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PR6 2008.Vp:Corelventura Pharmacological Reports Copyright © 2008 2008, 60, 755–770 by Institute of Pharmacology ISSN 1734-1140 Polish Academy of Sciences Review GABAB receptors in drug addiction Ma³gorzata Filip, Ma³gorzata Frankowska Laboratory of Drug Addiction Pharmacology, Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smêtna 12, PL 31-343 Kraków, Poland Correspondence: Ma³gorzata Filip, e-mail: [email protected] Abstract: Preclinical studies and clinical trials carried out within the past few years have provided a premise that g-aminobutyric acid (GABA) transmission and GABAB receptors play a modulatory role in the mechanism of action of different drugs of abuse. The present re- view summarizes the contribution of GABAB receptors to the rewarding, locomotor and discriminative stimulus properties of drugs of abuse and their withdrawal symptoms in laboratory animals. It also reviews the current knowledge about the GABAB receptor ligands in clinical trials, with a focus on their effects on presentation of the drug-associated cues and withdrawal-induced drug craving. Key words: addictive substances, discrimination, GABAB receptor ligands, locomotion, reward, reinstatement of seeking behavior, withdrawal, laboratory animals, clinical trials Introduction Recently published data (preclinical studies and clinical trials) have provided a premise that g-amino- butyric acid (GABA) and GABAB receptors play According to the World Health Organization (WHO), a modulatory role in the mechanism of action of dif- drug addiction is a chronic disease of the central nerv- ferent drugs of abuse [4, 35, 70, 102, 132, 147, 158]. ous system that is characterized by a loss of control over impulsive behavior that leads to compulsive drug seeking and taking and to relapses even after many months of abstinence. The clinical diagnosis of addiction is also defined GABAB receptors by the use of a psychoactive substance for a longer period or at higher doses than initially prescribed, drug cravings or unsuccessful attempts to cease the GABAB receptors, belonging to the metabotropic re- drug use, use of the drug despite the negative effect on ceptor family, were discovered at the end of the 1970s one’s social and professional life, increasing toler- by the Bowery’s research team [22] and were cloned ance, a withdrawal syndrome and desire to take the in 1997 by Bettler et al. [81]. These receptors are drug to alleviate these symptoms (according to DSM composed of a heterodimer of GABAB1 and GABAB2 IV, American Psychiatric Society). subunits [82, 116] (Fig. 1). Pharmacological Reports, 2008, 60, 755–770 755 Fig. 1. Structure of the GABAB receptor and its intracellular signal effectors Structure (so-called „orphan”) does not bind endogenous neuro- transmitter or receptor ligands, but contains all the The primary structure of both GABAB receptor molecular determinants required for the recognition subunits has been established. They are proteins with of G proteins and its activation [66, 123]. Moreover, a molecular weight of 130 kDa and 110 kDa, respec- the GABAB2 subunit functions as a carrier of the tively, and are composed of a chain of 961 (GABAB1) GABAB1 subunit and transports it from the endoplas- and 940-941 (GABAB2) amino acids. Both of them mic reticulum to the cell surface [42]. The function of have a long, extracellular amino terminus, seven the GABAB2 subunit is changed by so-called allosteric transmembrane domains and a short, intracellular car- modulators, i.e., substances that can attach to the intra- boxyl terminus forming a loop responsible for linking membrane domain of the GABAB2 subunit [15, 154]. both subunits [14, 82]. The GABAB1 subunit is en- Interestingly, both GABAB receptor subunits inter- coded by a gene localized to chromosome 6p21.3 act with many intra- and extracellular proteins. Re- in humans [82, 113], 20p12 in rats [93] and 17B1 in cently published studies on cell lines have demon- mice [118]. It is interesting to note that molecular bi- strated that the C-terminal domain of the GABAB1 ology techniques (cloning) have allowed researchers subunit binds ATF-4, 14-3-3 and tamalin, whereas to successfully distinguish at least eight biologically the C-terminal of the GABAB2 subunit binds the important isoforms of this subunit (a–h), with the MUPP-1, CHOP (Gadd 153) and b-filamin proteins. a and b isoforms being indispensable for GABAB het- These associated proteins fulfill different functions erodimer formation [14]. The GABAB1 subunit con- which include transcription factors (ATF-4, CHOP) tains a long, extracellular amino acid chain, where that produce long-term metabolic changes implicating binding sites for the endogenous neurotransmitter and new protein synthesis after GABAB receptor activa- ligands (agonists and antagonists) of GABAB recep- tion, structural proteins and proteins that are engaged tors are located [87]. in migration (14-3-3, tamalin, MUPP-1), proteins re- The GABAB2 subunit is encoded by a gene local- sponsible for receptor dimerization and synaptic lo- ized to 9q22.1-22.3 in humans [116], 5q24 in rats [93] calization, and proteins that anchor the GABAB re- and 4B1 in mice [118]. It is known that this subunit ceptor to the cell skeleton (b-filamin). Moreover, the 756 Pharmacological Reports, 2008, 60, 755–770 GABAB receptors and addiction Ma³gorzata Filip et al. Fig. 2. Localization of GABAB receptors to synaptic sites N-terminal of the GABAB1 subunit has been shown to glia (caudate nucleus, putamen), hypothalamus, olfac- bind fibulin and HNK-1, i.e., extracellular proteins. tory bulb and spinal cord [34, 49]. The role of HNK-1 protein has not been elucidated, Peripherally, GABAB receptors occur in the auto- but fibulin has been suggested to participate in the nomic ganglia, in the spleen, urinary bladder, small synaptic localization of GABAB1a and GABAB1b iso- intestine, lung, testis, stomach, pancreas, kidney, liver, forms [cf. 14]. oviducts, myocardium and skeletal muscles [120]. GABAB receptors are localized presynaptically on bodies and/or dendrites of GABAergic neurons (auto- Localization receptors) and non-GABAergic neurons (heterorecep- tors) or postsynaptically on non-GABAergic neurons GABAB receptors have been identified in both the [16, 82, 133] (Fig. 2). The presynaptic GABAB recep- central and peripheral nervous system. Within the tors are composed of the GABAB1a and GABAB2 central nervous system, the GABAB receptors are pre- subunits, whereas the postsynaptic receptors are built dominantly localized to neurons with their largest with the GABAB1b and GABAB2 subunits [16, 89]. density in the thalamic nuclei, cerebellum, amygdala and cortex. Considerable densities of these receptors Ligands have also been detected in the hippocampus, habe- nula, substantia nigra, ventral tegmental area, nucleus The discovery of the exogenous GABAB receptor accumbens septi, globus pallidus and hypothalamus ligand, baclofen, i.e., p-chlorophenyl-GABA, was [16, 23]. Other studies revealed that GABAB recep- a milestone in the characterization of these receptors. tors are expressed in the spinal cord (ventral and dor- Baclofen, which was synthesized by Heinrich Keberle sal horns) [99]. It is important to emphasize that the in 1962, 30 years before a GABAB receptor was distribution pattern of the GABAB1 and GABAB2 cloned, is a lipophilic GABA derivative that is active subunit transcripts and proteins in many structures of after peripheral administration, and possesses a high the central nervous system are similar, except for the affinity for the GABAB receptors and has a strong in- low expression of GABAB2 mRNA in the basal gan- trinsic activity. Baclofen is an optically active com- Pharmacological Reports, 2008, 60, 755–770 757 Tab. 1. GABA receptor ligands and their binding affinities pound, and its R isomer shows a three times greater B affinity for GABAB receptors and has a more efficient action than the racemate. The next-generation Drug GABAB receptor affinity References GABAB receptor agonists, which are still structural Ki (*IC50) (nM) baclofen analogues, were introduced in the 1980s and Agonists 1990s. These compounds, synthesized by the Swiss (R)-Baclofen 4.57 cf. 129 pharmaceutical company, NOVARTIS, and desig- nated with the symbol CGP, exhibit a three- to seven- (R,S)-Baclofen 14* 62 3-APPA (CGP 27492) 5 cf. 6 fold higher affinity for GABAB receptors compared to (R)-baclofen, high selectivity and easy penetration of 3-APMPA (SKF 97541, 16* cf. 129 CGP 35024) the blood-brain barrier (Tab. 1) [62]. CGP 44532 45* cf. 65 In the 1980s the first GABAB receptor antagonists, phaclofen, saclofen and 2-hydroxysaclofen, were syn- CGP 47656 85* 62 thesized. These compounds showed high receptor se- lectivity, but their low affinity for GABAB receptors Antagonists (Tab. 1) and weak brain penetration after peripheral CGP 35348 4.92 cf. 129 administration limited their use in pharmacological CGP 36216 43000* 119 studies [84]. The first antagonists able to cross the CGP 36742 (SGS 742) 4.84 cf. 129 blood-brain barrier and remain active after peripheral administration were compounds designated as CGP CGP 46381 4900* 64 35348, CGP 55845A and CGP 36742. However, their CGP 51176 6000* 64 CGP 52432 7.63 cf. 129 very low affinity for GABAB receptors limited their usability (Tab. 1) [63, 64]. Unlike the first-synthe- CGP 54626 8.85 cf. 129 sized antagonists, another series of GABAB receptor CGP 55845 8.53 cf. 129 blockers had a very high affinity for GABAB recep- CGP 56999A 80* cf. 67 tors, but did not cross the blood-brain barrier. Hence, CGP 62349 2* cf. 6 they were used only for in vitro studies. The synthesis CGP 64213 1.17* cf. 67 of SCH 50911 [17], a high-affinity (K = 6.42 nM), i CGP 71978 124* 121 highly-selective and easily brain-penetrable (after oral CGP 71979 1460* 121 treatment in animals) GABAB receptor antagonist was a breakthrough. Manipulations of the chemical CGP 71980 326* 121 structure of this antagonist yielded other derivatives CGP 71982 8* 121 (e.g., CGP 52432, CGP 54626, CGP 56999), which CGP 76290A 1.85* 121 had similar binding characteristics and in vivo activity CGP 76291A 69* 121 as SCH 50911 (Tab.
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