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S-20-3 Opioid receptor blockade
218
S-20 Addiction:from receptor to pharmacotherapy
Human receptor binding stud,ca using Dram imaging techniques and ge netlc studies of cloning receptor subunits could enhance our understanding of acute/chronic GABAergic drug action, and explain some of the indwiduaF to-individual differences in susceptibdity to drug abuse. Using PET and SPECT available radioligands for GABA and benzodiazepines receptors we can already investigate receptor distnbution and density, interactions w~th ethanol, as we!l as the functional integrity of neurophysiologically linked transmitter s y s t e m s ( e g GABA,nhibltion of dopamine) Studies of cloned GABA A receptor subunits reveal that mixtures of different suounits may form functional brain receptors with different actw~ties These chimenc receptors' propert!es make them ideal molecular tools with whictq to roves tigate the features necessary to confer ethanol, barbiturate, and benzodi azepme sensitivity on ligand-gated ch onde channel GABA receptors, thus improving our knowledge of the mechanism of drug dependence arrd its therapeutic treatment. Since the discovery of the benzodlazepine receptor recognlctlon site a large number of benzodlazepine and nonbenzoaiazepine drugs have oeen found to interact with these receptors N o w we know that the GABA A receptor can be positively or negatively modulated by compounds which range in actwlty from full agonists to full inverse agonists. GABA agonlsts have been already used for treating benzodLazepines and ethanol abuse and withdrawal (substitution approach} The suggestlon to use blockmgagents to 'reset' the receptor and reduce the reinforcing effects of sedatives needs to be fully pursued(antagonist approach)lGallager et al., 1986) Following the latter indication, GABAergtc compounds with different degrees of mtnnslcefficacy(e.g partialagonistsorpartiaiinverseagonists) could be tested for their efficacy in modulating the rewarding effects of, and craving for drugs of abuse acting directly and non at the GABA receptor.
References Gallager, DW. Hen~nger ~, and HeN nger @ (19861 Peqodlc benzodlazepqne antagontst administration prevents t~enzodlazep~qe withdrawal symptoms in primates Eur J Pharmacol 132, 3!-38 Hyman, SE (1993) Moiecular and cell b~ology of addtctlon Curt ODin Neurol 6 609 613 Le~denhetmer, N J and Hams, R A (1992) Acute effects of ethanol on GABAA receptor function: molecular and phystologlcal determlnanrs Adv Biochem Psychopharmacol 47, 269 279 Ticku. M K. Mhatre, M and Mehta, A K {1992) Modulation of GABAerg~c transmission by ethanol Adv Bioohem. Psychopharmacol 47,255-268 Yu S and HO. IK (1990) Effects of acute barbiturate administration tolerance and dependence on brain Gaba system comparison to alcohol and benzcdlazeoines Alco hol 7(3), 261 272
Opioid receptor blockade
actwity (s correlated with opiate withdrawal symptoms. Opioid antagonists precipitate withdrawal in part by blocking the inhibition of the cyclic AMP system Thus, the neurobiological effects of opioid antagonists are most obvious, when acutely administered to an animal that has been made opidid dependent. In the non-dependent state, this inhibition appears to have relatively little physiological manifestation; however, in the hypertrophied or upreguiated state, removal of the agonist inhibition by the antagonist has a notable effect in cell activation. A critical neurobioiogical concept is how an opioid antagonist such as naltrexone may reset intraneuronal mechanisms that have been altered by sustained opioid exposure. One concept is that the antagonist allows "h~dden" opioid receptors to be exposed for stimulation by endogenous Igands such as beta endorphin. This increase in receptor number will "rebaiance" the neuronal system of opioid receptor inhibition of the cyclic AMP second messenger system. Chronic opioid antagonist administration prevents opioid agonists from producing their physiological and subjective effects such as pain relief and prevents feedback inhibition of endogeneous opioids production. Thus. chronic naltrexone administration elevates beta endorphin, ACTH, and cortisol levels No tolerance develops to these elevations of endogenous oploids, and this elevation may be therapeutically useful. While full opioid antagonists have had limited clinical efficacy for opioid dependence, partial opioid antagonism may be therapeutically useful for opioid dependence and pure antagonism may be useful for alcoholism. The partial opioid antagonist buprenorphine has shown more promise for heroin addicts. Partial antagonists have interesting dose dependent effects with relatively strong agonists effects at low dosages turning into antagonism at high d o s a g e Clinical studies of buprenorphine have shown substantial declines ~n illicit heroin use as dosage is increased, to 12 to 20 mg. sublingual daily At these dosages, patients also have excellent compliance in contrast :o naltrexone Recent work with opioid anatagonists in alcoholism has indicated a substantial reduction in alcohol abuse with naltrexone treatment. Naltrexone clearw does not block alcohol's effects directly, but the elevation in beta endorphin levels by naltrexone may compensate for a neurobiological deficit in alcoholics, other mechanism for the efficacy of naltrexone and alcoholism have been suggested from animal studies and wilt be reviewed. In summary, the neurobiological of opioid antagonism is being increas,ngly elucidated by molecular biology studies and new therapeutic uses of full and partial anatagonists are developing including better opioid dependence treatments using buprenorphine and innovative alcoholism treatments using naltrexone.
is dopamine involved in opiate addiction?
Thomas R. Kosten Yale Unfversity School of Medicine Substance Abuse
Center 34 Park Street, Room S~05 New Haven, CT 06519 USA Understanding the mechanisms of acute and chronic opioid receptor block. ado has been advanced substantially by recent developments in molecule, biology The opioid receptor family including the mu. delta and kappa recep tors recently have been cloned and we nave been able to surmise that they have seven transmembrane segments and are all G protein coupled "-he seven transmembrane loops of amino acids jo~n an extracelluiar binding region for linkage to endogenous peptBdes such as beta-endorphins and enkephalins, and an intracellular portion has several s~tes for phosphorylatlon and linkage to G proteins All three receptors inhibit adenylyl cvclase and are coupled to ion channels, closing calcium and opening potassium channels though directG p r o t e m c o u p l i n g An~mportantchallenge~stouse amino acid substitutions and genetic mutations of this extraceliular region ~n order to more precisely identify binding and actwatlon sites for medica tionssuch as morph~ne and the antagonist naltrexone The precise linkage of this receptor proteLn to the potassium and calcium ~on channels in celia such as the locus ceruleus neurons now also can be addressed. Critical questions are how antagomsts bind to this receptor and prevent activation and how partial agonists interact with tins receptor in companson to full agonists or modu!ate it in',o high and low affinity states. The neuroblologyof the cyclic AMP second messenger systems has been most informative for understanding oploid tolerance and dependence and how acute opioid receptor blockade unmasks thks dependence through the precipitation of withdrawal symptoms Opolds such as morphine ~nh~b~t cychc AMP production through adenylyIcyclase With chronic op~old treat ment there is a compensatory nypert-opdy ~n the activity of this enzyme such that ffthe opioid inhibition ~s removed, levels of intraceilular cyclic AMP will markedly ~ncrease. This increase of cychc AMP will lead to increased neuronal actwlty ,n areas such as the locus ceruleus, and this neu'onal
Jan M. van Ree, Miriam A.F.M. Gerrits Department of Pharmaco/ogy, Rudolf Magnus/nstztute for Neurosciences, Utrecht University, Umversiteitsweg 100, 3584 CG Utrecht, The Netherlands A common denominator of most, if not all drugs of abuse are their reward,ng or re~nforcing properties. In animal experiments, these properties are the basis of the drug selfadministration paradigm, that has been shown to be a validated model of human drug dependence. The rewarding properties have also stimulated research to identify a c o m m o n neurobiological system underlying dependence to all abused drugs. Research on this issue over the last decade has primarily been focused on dopamine and particularly on the mesocorticolimbic dopamine system (Wise and Rompe, !989). Further evidence came from neurochemical studies, showing that most drugs of abuse have the ability to enhance dopamine release in the nucleus acoumbens, a terminal area of the mesocorticolimbic dopamine system (Di Chiari and Lmperato, 1988) Although this effect has been related to the rewarding or dependence creating properties of these drugs, direct evidence of such a relation e g . that blockade of the nucleus accumbens dopamine decreases the rewarding properties, has not been demonstrated :;onwnc~ngly, In particular the role of the nucleus accumbens dopamine in opiate reward has been questioned (Van Ree and Ramsey, 1987). but only a f e w studies have addressed this issue directly using the opiate selfadmim ~stratlon paradigm Neurotoxic lesions of the dopamine cellbodies in the ventral tegmental area and of the nucleus aecumbens cellbodies by use of kaimc acid attenuated intravenous opiate selfadministration during the maintenance phase of dependence, suggesting a critical involvement of these areas in opiate selfadministration. However. these studies are inconclusive with respect to dopamine and to a specific involvement of motor behavior. Intravenous heroin selfadministration was attenuated by systemic treatment with neuroleptic (antidopaminergic) treatment, but only at doses
S-20 Addiction:from receptor to pharmacotherapy
Human receptor binding stud,ca using Dram imaging techniques and ge netlc studies of cloning receptor subunits could enhance our understanding of acute/chronic GABAergic drug action, and explain some of the indwiduaF to-individual differences in susceptibdity to drug abuse. Using PET and SPECT available radioligands for GABA and benzodiazepines receptors we can already investigate receptor distnbution and density, interactions w~th ethanol, as we!l as the functional integrity of neurophysiologically linked transmitter s y s t e m s ( e g GABA,nhibltion of dopamine) Studies of cloned GABA A receptor subunits reveal that mixtures of different suounits may form functional brain receptors with different actw~ties These chimenc receptors' propert!es make them ideal molecular tools with whictq to roves tigate the features necessary to confer ethanol, barbiturate, and benzodi azepme sensitivity on ligand-gated ch onde channel GABA receptors, thus improving our knowledge of the mechanism of drug dependence arrd its therapeutic treatment. Since the discovery of the benzodlazepine receptor recognlctlon site a large number of benzodlazepine and nonbenzoaiazepine drugs have oeen found to interact with these receptors N o w we know that the GABA A receptor can be positively or negatively modulated by compounds which range in actwlty from full agonists to full inverse agonists. GABA agonlsts have been already used for treating benzodLazepines and ethanol abuse and withdrawal (substitution approach} The suggestlon to use blockmgagents to 'reset' the receptor and reduce the reinforcing effects of sedatives needs to be fully pursued(antagonist approach)lGallager et al., 1986) Following the latter indication, GABAergtc compounds with different degrees of mtnnslcefficacy(e.g partialagonistsorpartiaiinverseagonists) could be tested for their efficacy in modulating the rewarding effects of, and craving for drugs of abuse acting directly and non at the GABA receptor.
References Gallager, DW. Hen~nger ~, and HeN nger @ (19861 Peqodlc benzodlazepqne antagontst administration prevents t~enzodlazep~qe withdrawal symptoms in primates Eur J Pharmacol 132, 3!-38 Hyman, SE (1993) Moiecular and cell b~ology of addtctlon Curt ODin Neurol 6 609 613 Le~denhetmer, N J and Hams, R A (1992) Acute effects of ethanol on GABAA receptor function: molecular and phystologlcal determlnanrs Adv Biochem Psychopharmacol 47, 269 279 Ticku. M K. Mhatre, M and Mehta, A K {1992) Modulation of GABAerg~c transmission by ethanol Adv Bioohem. Psychopharmacol 47,255-268 Yu S and HO. IK (1990) Effects of acute barbiturate administration tolerance and dependence on brain Gaba system comparison to alcohol and benzcdlazeoines Alco hol 7(3), 261 272
Opioid receptor blockade
actwity (s correlated with opiate withdrawal symptoms. Opioid antagonists precipitate withdrawal in part by blocking the inhibition of the cyclic AMP system Thus, the neurobiological effects of opioid antagonists are most obvious, when acutely administered to an animal that has been made opidid dependent. In the non-dependent state, this inhibition appears to have relatively little physiological manifestation; however, in the hypertrophied or upreguiated state, removal of the agonist inhibition by the antagonist has a notable effect in cell activation. A critical neurobioiogical concept is how an opioid antagonist such as naltrexone may reset intraneuronal mechanisms that have been altered by sustained opioid exposure. One concept is that the antagonist allows "h~dden" opioid receptors to be exposed for stimulation by endogenous Igands such as beta endorphin. This increase in receptor number will "rebaiance" the neuronal system of opioid receptor inhibition of the cyclic AMP second messenger system. Chronic opioid antagonist administration prevents opioid agonists from producing their physiological and subjective effects such as pain relief and prevents feedback inhibition of endogeneous opioids production. Thus. chronic naltrexone administration elevates beta endorphin, ACTH, and cortisol levels No tolerance develops to these elevations of endogenous oploids, and this elevation may be therapeutically useful. While full opioid antagonists have had limited clinical efficacy for opioid dependence, partial opioid antagonism may be therapeutically useful for opioid dependence and pure antagonism may be useful for alcoholism. The partial opioid antagonist buprenorphine has shown more promise for heroin addicts. Partial antagonists have interesting dose dependent effects with relatively strong agonists effects at low dosages turning into antagonism at high d o s a g e Clinical studies of buprenorphine have shown substantial declines ~n illicit heroin use as dosage is increased, to 12 to 20 mg. sublingual daily At these dosages, patients also have excellent compliance in contrast :o naltrexone Recent work with opioid anatagonists in alcoholism has indicated a substantial reduction in alcohol abuse with naltrexone treatment. Naltrexone clearw does not block alcohol's effects directly, but the elevation in beta endorphin levels by naltrexone may compensate for a neurobiological deficit in alcoholics, other mechanism for the efficacy of naltrexone and alcoholism have been suggested from animal studies and wilt be reviewed. In summary, the neurobiological of opioid antagonism is being increas,ngly elucidated by molecular biology studies and new therapeutic uses of full and partial anatagonists are developing including better opioid dependence treatments using buprenorphine and innovative alcoholism treatments using naltrexone.
is dopamine involved in opiate addiction?
Thomas R. Kosten Yale Unfversity School of Medicine Substance Abuse
Center 34 Park Street, Room S~05 New Haven, CT 06519 USA Understanding the mechanisms of acute and chronic opioid receptor block. ado has been advanced substantially by recent developments in molecule, biology The opioid receptor family including the mu. delta and kappa recep tors recently have been cloned and we nave been able to surmise that they have seven transmembrane segments and are all G protein coupled "-he seven transmembrane loops of amino acids jo~n an extracelluiar binding region for linkage to endogenous peptBdes such as beta-endorphins and enkephalins, and an intracellular portion has several s~tes for phosphorylatlon and linkage to G proteins All three receptors inhibit adenylyl cvclase and are coupled to ion channels, closing calcium and opening potassium channels though directG p r o t e m c o u p l i n g An~mportantchallenge~stouse amino acid substitutions and genetic mutations of this extraceliular region ~n order to more precisely identify binding and actwatlon sites for medica tionssuch as morph~ne and the antagonist naltrexone The precise linkage of this receptor proteLn to the potassium and calcium ~on channels in celia such as the locus ceruleus neurons now also can be addressed. Critical questions are how antagomsts bind to this receptor and prevent activation and how partial agonists interact with tins receptor in companson to full agonists or modu!ate it in',o high and low affinity states. The neuroblologyof the cyclic AMP second messenger systems has been most informative for understanding oploid tolerance and dependence and how acute opioid receptor blockade unmasks thks dependence through the precipitation of withdrawal symptoms Opolds such as morphine ~nh~b~t cychc AMP production through adenylyIcyclase With chronic op~old treat ment there is a compensatory nypert-opdy ~n the activity of this enzyme such that ffthe opioid inhibition ~s removed, levels of intraceilular cyclic AMP will markedly ~ncrease. This increase of cychc AMP will lead to increased neuronal actwlty ,n areas such as the locus ceruleus, and this neu'onal
Jan M. van Ree, Miriam A.F.M. Gerrits Department of Pharmaco/ogy, Rudolf Magnus/nstztute for Neurosciences, Utrecht University, Umversiteitsweg 100, 3584 CG Utrecht, The Netherlands A common denominator of most, if not all drugs of abuse are their reward,ng or re~nforcing properties. In animal experiments, these properties are the basis of the drug selfadministration paradigm, that has been shown to be a validated model of human drug dependence. The rewarding properties have also stimulated research to identify a c o m m o n neurobiological system underlying dependence to all abused drugs. Research on this issue over the last decade has primarily been focused on dopamine and particularly on the mesocorticolimbic dopamine system (Wise and Rompe, !989). Further evidence came from neurochemical studies, showing that most drugs of abuse have the ability to enhance dopamine release in the nucleus acoumbens, a terminal area of the mesocorticolimbic dopamine system (Di Chiari and Lmperato, 1988) Although this effect has been related to the rewarding or dependence creating properties of these drugs, direct evidence of such a relation e g . that blockade of the nucleus accumbens dopamine decreases the rewarding properties, has not been demonstrated :;onwnc~ngly, In particular the role of the nucleus accumbens dopamine in opiate reward has been questioned (Van Ree and Ramsey, 1987). but only a f e w studies have addressed this issue directly using the opiate selfadmim ~stratlon paradigm Neurotoxic lesions of the dopamine cellbodies in the ventral tegmental area and of the nucleus aecumbens cellbodies by use of kaimc acid attenuated intravenous opiate selfadministration during the maintenance phase of dependence, suggesting a critical involvement of these areas in opiate selfadministration. However. these studies are inconclusive with respect to dopamine and to a specific involvement of motor behavior. Intravenous heroin selfadministration was attenuated by systemic treatment with neuroleptic (antidopaminergic) treatment, but only at doses