuation of mu-opioid receptor (MOP receptor)-mediated antinociception. Buprenorphine, a high-affinity partial MOP receptor agonist also binds to NOP receptors with 80 nM affinity. The buprenorphine-induced inverted U-shaped dose-response curve for antinociception may be due to NOP receptor activation, given that, in the presence of the NOP receptor antagonist, 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J113397), or in NOP receptor knockout mice, buprenorphine has a steeper dose-response curve and acts as a full agonist. To further explore the involvement of the direct activation of NOP receptors by buprenorphine and other compounds that activate both NOP and MOP receptors, the antinociceptive effects of 1-(1-(2,3,3alpha,4,5,6-hexahydro-1H-phenalen-1-yl)piperidin-4-yl)-indolin-2-one. (SR16435), 3-ethyl-1-(1-(4-isopropylcyclohexyl)piperidin-4-yl)-indolin-2-one (SR16507), buprenorphine, pentazocine, and morphine, compounds with varying levels of MOP and NOP receptor affinity and efficacy, were assessed in mice using the tail-flick assay. The ability of the selective NOP receptor antagonist (-)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB-612111) to potentiate antinociception induced by the above compounds was examined to investigate whether activation of NOP receptors leads to attenuation of MOP receptor-mediated antinociception. SB-612111 potentiated antinociception induced by buprenorphine and the other mixed NOP/MOP receptor agonists SR16435 and SR16507. However, SB-612111 had no effect on pentazocine or morphine antinociception, two compounds with no NOP receptor-binding affinity. These results further support the hypothesis that activation of NOP receptors can lead to attenuation of MOP receptor-mediated antinociception elicited by mixed NOP/MOP receptor compounds such as buprenorphine, SR16435, and SR16507 and that, although buprenorphine has low efficacy in vitro, it has significant NOP receptor agonist activity in vivo.
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http://dx.doi.org/10.1124/jpet.109.156711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2784721PMC
December 2009

Activity of new NOP receptor ligands in a rat peripheral mononeuropathy model: potentiation of morphine anti-allodynic activity by NOP receptor antagonists.

Eur J Pharmacol 2009 May 12;610(1-3):49-54. Epub 2009 Mar 12.

Center for Health Sciences, SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025, USA.

The effect of new NOP receptor agonists and antagonists in the rat chronic constriction injury model was investigated. Intraperitoneally administered NOP receptor agonist SR14150 and antagonists SR16430 and SR14148, had no effect on mechanical allodynia when given alone. The nonselective NOP/mu-opioid receptor agonist SR16435, however, produced an anti-allodynic response, similar to morphine and reversible by naloxone. Notably, co-administration of the NOP receptor antagonists potentiated the anti-allodynic activity of both morphine and SR16435. Increased levels of the NOP receptor are implicated in the reduced efficacy of morphine in neuropathic pain. Our results suggest the utility of NOP receptor antagonists for potentiating opioid efficacy in chronic pain.
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http://dx.doi.org/10.1016/j.ejphar.2009.03.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2742704PMC
May 2009

Rodent models of nicotine reward: what do they tell us about tobacco abuse in humans?

Pharmacol Biochem Behav 2009 Feb 24;91(4):481-8. Epub 2008 Dec 24.

Department of Psychology, 500 West University Avenue, University of Texas at El Paso, El Paso, TX 79968, USA.

Tobacco products are widely abused in humans, and it is assumed that nicotine is the key substrate in these products that produces addiction. Based on this assumption, several pre-clinical studies have utilized animal models to measure various aspects of nicotine addiction. Most of this work has focused on behavioral measures of nicotine and how other variables contribute to these effects. Here we discuss the most commonly used animal models including, self-administration (SA), place conditioning (PC), and the intracranial self-stimulation (ICSS) paradigms in rodents. The strengths, limitations and procedural variables of these models are reviewed, followed by a discussion of how the animal models have been used to study factors such as age, sex, stress, and the effects of tobacco products other than nicotine. These factors are discussed in light of their influences on human tobacco abuse. The rodent models are evaluated in the context of face, predictive, and construct validity, and we propose that inclusion of factors such as age, sex, stress and other constituents of tobacco aside from nicotine can increase the utility of these animal models by more closely mimicking human tobacco abuse.
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http://dx.doi.org/10.1016/j.pbb.2008.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2646496PMC
February 2009

Hypocretin/orexin and nociceptin/orphanin FQ coordinately regulate analgesia in a mouse model of stress-induced analgesia.

J Clin Invest 2008 Jul;118(7):2471-81

Biosciences Division, SRI International, Menlo Park, California 94025, USA.

Stress-induced analgesia (SIA) is a key component of the defensive behavioral "fight-or-flight" response. Although the neural substrates of SIA are incompletely understood, previous studies have implicated the hypocretin/orexin (Hcrt) and nociceptin/orphanin FQ (N/OFQ) peptidergic systems in the regulation of SIA. Using immunohistochemistry in brain tissue from wild-type mice, we identified N/OFQ-containing fibers forming synaptic contacts with Hcrt neurons at both the light and electron microscopic levels. Patch clamp recordings in GFP-tagged mouse Hcrt neurons revealed that N/OFQ hyperpolarized, decreased input resistance, and blocked the firing of action potentials in Hcrt neurons. N/OFQ postsynaptic effects were consistent with opening of a G protein-regulated inwardly rectifying K+ (GIRK) channel. N/OFQ also modulated presynaptic release of GABA and glutamate onto Hcrt neurons in mouse hypothalamic slices. Orexin/ataxin-3 mice, in which the Hcrt neurons degenerate, did not exhibit SIA, although analgesia was induced by i.c.v. administration of Hcrt-1. N/OFQ blocked SIA in wild-type mice, while coadministration of Hcrt-1 overcame N/OFQ inhibition of SIA. These results establish what is, to our knowledge, a novel interaction between the N/OFQ and Hcrt systems in which the corticotropin-releasing factor and N/OFQ systems coordinately modulate the Hcrt neurons to regulate SIA.
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http://dx.doi.org/10.1172/JCI35115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2423866PMC
July 2008

Genetics of nicotine dependence and pharmacotherapy.

Biochem Pharmacol 2008 Jan 19;75(1):178-95. Epub 2007 Aug 19.

Center for Health Sciences, SRI International, Menlo Park, CA 94025, USA.

Nicotine dependence is substantially heritable. Several regions across the genome have been implicated in containing genes that confer liability to nicotine dependence and variation in individual genes has been associated with nicotine dependence. Smoking cessation measures are also heritable, and measured genetic variation is associated with nicotine dependence treatment efficacy. Despite significant strides in the understanding of the relative contribution of genetic and environmental factors to nicotine dependence and treatment, emergent challenges necessitate interdisciplinary coordinated effort for effective problem solving. These challenges include refinement of the nicotine dependence phenotype, better understanding of the dynamic interplay between genes and environment in nicotine dependence etiology, application and development of molecular and statistical methodology that can adequately address vast amounts of data, and continuous translational cross-talk.
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http://dx.doi.org/10.1016/j.bcp.2007.08.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2238639PMC
January 2008

Anti-nociceptive and anti-allodynic effects of a high affinity NOP hexapeptide [Ac-RY(3-Cl)YRWR-NH2] (Syn 1020) in rodents.

Eur J Pharmacol 2007 Mar 17;560(1):29-35. Epub 2007 Jan 17.

SRI International, Center for Health Sciences, 333 Ravenswood Ave., Menlo Park, CA 94025, USA.

There has been a flurry of activity to develop agonists and antagonists for the member of the opioid receptor family, NOP receptor (also known as ORL1), in part to understand its role in pain. Modifications of a hexapeptide originally identified from a combinatorial library have led to the discovery of a high affinity hexapeptide agonist Ac-RY(3-Cl)YRWR-NH2 (Syn 1020). In the following experiments we characterized the anti-nociceptive effects of Syn 1020 in the tail-flick model of acute pain and the diabetic neuropathy model of chronic pain in mice and rats, respectively. Acute antinociception was assessed using the tail-flick assay in mice in which animals received intracerebroventricular (i.c.v.) or subcutaneous (s.c.) injections of Syn 1020 alone or with morphine and were tested for tail-flick latencies. In the chronic pain model, diabetic neuropathy was induced by injections of streptozotocin in rats. Tactile allodynia was measured, with von Frey hair filaments, following intraperitoneal (i.p.) injections of Syn 1020 or gabapentin (positive control). In mice, i.c.v. injections of Syn 1020 did not have any pro- or anti-nociceptive effects, however, Syn 1020 reversed morphine antinociception with a similar potency as N/OFQ (the natural ligand to NOP). S.c. injections of Syn 1020 in mice also produced analgesic effects. In rats, i.p, injections of Syn 1020 produced anti-allodynic effects. Thus, Syn 1020, a NOP receptor directed peptide, administered systemically has anti-nociceptive activity in both acute and chronic pain models in mice and rats respectively.
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http://dx.doi.org/10.1016/j.ejphar.2006.12.015DOI Listing
March 2007

SR 16435 [1-(1-(bicyclo[3.3.1]nonan-9-yl)piperidin-4-yl)indolin-2-one], a novel mixed nociceptin/orphanin FQ/mu-opioid receptor partial agonist: analgesic and rewarding properties in mice.

J Pharmacol Exp Ther 2007 Feb 28;320(2):934-43. Epub 2006 Nov 28.

Center for Health Sciences, SRI International, Menlo Park, CA 94025, USA.

We identified a novel nociceptin/orphanin FQ (NOP)/mu-opioid receptor agonist, SR 16435 [1-(1-(bicyclo[3.3.1]nonan-9-yl)piperidin-4-yl)indolin-2-one], with high binding affinity and partial agonist activity at both receptors. It was hypothesized that SR 16435 would produce antinociception and yet, unlike morphine, would have diminished rewarding properties and tolerance development. Antinociception was assessed in mice using the tail-flick assay, whereas behavioral and rewarding effects were assessed using the place conditioning (PC) paradigm. PC was established by pairing drug injections with a distinct compartment. Behavioral effects were measured after acute and repeated drug administration, and the test for PC was carried out 24 h after four drug- and vehicle-pairing sessions. SR 16435 produced an increase in tail-flick latency, but SR 16435-induced antinociception was lower than that observed with morphine. Given that naloxone blocked SR 16435-induced antinociception, it is highly likely that this effect was mediated by mu-opioid receptors. Compared with morphine, chronic SR 16435 treatment resulted in reduced development of tolerance to its antinociceptive effects. SR 16435-induced conditioned place preference (CPP) was evident, an effect that was probably mediated via mu-opioid receptors, as it was reversed by coadministration of naloxone. NOP agonist activity was also present, given that SR 16435 decreased global activity, and this effect was partially reversed with the selective NOP antagonist, SR 16430 [1-(cyclooctylmethyl)-4-(3-(trifluoromethyl)phenyl)piperidin-4-ol]. Naloxone, however, also reversed the SR 16435-induced decrease in activity, indicating that both opioid and NOP receptors mediate this behavior. In summary, the mixed NOP/mu-opioid partial agonist SR 16435 exhibited both NOP and mu-opioid receptor-mediated behaviors.
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http://dx.doi.org/10.1124/jpet.106.111997DOI Listing
February 2007

Synthesis and in vitro biological evaluation of a carbon glycoside analogue of morphine-6-glucuronide.

Bioorg Med Chem Lett 2005 Mar;15(6):1583-6

Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121-2804, USA.

Attachment of a glucose moiety to 6-beta-aminomorphine afforded compound 3, where the glucose moiety was linked to the C-6 nitrogen atom by a two-carbon bridge. The synthesis of 3 was accomplished in eight steps from 3-triisopropylsilyl-6-beta-aminomorphine and 2,3,4,6-tetra-O-benzyl-D-glucose. The C-glycoside 3 was prepared with the objective of examining a metabolically stable analogue of morphine-6-glucuronide and determining the potency and selectivity of opioid receptor binding. Competition binding assays showed that 3 bound to the mu opioid receptor with a Ki value of 3.5 nM. The C-glycoside 3 exhibited delta/mu and kappa/mu selectivity ratios of 76 and 165, respectively. The synthetic intermediate (i.e., benzyl precursor, compound 11) bound to the mu opioid receptor with a Ki value of 0.5 nM, was less selective for the mu opioid receptor. The [35S]GTPgammaS assay was used to evaluate the functional properties of compounds 3 and 11. Compound 3 was determined to be a full agonist at the mu opioid receptor, whereas compound 11 was found to be a partial agonist. Compound 3 was determined to be very stable in the presence of human liver S9, and rat and monkey liver microsomes: no detectable loss of 3 was observed up to 90 min. Compound 3 was also very stable at pH 2 and pH 7.4, suggesting that 3 possessed properties for sustained duration of action.
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http://dx.doi.org/10.1016/j.bmcl.2005.01.072DOI Listing
March 2005

Genetics and drug use as a complex phenotype.

Subst Use Misuse 2004 ;39(10-12):1515-69

Center for Health Sciences, SRI International, Menlo Park, California 94025, USA.

Drug use is a complex behavior influenced by multiple biological, family, and sociocultural factors. The concurrent use/misuse of multiple drugs is often seen and drug use also co-occurs with other psychiatric conditions. Behavior and molecular genetic studies support an important posited role of genes in drug use. This posited genetic risk does not appear to be conferred by one or two major genes manifesting large effects, but rather by a number of genes manifesting smaller effects. Genetic factors explain, on average, only about half of the total variability in drug use, with the remaining variability influenced by environmental factors. Also, genetic risk may be differentially expressed in the presence vs. absence of particular environmental conditions. Thus, investigation of environmental factors and their interaction with genetic risk is a necessary component of genetic research. While the full potential of genetic investigations for the prevention of drug misuse has yet to be realized, an example of the impact of risk factor modification under various conditions of gene-environment interaction is provided, and the implications for use of genetic information in drug-misuse prevention are discussed. The multifactorial nature of drug use necessitates coordinated investigation from multiple disciplines and timely dissemination of scientific findings. In addition, this work demands adherence to the highest standards of confidentiality and ethical use of genetic information to best inform future prevention efforts.
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http://dx.doi.org/10.1081/ja-200033202DOI Listing
February 2005

Design, chemical synthesis, and biological evaluation of thiosaccharide analogues of morphine- and codeine-6-glucuronide.

J Med Chem 2004 Nov;47(23):5809-15

Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, California 92121-2804, USA.

A series of 6-beta-thiosaccharide analogues of morphine-6-glucuronide (M6G) and codeine-6-glucuronide (C6G) were synthesized and evaluated with the objective of preparing an analogue of M6G with improved biological activity. The affinity of the thiosaccharide analogues of M6G and C6G was examined by competitive binding assays at mu, delta, and kappa opioid receptors. The thiosaccharide compounds in the morphine series 5b, 5e, 6a, and 6c showed 1.5-2.4-fold higher affinity for the mu receptor than M6G, but were generally less selective than M6G. The functional activity of the M6G and C6G analogues was examined with the [35S]GTP-gamma-S assay. Compounds 5b and 5e were determined to be full mu agonists, whereas compounds 6a and 6c were partial mu agonists. The in vivo antinociceptive activity of compound 5b was evaluated by the tail flick latency test, giving an ED50 of 2.5 mg/kg.
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http://dx.doi.org/10.1021/jm049554tDOI Listing
November 2004

Synthesis and biological evaluation of some 6-arylamidomorphines as analogues of morphine-6-glucuronide.

Bioorg Med Chem 2004 Nov;12(22):5983-90

Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121-2804, USA.

A series of 6-beta-arylamidomorphines was synthesized and biologically evaluated. Various aryl substituents were introduced into the arylamidomorphines to examine substituent structure-activity relationships. Competition binding assays showed that compounds 10a-h bound to the mu opioid receptor with high affinity (0.2-0.6 nM). Functional assays showed that compounds 10a-h acted as full mu opioid receptor agonists. The ED(50) of compound 10e.HCl as an analgesic was 12.6 mg/kg in the tail flick latency test in the rat.
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http://dx.doi.org/10.1016/j.bmc.2004.08.019DOI Listing
November 2004

Intergenerational transmission of tobacco use and dependence: a transdisciplinary perspective.

Nicotine Tob Res 2003 Dec;5 Suppl 1:S55-69

Brown Medical School, Centers for Behavioral & Preventive Medicine, Providence, RI 02903, USA.

Numerous questions remain regarding the intergenerational transmission of tobacco use and dependence, and some of these questions are best approached from a transdisciplinary perspective. For example, considering both genetic and environmental influences on cigarette smoking promises to be a fruitful venue for future investigations. In this paper, we consider the evidence regarding intergenerational influences on the transmission of tobacco use and nicotine dependence in both humans and animal models; our focus will be on genetic influences, in utero exposure to nicotine, and some postnatal influences. Research gaps that exist between scientific disciplines are highlighted, and some directions for future research are suggested.
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http://dx.doi.org/10.1080/14622200310001625500DOI Listing
December 2003

Environmental and genetic determinants of tobacco use: methodology for a multidisciplinary, longitudinal family-based investigation.

Cancer Epidemiol Biomarkers Prev 2003 Oct;12(10):994-1005

Center for Health Sciences, SRI International, Menlo Park, California 94025, USA.

This article describes the ongoing collaborative effort of six research teams to operationalize and execute an integrative approach to the study of gene x environment interactions in the development of tobacco dependence. At the core of the project is a longitudinal investigation of social and behavioral risk factors for tobacco use in individuals who were, on average, 13 years of age at intake and for whom smoking outcomes extending from early adolescence to young adulthood have been characterized previously (current average age of the cohort is 29 years). The conceptual framework for the integrative approach and the longitudinal investigation on which the study is based is presented. A description is also provided of the methods used to: (a) recruit participants and families to provide DNA samples and information on tobacco use; (b) assess participants for relevant tobacco-related phenotypes including smoking history, current use of tobacco, and nicotine metabolism; (c) assess the quality of the DNA samples collected from participants for genome-wide scanning and candidate gene analysis; (d) examine several research questions concerning the role of genetic and environmental factors in the onset and maintenance of tobacco use; and (e) ensure adherence to local and federal guidelines for ethical and legal investigations of genotypic associations with tobacco-related phenotypes in families. This investigation is unique among ongoing studies of the genetics of tobacco dependence in the extent to which equal importance has been assigned to both phenotypic and genotypic measurements.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2587265PMC
October 2003

Attenuation of relapse to cocaine seeking by dopamine D1 receptor agonists and antagonists in non-human primates.

Psychopharmacology (Berl) 2003 Jul 27;168(1-2):124-131. Epub 2003 Feb 27.

New England Regional Primate Research Center, Harvard Medical School, Southborough, Massachusetts, USA.

Rationale: Dopamine D(1) receptor agonists and antagonists attenuate reinstatement of cocaine seeking in a non-human primate model of relapse. The mechanisms by which these different classes of D(1) receptor drugs produce these similar effects on cocaine seeking are unknown.

Objectives: This study investigated how D(1) receptor agonists and antagonists alter the shape and position of the dose-response function for reinstatement of drug seeking induced by a cocaine prime accompanied by restoration of the cocaine-paired stimulus.

Methods: Squirrel monkeys were given extensive histories of cocaine self-administration under a second-order fixed-interval, fixed-ratio schedule of i.v. drug injection. Drug seeking was then extinguished by replacing cocaine with vehicle and eliminating the cocaine-paired stimulus. In subsequent test sessions, in which the cocaine-paired stimulus was re-introduced, priming injections of cocaine alone or combined with the different D(1) receptor high- and low-efficacy agonists and antagonists (SKF 82958, SKF 81297, SKF 83959, ecopipam; n=3-4 per drug condition) were tested for their ability to reinstate extinguished cocaine seeking.

Results: Cocaine priming accompanied by the restoration of the cocaine-paired stimulus induced a dose-dependent reinstatement of drug seeking. When combined with cocaine, all D(1) receptor agonists and antagonists produced rightward and downward shifts in the cocaine dose-response function. However, combined pretreatment of SKF81297 (agonist) and ecopipam (antagonist) inhibited cocaine seeking less than either drug individually.

Conclusions: These findings suggest that D(1) receptor high- and low-efficacy agonists as well as antagonists attenuate reinstatement of cocaine seeking in part via pharmacologically opposing actions at a common population of D(1) receptors.
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http://dx.doi.org/10.1007/s00213-002-1365-yDOI Listing
July 2003

Effects of 7-OH-DPAT on cocaine-seeking behavior and on re-establishment of cocaine self-administration.

Pharmacol Biochem Behav 2002 Jun;72(3):623-32

Department of Psychology, Arizona State University, Box 871104, Tempe 85287-1104, USA.

Effects of the D2-like dopamine agonist, 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT), on cocaine-seeking behavior and re-establishment of cocaine self-administration were examined. Rats were trained to lever press for cocaine infusions (0.25 mg/kg iv). Some were then tested for cocaine-seeking behavior (i.e., lever presses in the absence of cocaine re-inforcement) immediately following acute 7-OH-DPAT (0.001, 0.01, 0.1, or 1.0 mg/kg sc) or saline administration. Others were tested immediately or 2-23 h following repeated daily 7-OH-DPAT (1.0 mg/kg sc) or saline administration for extinction of cocaine-seeking behavior, cocaine re-instatement of cocaine-seeking behavior, and re-establishment of cocaine self-administration following extinction. 7-OH-DPAT-induced changes in locomotion were also assessed. Cocaine-experienced animals exhibited cross-tolerance to the transient hypoactivity produced by acute 7-OH-DPAT administration. Acute administration of low doses (0.01-0.1 mg/kg) of 7-OH-DPAT attenuated cocaine-seeking behavior, whereas the highest dose (1.0 mg/kg) initially attenuated, then increased, cocaine-seeking behavior. In animals tested immediately following one of the repeated administrations, 7-OH-DPAT did not alter cocaine self-administration, but sensitized locomotion. Repeated 7-OH-DPAT administration also increased cocaine-seeking behavior when administered 0 h, but not 2 or 4 h, before cocaine priming (15 mg/kg ip) and testing. In animals tested 17-23 h following one of the repeated administrations, cocaine-seeking behavior and re-establishment of cocaine self-administration were attenuated, but maintenance of self-administration following re-establishment, cocaine re-instatement of extinguished cocaine-seeking behavior, and spontaneous locomotion were unaltered. The findings suggest that following repeated administration, 7-OH-DPAT produces a transient increase (<2 h) in incentive motivation for cocaine that is followed by a protracted decrease in incentive motivation for cocaine.
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http://dx.doi.org/10.1016/s0091-3057(02)00731-1DOI Listing
June 2002