GABAB receptors as a therapeutic strategy in substance use disorders: focus on positive allosteric modulators.

Neuropharmacology xxx (2014) 1e12

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Review

GABAB receptors as a therapeutic strategy in substance use disorders: Focus on positive allosteric modulators Małgorzata Filip a, *, Małgorzata Frankowska a, Anna Sadakierska-Chudy a, Agata Suder a, Łukasz Szumiec a, Paweł Mierzejewski b, Przemyslaw Bienkowski b, ski a, John F. Cryan c, d Edmund Przegalin w, Sme˛ tna 12, Poland Laboratory of Drug Addiction Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, 31-343 Krako Department of Pharmacology, Institute of Psychiatry and Neurology, 02-957 Warsaw, Sobieskiego 9, Poland Alimentary Pharmabiotic Center, University College Cork, Cork, Ireland d Department of Anatomy and Neuroscience, University College Cork, Western Gateway Building, Room 386, Cork, Ireland a

b c

a b s t r a c t Keywords: GABAB receptors Abuse Addiction Discrimination Reward Sensitization Drug-seeking behavior

g-Aminobutyric acid B (GABAB) receptors and their ligands are postulated as potential therapeutic targets for the treatment of several brain disorders, including drug dependence. Over the past fifteen years positive allosteric modulators (PAMs) have emerged that enhance the effects of GABA at GABAB receptors and which may have therapeutic effects similar to those of agonists but with superior side-effect profiles. This review summarizes current preclinical evidence supporting a role of GABAB receptor PAMs in drug addiction in several paradigms with relevance to reward processes and drug abuse liability. Extensive behavioral research in recent years has indicated that PAMs of GABAB receptors may have a therapeutic efficacy in cocaine, nicotine, amphetamine and alcohol dependence. The magnitude of the effects observed are similar to that of the clinically approved drug baclofen, an agonist at GABAB receptors. Moreover, given that anxiolytic effects are also reported with such ligands they may also benefit in mitigating the withdrawal from drugs of abuse. In summary, a wealth of data now supports the benefits of GABAB receptor PAMs and clinical validation is now warranted. This article is part of a Special Issue entitled ‘GABAergic signaling’. © 2014 Published by Elsevier Ltd.

1. Introduction Substance use disorders (SUD) have immense health and societal impact. SUD refer to either alcohol/drug abuse (maladaptive substance use resulting in failure to fulfill major role obligations, physical risk to self or continued use despite persistent problems) or alcohol/drug dependence (substance abuse with additional evidence of tolerance, withdrawal or compulsive substance use) (American Psychiatric Association, 2013). Drugs of abuse activate brain reward circuits including the mesolimbic dopamine system with long-term drug intake leading to dysfunctions of brain regions involved in learning & memory (the amygdala and hippocampus), habit forming learning (the dorsal striatum), salience attribution and inhibitory control (the prefrontal cortex) (Volkow et al., 2003). These functions are controlled by glutamatergic neurotransmission (Tzschentke and Schmidt, 2003; Volkow et al., 2003). The most * Corresponding author. Tel.: þ48 12 6623293. E-mail address: mal.fi[email protected] (M. Filip).

important changes in the glutamategic neurotransmission, including its basal extrasynaptic levels, receptor and transporter expression, are reported during withdrawal from drugs of abuse and during drug-induced relapse (Pomierny-Chamioło et al., 2014). Research during the past decade shows that repeated drug of abuse administration causes a number of alterations in dopamine and glutamate transmission in the striatum, including the nucleus accumbens (Vanderschuren and Kalivas, 2000; Nestler, 2001). Dopamine and glutamate terminals synapse on g-aminobutyric acid (GABAergic spiny cells in the nucleus accumbens (Sesack and Pickel, 1990), and spiny cell axons collateralize to provide GABAergic innervation of near adjacent spiny neurons (Pennartz et al., 1994). There is also evidence for reciprocal presynaptic modulation between GABA, dopamine, and glutamate in the accumbens (Harsing and Zigmond, 1997; Schoffelmeer et al., 2000), posing a role for altered GABA transmission in mediating long-term adaptations to drugs of abuse. There is also a growing awareness for the role of the GABAergic system itself in drug dependence. Indeed several reports from the last decade uncovered changes in

http://dx.doi.org/10.1016/j.neuropharm.2014.06.016 0028-3908/© 2014 Published by Elsevier Ltd.

Please cite this article in press as: Filip, M., et al., GABAB receptors as a therapeutic strategy in substance use disorders: Focus on positive allosteric modulators, Neuropharmacology (2014), http://dx.doi.org/10.1016/j.neuropharm.2014.06.016

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M. Filip et al. / Neuropharmacology xxx (2014) 1e12

extracellular GABA levels in animals following extinction from cocaine self-administration (Tang et al., 2005; Wydra et al., 2013). Significant qualitative differences between active (an increase in) and passive (a reduction in) cocaine exposure in the extracellular accumbal and pallidal GABA baseline levels during a short drug abstinence were observed which generated a hypothesis that motivational mechanisms have a major impact on the cocaine action on the accumbens-ventral pallidal GABA system (Wydra et al., 2013). GABA acts via ionotropic (GABAA and GABAC) and metabotropic (GABAB) receptors. GABAB receptors are potential therapeutic approach for the treatment of pain, anxiety and depression. However, its role as a potential target in SUD has received the most attention. Preclinical research has shown that the GABAB receptor plays a crucial role in mediating the behavioral and molecular effects of drugs of abuse, with activation of the GABAB receptor being identified as a potential anti-addictive therapeutic strategy (Roberts, 2005; Vlachou and Markou, 2010). In rodents, the GABAB receptor agonist baclofen blocks cocaine-induced hyperlocomotion (Kalivas and Stewart, 1991) and cocaine-conditioned hyperlocomotion (Hotsenpiller and Wolf, 2003). Intra-VTA application of baclofen attenuates cocaine self-administration (Brebner et al., 2000). Furthermore, VTA neurons release DA in the NAc and prefrontal cortex (Kalivas, 1993) and baclofen antagonizes nicotine-, cocaine-, and morphine-induced DA release in the NAc (Fadda et al., 2003). Human studies have shown that the GABAB receptor agonist baclofen can reduce cue-associated cocaine craving as well as reduce cocaine use in a double-blind placebo-controlled trial (Vocci and Elkashef, 2005; Young et al., 2014). Activation of GABAB receptors by orthosteric (full) agonists induces side-effects, such as sedation, myorelaxation, hypothermia, tolerance and cognitive disruption. Positive allosteric modulators (PAMs) of the GABAB receptors are devoid of intrinsic agonistic activity and synergistically enhance the effects of GABA at GABAB receptors only in those synapses where and when endogenous GABA is present (see Urwyler, 2011). Because of this more physiological mechanism of action, GABAB PAMs have a better therapeutic index and display less adverse effects than orthosteric agonists. This review summarizes current data from preclinical studies of reward processes and drug abuse liability, which suggest a role of GABAB receptor PAMs in treating drug addiction. 2. GABAB receptors GABAB receptors were cloned in the late 1990s (Kaupmann et al., 1997). In a functional form, they are composed of either a GABAB1a or a GABAB1b subunit isoform, which heterodimerizes with a GABAB2 subunit to form either a GABAB(1a,2) or a GABAB(1b,2) receptor heterodimer (Bettler et al., 2004). The GABAB1a-GABAB2 heterodimers predominantly exist as presynaptic receptors, whereas the GABAB1b-GABAB2 exist as postsynaptic receptors (Bischoff et al., 1999; Kulik et al., 2003). Using a proteomic-based approach, it was recently shown that functional GABAB receptors in the brain form high-molecular-mass complexes of GABAB1, GABAB2 and some potassium channel tetramerization domain-containing (KCTD) proteins (Schwenk et al., 2010). These proteins include 8, 12, 12b and 16 subtypes showing distinct expression profiles in the brain and link to the carboxy terminus of GABAB2. In other words, the KCTD proteins act as auxiliary subunits of GABAB receptors that seem to determine the pharmacology (increase agonist potency) and kinetics (accelerating onset and promoting desensitization) of the receptor response (Schwenk et al., 2010; Turecek et al., 2014). GABAB receptors have been identified in the central nervous system (CNS), peripheral nervous system as well as in several

peripheral organs. In the CNS (see Table 1), the regions with the highest expression of GABAB receptors are the hippocampus, thalamic nuclei, cerebellum, amygdala, neocortex and habenula. Slightly lower densities of these receptors have also been detected in the subcortical areas, the hypothalamus and also in the spinal cord (Table 1). The GABAB1 and GABAB2 subunits are expressed mainly in neurons; however, they are also detectable in glial cells pez-Bendito et al., 2004; Luja n and Shigemoto, 2006). Combined (Lo electron microscopy and high-resolution immunocytochemistry have localized GABAB receptors within the spines and shafts of dendrites corresponding to the location of GABAergic terminals (GABAB receptors function as autoreceptors) and glutamatergic synapses (GABAB receptors function as heteroreceptors) (Kulik et al., 2003, 2006). Peripherally, GABAB receptors occur in the autonomic ganglia, in the spleen, urinary bladder, small intestine, lung, testis, stomach, pancreas, kidney, liver, oviducts, myocardium and skeletal muscles (Ong and Kerr, 1990; Hyland and Cryan, 2010). Gene localization and knock-out phenotype of GABAB receptors are shown in Table 1. GABAB receptors are involved in several physiological and pathophysiological events, such as spasticity, pain, cognitive function, anxiety, mood disorders, epilepsy and drug addiction (Cryan and Slattery, 2010; Filip et al., 2007; Filip and Frankowska, 2007, 2008; Froestl, 2010; Vlachou and Markou, 2010). For example, baclofen, the first selective GABAB receptor agonist, has shown efficacy towards muscle spasms associated with multiple sclerosis and stroke, overactive bladder, gastroesophageal reflux disease, chronic cough, asthma, epilepsy, migraine and pain (Cryan and Kaupmann, 2005; Jacobson and Cryan, 2008; Filip and Frankowska, 2008; Froestl, 2010). It also displays an anxiolytic profile in both clinical and preclinical investigations (Cryan and Kaupmann, 2005; Jacobson and Cryan, 2008). Baclofen in low doses reduced pro-depressive behavior in naïve rats as well as pro-depressive symptoms during cocaine withdrawal in addicted animals (Frankowska et al., 2007, 2010). However, the off-target effects of baclofen (short duration of action, rapid tolerance, narrow therapeutic margin and side effects such as sedation, dizziness, nausea, muscle weakness and mental confusion) greatly limit its clinical use (Bowery, 2006). g-Hydroxybutyric acid (GHB) is thought to be GABAB receptor agonist/ partial agonist. However, studies in knockout mice failed to verify such an interaction (Kaupmann et al., 2003). It may function as an endogenous neuromodulator/neurotransmitter to regulate (increase or decrease) neuronal activity. Unlike full GABAB receptor agonists which affect GIRK channels in both dopamine and GABA neurons of the VTA, GHB activates GIRK channels only in GABAergic neurons (Cruz et al., 2004). It was marketed as an anesthetic, but due to its side effects like seizures and coma was withdrawn. Nowadays, GHB is approved as a blocker of excessive daytime sleepiness/cataplexy (Kothare and Kaleyias, 2010) or illicitly used as a “recreational drug” by sexual predators, body builders and club goers (Kapoor et al., 2013). Apart from GABAB receptor agonists, antagonists as well as PAMs, have been identified (Filip and Frankowska, 2008). Competitive ligands (agonists and antagonists) bind to the GABAB1 subunit within the extracellular N-terminal domain (the orthosteric binding site) (Galvez et al., 2000; Kniazeff et al., 2011). Agonist binding to N-terminal orthosteric domain leads to the activation of G proteins via the cytoplasmic side of the GABAB2 subunit transmembrane domains (Padgett and Slesinger, 2010). The GABAB2 subunit, on the other hand, contains a binding site for PAMs, which is not associated with the N-terminal Venus Flytrap domain of this subunit (see above). The allosteric modulator binding pocket is located within the heptahelical domain of the GABAB2 subunit (Pin zeau, 2007; Urwyler, 2011). and Pre



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Table 1 Characterization of GABAB receptors: the molecular structure, signaling pathways, localization (high; low) and knockout mouse phenotype. GABAB receptors

Refs

GABAB2 GABAB1 GABAB1a GABAB1b (GABAB1c-k) Gen localization 6p21.3 human; 20p12 rat; 17.19.1bcM mice 9q22.1-q22.3 human; 5q22 rat; 4B1 mice Protein structure 960e844 amino acid (rat) 941 amino acid (rat) Main signaling Gi/o inhibition of adenylate cyclase activation and cAMP formation inhibition of voltage-gate pathway N/P/Q- Caþþ channels (presynaptically) inwardly rectifying Kþ channels (postsynaptically) Distribution in the rodent CNS anatomical hippocampus; thalamus nuclei; cerebellum; amygdala; neocortex; habenula; substania nigra; ventral tegmental area; nucleus accumbens; globus pallidus; hypothalamus; spinal cord neuronal autoreceptors (GABAergic terminals) heteroreceptors (Glutamatergic, DAergic soma, axon and terminals) Knock-out phenotype pharmacology absence of agonist and antagonist binding and G protein reduction of agonist and antagonist activation binding, absence of G protein activation physiology disinhibition/absence of LTP, absence of presynaptic absence of presynaptic receptors receptors stereotypical circling, delayed sleep behavioral stereotypical circling, delayed sleep phase, phase, proconvulsant activity, hyperalgesia, proconvulsant activity, hyperalgesia, hyperlocomotion, hyperlocomotion, memory impairment, memory impairment, anxiety inactive on anxiolytics, anxiety, antidepressant-like behavior antidepressant-like behavior

Bettler et al., 2004 Lee et al., 2010

Subunits Isoform

3. GABAB receptor PAMs PAMs of GABAB receptors have little or no agonist activity of their own, but they induce changes in the receptor protein that affect both the potency and efficacy of orthosteric agonists (Pin and zeau, 2007; Froestl, 2010; Urwyler, 2011). Importantly, because Pre GABAB receptor PAMs are less prone to the development of tolerance, they are better alternatives than GABAB receptor orthosteric agonists (see above). Several GABAB receptor PAMs have been synthetized (Table 2). The first synthesized and well-characterized GABAB receptor PAMs were CGP7930 and its analog CGP13501 (Urwyler et al., 2001). In vitro studies indicate that CGP7930 enhances GABAB receptor-stimulated [35S]GTPgS binding in cultured cells and rat brain membranes by increasing the potency and efficacy of GABA (Urwyler et al., 2001; see Adams and Lawrence, 2007; Froestl, 2010). In membrane fractions of HEK293 cells, the EC50 for GABA was increased 3-fold by 0.1 nM CGP7930 and 10-fold by 1.0 nM CGP7930, while the compound alone produced no significant effect on basal [35S]GTPgS binding (Binet et al., 2004). In rat prefrontal cortex and cerebellum membrane fractions, 100 mM CGP7930 enhanced baclofen (30 mM)-induced [35S]GTPgS binding by 241% and 1530%, respectively, relative to baseline (Onali et al., 2003; Hensler et al., 2012). In human frontal cortex membrane preparations post mortem, CGP7930 (100 mM) enhanced the potency of GABA in stimulating [35S]GTPgS binding by four-fold and increased the maximal response by 82.5% and

http://www.ncbi.nlm.gov/gene Sakaba and Neher, 2003

Bowery et al., 1987; Bischoff et al., 1999 Kulik et al., 2003, 2006; Ulrich et al., 2007 Schuler et al., 2001; Gassmann et al., 2004; Mombereau et al., 2004, 2005; Jacobson et al., 2006, 2007; Shaban et al., 2006; Vigot et al., 2006; Magnaghi et al., 2008; Vienne et al., 2010;

inhibited forskolin-stimulated adenylyl cyclase activation (Olianas et al., 2005). The compound GS39783 more potently increased the potency and efficacy of GABA in [35S]GTPgS binding assays than did CGP7930. The EC50 of GABA in the presence of 30 mM GS39783 was decreased approximately 8-fold from 3.59 mM to 0.45 mM, and the maximal basal activity increased from 100% to 217% (Urwyler et al., 2003, 2005). In 2007, NVP-BHF177, a less toxic analog of GS39783 was shown to bind to the sixth transmembrane domain of the GABAB2 subunit receptor (Guery et al., 2007). Another GABAB receptor PAM developed by Roche was racBHFF. This PAM increased the potency and efficacy with which GABA stimulated [35S]GTPgS binding to membrane preparations from cells and with which baclofen induced electrophysiological responses from hippocampal slices (Malherbe et al., 2008; Hensler et al., 2012). At 0.3 mM, rac-BHFF enhanced the EC50 of GABA in recombinant cells more then 15-fold (Malherbe et al., 2008). The novel GABAB receptor PAM CMPPE potentiates GABAstimulated [35S]GTPgS binding to membranes prepared from a human recombinant cell line and from rat brain cortex (Perdona et al., 2011). Recently, the Corelli group identified two novel thiophene derivatives, COR627 and COR628, which act as GABAB receptor PAMs in rat cortical membranes. Both compounds potentiated GABA- and baclofen-induced [35S]GTPgS binding to naïve GABAB receptors, without eliciting any agonist activity when given alone. A 30-mM concentration of COR627 or COR628 increased the potency of GABA 4-fold: the EC50 of GABA in the

Table 2 GABAB receptor PAMs. Positive allosteric modulator

Chemical name

References

CGP7930 CGP13501 GS39783 NVP-BHF177 rac-BHFF CMPPE COR627 COR628 ADX71441 ADX71943

2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl)-phenol 3,5-bis(1,1-dimethylethyl)-4-hydroxy-a,a-dimethylbenzenepropanal N,N'-dicyclopentyl-2-(methylthio)-5-nitro-4,6-pyrimidinediamine N-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-2-methyl-5-[4-(trifluoromethyl)phenyl]-4-pyrimidinamine (R,S)-5,7-bis(1,1-dimethylethyl)-3-hydroxy-3(trifluoromethyl)-2(3H)-benzofuranone 2-{1-[2-(4-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]-2-piperidinyl}ethanol methyl 2-(1-adamantanecarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate methyl 2-(cyclohexanecarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate Not disclosed N-(5-(4-(4-cyano-3-methoxybenzyl)-6-methoxy-3,5-dioxy-4,5-dihydro-1,2,4-triain-2(3H)-yl)-2-fluorophenyl)acetamide

Urwyler et al., 2001 Urwyler et al., 2001 Urwyler et al., 2003 Guery et al., 2007 Malherbe et al., 2008 Perdona et al., 2011 Castelli et al., 2012 Castelli et al., 2012 Ayad et al., 2013 Kalinichev et al., 2014


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absence of COR627 or COR628 was 4.87 mM, while in the presence of the PAMs the EC50 of GABA was 1.13 mM and 1.28 mM, respectively. In the last 5 years, Addex Pharmaceuticals announced new, orally available GABAB receptor PAMs, called ADX71441 and ADX71943; the first drug received approval for phase I clinical studies (Addex Therapeutics Webpage). ADX71943 enhanced an EC20 of the endogenous orthosteric agonist GABA with an efficacy of 181% and an EC50 of 96 nM, but when tested alone it did not show any activity in a HEK293 stable cell line co-expressing the human GABAB1a-GABAB2 heterodimer (Kalinichev et al., submitted for publication). Furthermore, only in the presence of an EC50 of baclofen, ADX71943 enhanced (>260%) the binding of [35S]GTPgS on GABAB receptor with the EC50 values of 28 nM and 116 nM on rat and human cortical membranes, respectively (Kalinichev et al., submitted for publication). Of note, in contrast to other GABAB receptor PAMs, ADX71943 displays a peripheral activity profile only (Kalinichev et al., submitted for publication). GABAB receptor PAMs show several in vivo functional effects in preclinical research. A variety of studies showed that almost all GABAB PAMs (i.e., CGP7930, BHF177, COR627, COR628, rac-BHFF) potentiated the sedative/hypnotic effect and loss of righting induced by baclofen or in rodents (Carai et al., 2004; Malherbe et al., 2008; Koek et al., 2010; Castelli et al., 2012; Mugnaini et al., 2013), while CGP7930, BHF177, COR627, COR628, GS39783, rac-BHFF or CMPPE did not change locomotor activity or have an effect on the loss of righting reflex (Carai et al., 2004; Frankowska et al., 2007; Koek et al., 2010; Perdona et al., 2011; Cryan et al., 2004). ADX71943 had no effect on locomotor activity in a novel environment and did not reduce rotarod activity in mice and rats, however, lack of its activity reflects its inability to penetrate the CNS (Kalinichev et al., submitted for publication). In a drug discrimination test, CGP7930 produced a weak (41%) baclofen-appropriate responding and enhanced the discriminative stimulus effects of baclofen, but not of in pigeons (Koek et al., 2012). Partial substitution (49e74%) for training drugs was seen for another GABAB PAM, rac-BHFF, in g-hydroxybutyrate- and baclofen-discrimination in pigeons, while in combination studies rac-BHFF enhanced the discriminative stimulus effects of baclofen but not of g-hydroxybutyrate (Koek et al., 2012). rac-BHFF by itself induced discriminative stimulus effects in pigeons which were not mimicked by baclofen, g-hydroxybutyrate or diazepam, suggesting difference in its subjective properties (Koek et al., 2013). Some GABAB PAMs showed an anxiolytic-like profile in rodent test/models. Thus, CGP7930 and GS39783 were active in the elevated zero maze (Frankowska et al., 2007) or plus maze (Cryan et al., 2004; Mombereau et al., 2004) in rats. In the mouse model of stress-induced hyperthermia rac-BHFF exhibited anxiolytic-like activity (Malherbe et al., 2008). ADX71441 showed anxiolytic-like effects in the mouse marble burying and elevated plus maze tests (Kalinichev et al. unpublished), while another ADDEX drug, the peripherally-acting ADX71943 was as expected inactive in the mouse elevated plus maze (Kalinichev et al., submitted for publication). In contrast to above centrally-acting PAMs, BHF177 had no effect in the elevated plus maze, light/dark box, or Vogel conflict test in mice suggesting that it has no anxiolytic-like profile (Li et al., 2013). Regarding the effects of GABAB receptor PAMs on conditioned fear responses BHF177 did not display activity on fear memory retrieval in contextual and cued fear conditioning or spatial learning and memory in the Barnes maze in mice what indicates its minimal impairment of learning and memory in mice (Li et al., 2013). Similarly, recent data has shown that GS39783 failed to affect the acquisition, expression or extinction of fear memories (Sweeney et al., 2013).

There are still not unequivocal literature data reflecting GABAB PAMs effects in animal models predictive of antidepressant activity. Thus, CGP7930 significantly decreased immobility time in a modified forced swimming test in rats (Frankowska et al., 2007), while GS39783 did not possess antidepressantlike properties in this test (Cryan et al., 2004; Mombereau et al., 2004). Indeed GABAB receptor antagonists have been shown to have antidepressant-like potential and enhance adult hippocampal neurogenesis (Slattery et al., 2005; Felice et al., 2012). There has been limited but interesting data of GABAB receptor PAMs in other neuroscience indications. GS39783 exhibited antipsychotic-like effects on MK-801- and amphetamine-induced ska et al., 2011) whereas GS39783 hyperactivity in mice (Wieron and CMPPE significantly decreased food intake in rodents (Perdona et al., 2011) which means that only little activity of GABAB receptors by their PAMs is necessary to control food consumption. The newly discovered ADDEX drugs have been characterized in rodent models of pain (Kalinichev et al., 2013, Kalinichev et al., submitted for publication). Being a balanced central-peripheral GABAB receptor PAM, ADX 71441 reduced visceral pain in the acetic acid writhing test and chronic osteoarthritic-like pain in the monosodium iodoacetate-induced model (M. Kalinichev, unpublished observations). The peripherally-acting ADX71943 showed efficacy in an osteoarthritis pain model where it increased pain sensitivity (mechanical hyperalgesia) and pain produced by a normally innocuous stimulus (allodynia). Very recent study confirmed the antinociceptive efficacy of ADX71943 in the mouse visceral pain as well as in acute pain and in mediated primarily by inflammation of the peripheral tissue persistent pain in rodents (Kalinichev et al., submitted for publication). From 2010, Addex began testing ADX71943 in clinical trials for the treatment of osteoarthritic pain and chronic nociceptive pain (Ayad et al., 2013). ADX71441 was also active against the signs of bladder overactivity in two rodent models, such as bladder overactivity in conscious mice undergoing water overload, and overactivity induced by intravesicle administration of diluted acetic acid in anaesthetized guinea pigs (Kalinichev et al., 2014a,b). 4. GABAB receptor PAMs in drug addiction Several literature reports support the activity of PAMs at modulating the GABAB receptor-mediated behavioral effects induced by various drugs of abuse. 4.1. GABAB receptor PAMs and drug-evoked hyperlocomotion Locomotor hyperactivity depends on stimulation of the mesoaccumbens DAergic pathway from the VTA to the NAC (so-called “reward” pathway) (e.g., Filip and Siwanowicz, 2001; Hedou et al., 1999; Heidbreder et al., 1999), and it is proposed to serve as an index of the stimulatory and euphorigenic-like effects of drugs of abuse (Wise and Bozarth, 1987; Phillips and Shen, 1996). Drugs of abuse belonging to different classes (alcohol and psychostimulants, including nicotine) increase locomotor activity in mice, and this effect appears to be under the regulation of GABAB receptors. In fact, several GABAB receptor PAMs of these receptors potently suppressed the hyperactivity induced by alcohol, cocaine or nicotine in mice (Table 3). In this respect, GS39783 and CGP7930 mimic orthosteric agonists such as baclofen at GABAB receptors (for review see Filip and Frankowska, 2007), and their effects in this regard may suggest antiaddictive therapeutic potential.



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Table 3 GABAB receptor PAMs and drugs of abuse-evoked hyperlocomotion. Drug of abuse (dose; route of administration)

Species (sex)

PAM (dose-range, route of administration)

Change

References

Alcohol (2 g/kg, ip)

Mice DBA/2J (male) Mice Albino Swiss (male) Mice C57/BL/6J (male) Mice CD1 (male) Mice CD1 (male)

GS39783 (1, 3, 10, 30 ip)

Y

Kruse et al., 2012

GS39783 (5, 10, 30 mg/kg, ip) GS39783 (10, 30, 100 mg/kg, po)

Y Y

ska et al., 2011 Wieron Lhuillier et al., 2007

GS39783 (25, 50 mg/kg, ig) CGP7930 (25, 50 mg/kg, ig)

Y Y

Lobina et al., 2011 Lobina et al., 2011

Amphetamine (3 mg/kg, ip) Cocaine (10 mg/kg, ip) Nicotine (0.05 mg/kg, sc) Nicotine (0.05 mg/kg, sc) Y e reduction. Effective doses are marked in bold.

4.2. GABAB receptor PAMs and drug-evoked sensitization Repeated, intermittent administration of drugs of abuse induces a robust enhancement in locomotor stimulation that may exist for a long time. This phenomenon, known as locomotor sensitization, has been proposed to predict the addictive property of a drug combined with forms of neuronal adaptations linked to an enhancement of the reinforcing and motivational aspects of drugs of abuse (Robinson and Berridge, 1993; Steketee and Kalivas, 2011). Two separate temporal domains of drug-induced sensitization within neuronal networks have been identified; the induction of sensitization refers to transient neuroadaptive changes that appear during acquisition of sensitization, while the expression of sensitization is linked to long-term neuroadaptations resulting from repeated drug exposure (Robinson and Berridge, 1993; Steketee and Kalivas, 2011). Limited literature reports show that systemic administration of GS39783 to mice does not alter the expression of locomotor sensitization induced by chronic alcohol or cocaine (Table 4). In other words, pharmacological stimulation of rodent brain GABAB receptors by PAMs does not protect against the neuroplasticity evoked by repeated administration of drugs of abuse. In the development phase of sensitization, equivocal results indicate that

the systemic administration of GS39783 either enhances alcoholinduced locomotor sensitization (Kruse et al., 2012) or attenuates the enhanced locomotor effects of cocaine in mice treated repeatedly with the drug (Lhuillier et al., 2007). It should be stressed that potentiation of alcohol sensitization in mice was observed when both GS39783 and alcohol were available. The procedure used by Kruse et al. (2012) differs from typical sensitization protocols used to evaluate the expression phase, where only a challenge dose of a drug of abuse is examined. If the potentiation of alcohol sensitization requires sufficient GABAB receptor stimulation and whether PAMs at GABAB receptors have therapeutic utility in the treatment of addiction (in terms of neuroadaptation safety), it is an open question requiring further study. Further study is also needed to explore these issues in the context of drug and alcohol abuse. 4.3. GABAB receptor PAMs and drug discrimination A separate report reveals no evidence of a PAM-GABAB receptormediated mitigation of the subjective effects of cocaine in rats (Table 5), as CGP7930 did not mimic cocaineediscriminative effects in substitution studies, and in combination with cocaine, it did not produce a shift in the cocaine doseeresponse curve (Filip et al., 2007). Another recent report confirmed a separation between the

Table 4 GABAB receptor PAMs and drugs of abuse-evoked sensitization. Drug of abuse (dose; route of administration) Development Alcohol (2 g/kg, ip for 12 days) Cocaine (20 mg/kg, ip for 14 days)

Expression Alcohol (2 g/kg, ip for 12 days) Cocaine (20 mg/kg, ip for 14 days)

Species (sex)


Change

References

Mice DBA/2J (male) Mice C57/BL/6J (male)

GS39783 (30 mg/kg, ip)

[

Kruse et al., 2012

GS39783 (30 mg/kg, po)

Y

Lhuillier et al., 2007

GS39783 (30 mg/kg, ip)

∅

Kruse et al., 2012

GS39783 (30 mg/kg, po)

∅

Lhuillier et al., 2007

Mice DBA/2J (male) Mice C57/BL/6J (male)

Y e reduction, [ e enhancement, ∅ e no effect. Effective doses are marked in bold.

Table 5 GABAB receptor PAMs and the discriminative stimulus properties of drugs of abuse . Training drug of abuse (dose; route of administration) Substitution studies Cocaine (10 mg/kg, ip) Combination studies Cocaine (10 mg/kg, ip)

Species (sex)


Change

References

Rats Wistar (male)

CGP7930 (30, 100 mg/kg, ip)

∅

Filip et al., 2007

Rats Wistar (male)

CGP7930 (30, 100 mg/kg, ip)

∅

Filip et al., 2007

∅ e no effect.


6


Table 6 GABAB receptor PAMs and drugs of abuse-evoked reward in self-administration and conditioned place preference procedures. Drug of abuse (training dose; route of administration; schedule of reinforcement) Self-administration Alcohol (10% v/v, two bottle choice) for 5 days Alcohol (10% v/v, two bottle choice) for 5 days Alcohol (10% v/v, two bottle choice) for 4 weeks Alcohol (10% v/v, two bottle choice) for 4 weeks Alcohol 10% v/v oral SA for 4 weeks FR3 Alcohol 10% v/v oral SA for 4 weeks FR3 Alcohol 15% v/v oral SA FR4 Alcohol 15% v/v oral SA for 20 days PR Alcohol 15% v/v oral SA for 20 days FR4 Alcohol 15% v/v oral SA for 20 days PR Alcohol 15% v/v oral SA for 20 days, FR4 Alcohol 15% v/v oral SA for 25 days RR 55 Alcohol 15%v/v oral SA for 20e30 days FR4 Alcohol 15%v/v oral SA for 20e30 days FR4 Alcohol 15%v/v oral SA for 20e30 days FR4 Alcohol 15%v/v oral SA for 20e30 days PR Alcohol 15% v/v oral SA for 20e30 days PR Alcohol 15% v/v oral SA for 20e30 days PR Alcoholic beer 9% v/v oral SA for 20 days FR3 Alcohol (10% v/v oral for 4 weeks) Two-bottle choice Alcohol 20% v/v oral DID for 5 days Alcohol 20% v/v two-bottle choice DID for 4 days Alcohol 20% v/v two-bottle choice IA for 4 weeks Cocaine (1.5 mg/kg/infusion iv) SA FR1 Cocaine (1.5 mg/kg/infusion iv) SA FR1 Cocaine (1.5 mg/kg/infusion iv) SA PR

Species (sex)


Change

References

Rats Sardinian alcohol-preferring (male) Rats Sardinian alcohol-preferring (male) Rats Sardinian alcohol-preferring (male) Rats Sardinian alcohol-preferring (male) Male rats Indiana alcohol-preferring (male)

GS39783 (6.25, 12.5, 25 mg/kg, ig), repeated 5 daily treatment

Y

Orrù et al., 2005

CGP7930 (25, 50, 100 mg/kg, ig), repeated 5-day treatment

Y

Orrù et al., 2005

GS39783 (50, 100 mg/kg, ig), repeated 5 daily treatment

Y

Orrù et al., 2005

CGP7930 (50, 100 mg/kg, ig), repeated 5 daily treatment

Y

Orrù et al., 2005

CGP7930 (10, 20 mg/kg, ip)

Y

Liang et al., 2006

Male rats Indiana alcohol-preferring (male)

CGP7930 (10 mg/kg, ip) þ baclofen (2 mg/kg, ip)

Y

Liang et al., 2006

Rats Sardinian alcohol-preferring (male) Rats Sardinian alcohol-preferring (male) Rats Sardinian alcohol-preferring (male) Rats Sardinian alcohol-preferring (male) Rats Sardinian alcohol-preferring (male) Rats Sardinian alcohol-preferring (male) Rats Sardinian alcohol-preferring (male) rats Indiana alcohol-preferring (male)

GS39783 (25, 50, 100 mg/kg, ig)

Y

Maccioni et al., 2007

GS39783 (25, 50, 100 mg/kg, ig)

Y


BHF177 (12.5, 25, 50 mg/kg, ig)

Y


BHF177 (12.5, 25, 50 mg/kg, ig)

Y


rac-BHFF (50, 100, 200 mg/kg, ig)

Y

Maccioni et al., 2010a

GS39783 (25, 50, 100 mg/kg ig)

Y

Maccioni et al., 2010b

GS39783 (25,50, 100 mg/kg, ig)

Y


GS39783 (25, 50, 100 mg/kg, ig)

Y


GS39783 (25, 50, 100 mg/kg, ig)

Y


GS39783 (25, 50, 100 mg/kg, ig)

Y


GS39783 (25, 50, 100 mg/kg, ig)

Y


Rats Alco Alcohol (male)

GS39783 (25, 50, 100 mg/kg, ig)

∅


Male mice C57Bl/6J

BHF-177 (3.75, 7.5, 15, 30 mg/kg ip)

Y

Orrù et al., 2012

Rats Sardinian alcohol-prefering (male)

rac-BHFF (50, 100, 200 mg/kg, ig) for 7 days

Y

Loi et al., 2013

Male mice C57BL/6J

GS39783 (30 mg/kg, ip)

Y

Male mice C57BL/6J

ADX71441 (3, 10, 30 mg/kg, po)

Y

Linsenbardt and Boehm II, 2013 Hwa et al., 2014

Male mice C57BL/6J

ADX71441 (3, 10, 17 mg/kg, po)

Y

Hwa et al., 2014

Rats Sprague Dawley (male)

GS39783 (10 mg/kg, ip)

(Y)

Smith et al., 2004


CGP7930 (10 mg/kg, ip)

(Y)

Smith et al., 2004


GS39783 (3, 10, 30 mg/kg, ip)

Y

Smith et al., 2004

Rats Alco Alcohol (male) Rats Sardinian alcohol-preferring (male) Rats Indiana alcohol-preferring (male)



7

Table 6 (continued ) Drug of abuse (training dose; route of administration; schedule of reinforcement)

Species (sex)


Change

References

Cocaine (1.5 mg/kg/infusion iv) SA PR Cocaine (1.5 mg/kg/infusion iv) SA DT3 Cocaine (1.5 mg/kg/infusion iv) SA DT3 Cocaine (0.5 mg/kg/infusion iv) SA for 14 day FR5 Nicotine (0.3 mg/kg, iv) SA FR5 Nicotine (0.3 mg/kg, iv) SA FR5 Nicotine (0.3 mg/kg, iv) SA FR5 Nicotine (0.3 mg/kg, iv) SA FR5 Nicotine (0.3 mg/kg, iv) SA FR5 Nicotine (0.3 mg/kg, iv) SA PR Nicotine (0.03 mg/kg/infusion iv) SA for 21 days FR5 Conditioned place preference Nicotine (0.06 mg/kg, sc) for 4 days Nicotine (0.06 mg/kg, sc) for 4 days


CGP7930 (3, 10, 30 mg/kg, ip)

Y

Smith et al., 2004


GS39783 (3, 10, 30 mg/kg, ip)

Y

Smith et al., 2004


CGP7930 (30 mg/kg, ip)

Y

Smith et al., 2004

Rats Wistar (male)

CGP 7930 (10, 30, 100 mg/kg, ip)

Y

Filip et al., 2007

Rats Wistar (male)

CGP7930 (5, 10, 30 mg/kg, ip)

Y

Paterson et al., 2008

Rats Wistar (male)

BHF177 (10, 20, 40 mg/kg, po)

Y


Rats Wistar (male)

GS39783 (10, 20, 40 mg/kg, po)

Y


Rats Wistar (male)

GS39783 (10, 20, 40 mg/kg, po) þ CGP44532 (0.125 mg/kg, sc) GS39783 (10, 20, 40 mg/kg, po) þ CGP44532 (0.25 mg/kg, sc) BHF177 (10, 20, 40 mg/kg, po)

Y


Y


Y


Rats Wistar (male) Rats Wistar (male) Rats Wistar (male)

BHF177 (20 mg/kg, po) for 14 days

Y

Vlachou et al., 2011a

Rats Wistar (male) Rats Wistar (male)

GS39783 (30, 100 mg/kg, po) GS39783 (30, 100 mg/kg, po)

Ya ∅b

Mombereau et al., 2007 Mombereau et al., 2007

[ e enhancement, Y e reduction, (Y) e reduction of drug lower doses, ∅ e no effect, a e development, b e expression; DID e drinking in the dark, DT e discrete trials, FR e fixed ratio, IA e intermittent access, PR e progressive ratio, RR 55 e reinforcement requirement 55. Effective doses are marked in bold.

subjective effects of GABAB receptor PAMs or drugs of abuse, as alcohol, cocaine, or nicotine did not evoke a discriminative stimulus similar to that of rac-BHFF in pigeons (Koek et al., 2013). 4.4. GABAB receptor PAMs and drug reward Consistent data show that alterations in GABAB receptor signaling regulate brain reward pathways (for review see: Filip and Frankowska, 2008). The first study with using a variety of procedures having relevance to reward processes and cocaine abuse liability showed that GABAB receptor PAMs, including CGP7930 and GS39783, decreased cocaine-maintaining responses under progressive-ratio, fixed-ratio and discrete-trial schedules of reinforcement (Table 6; Smith et al., 2004). These behavioral procedures indicate that the enhancement of GABAB receptor signaling acts to decrease the strength of drug motivational properties (progressive-ratio), drug intake and its reinforcing properties (fixed-ratio) and a circadian-dependent pattern of responding (discrete-trial). Moreover, findings from Smith et al. (2004), later confirmed by Filip et al. (2007), in cocaine self-administration procedures allowed for a conclusion regarding the potential utility of GABAB receptor PAMs for cocaine dependence. Numerous studies have reported GABAB receptor PAM-induced suppression of alcohol drinking, relapse-like drinking, and alcohol reinforcing, rewarding, stimulating, and motivational properties in rats and mice. As documented by Colombo and co-workers, acute administration of PAMs (CGP7930, GS39783, and BHF177) reduced alcohol drinking in rats under an “alcohol vs. water” choice regimen and alcohol reinforcement and motivation in oral selfadministration operant procedures (Table 6). These inhibitory actions of GABAB receptor PAMs were observed at doses devoid of any behavioral toxicity (motor incoordination, sedative effects; Liang

et al., 2006; Maccioni et al., 2007, 2008, 2009, 2010a), decreased daily food intake (Maccioni et al., 2008, 2009, 2010a; Loi et al., 2013). Of note, rac-BHFF was also found to suppress blood alcohol levels in rats; however, the mechanism is presently unknown (Maccioni et al., 2010a). The importance for the above-cited papers is that most of these studies were performed on rats selectively bred for alcohol preference (Table 6) that, despite having the same phenotype (high alcohol preference vs. water preference), the rats had distinct genetic backgrounds and natures of alcohol preference. In other words, the inhibitory actions of GABAB receptor PAMs in alcohol-preferring rats may underscore the potential usefulness of these drugs across many alcohol typologies. A recent paper by Linsenbardt and Boehm II (2013) described a detailed analysis of the inhibitory effects of the GABAB PAM GS39783 in mice exposed to daily binge alcohol consumption. This drug entirely abolished alcohol intake during the initial (15 min) period of the study, which may implicate its effects on eliminating alcohol “front-loading” and overall intake during the whole session. Interestingly, repeated treatment with CGP7930, GS39783 or rac-BHFF resulted in a reduced daily alcohol intake (Orrù et al., 2005; Loi et al., 2013), with the most efficacious action observed for rac-BHFF (up to a 7-day treatment period), suggesting no tolerance to the inhibitory effects. Most recent report by Hwa et al. (2014) showed that ADX 71441 markedly and specifically reduce alcohol consumption in mouse models of “binge”-like drinking-in-the-dark and in a model of long-term, excessive drinking, intermittent access to ethanol. Such finding on C57BL/6J mice, being an inbred strain with a high ethanol preference, extends previous observations on GABAB receptor PAMs to decrease voluntary ethanol intake without altering water intake and suggests GABAB receptor PAMs for treatment of alcoholism. Preclinical evidence also suggests that PAMs of GABAB receptors display a high capacity to suppress the reinforcing, reward-


8


Table 7 GABAB receptor PAMs and changes in drugs of abuse-evoked reward in ICSS procedures. ICSS behavior (area with electrode implantation)

Drug of abuse (training dose; route of administration)

Species (sex)


Change

References

LH LH LH

Cocaine (10 mg/kg, ip) Nicotine (0.4 mg/kg, sc) Nicotine 3.16 mg/kg/day, sc (micropumps) for 7 days

Rats SpragueeDawley (male) Rats Wistar (male) Rats Wistar (male)

GS39783 (10, 30, 100 mg/kg, po) BHF177 (3.75, 5, 7.5, 15, 30 mg/kg, ip) BHF177 (7.5, 15 mg/kg, ip)

Y Y [

Slattery et al., 2005 Paterson et al., 2008 Vlachou et al., 2011a

[ e enhancement, Y e reduction. LH e lateral hypothalamus. Effective doses are marked in bold.

enhancing and motivational properties of nicotine (Tables 7 and 8). GS39783 (30e100 mg/kg p.o.) during the conditioning phase blocked the rewarding effects of nicotine in the CPP paradigm in rats. However, GS39783 did not significantly alter the CPP effects of nicotine when given only immediately before the CPP test. These effects correlated directly with long-term molecular changes in brain plasticity, most notably an accumulation of DeltaFosB in the nucleus accumbens. Paterson et al. (2008) reported a similar mechanism of action of GS39783 and the GABAB receptor orthosteric agonist CGP44532, when given in combination, they showed additive effects in rats trained to self-administered nicotine. Another finding from the same group (Vlachou et al., 2011a) indicates that repeated administration of BHF177 for 14 days decreased nicotine (but not food) self-administration, with practically no tolerance development, while the termination of repeated GABAB receptor PAM treatment returned nicotine self-administration to control levels. It should be mentioned that findings have shown that the GABAB receptor PAM BHF177 exacerbated nicotine withdrawal-induced anhedonia assessed in the rat self-stimulation model. Thus, a lack of antidepressant-like effects in the nicotine withdrawal/ICSS model of anhedonia limits the use of BHF177 for that application, and further studies are warranted (Vlachou et al., 2011b). 4.5. GABAB receptor PAMs and drug-seeking behavior Unequivocal results indicate the inhibitory effects of GABAB receptor PAMs on seeking behavior induced in rats during a drug-free period (Table 8). Thus, CGP7930 reduced the cocaine-primed or cue-induced reinstatement of cocaine seeking (Filip and Frankowska, 2007), while BHF177 reduced cue-induced nicotine seeking (Vlachou et al., 2011a). Neither GABAB receptor PAM affected reinstatement of food seeking (Filip and Frankowska, 2007; Vlachou et al., 2011a), suggesting that they do not influence animal motor performance and thus more specifically reduce seeking behavior. Specific effects were also reported for GS39783 injected into the ventral tegmental area, which resulted in suppressed alcohol-seeking behavior in Long-Evans rats (Leite-Morris et al., 2008).

4.6. Neurochemical mechanisms of GABAB receptor PAMs in drug addiction GABAB receptors are widely distributed in several areas of the brain that are part of the reward circuitry, where they negatively modulate reward, reinforcement, and reinstatement of drug seeking (Laviolette and van der Kooy, 2003; Sagara et al., 2008; Xi et al., 2009; Yang et al., 2009). The mechanism through which GABAB receptor PAMs act to inhibit behavioral responses to drugs of abuse seems to be dependent on their inhibitory involvement in the regulation of the mesoaccumbal dopamine system, which plays an important role in the reinforcing and seeking properties of all addictive substances (Fig. 1; Filip et al., 2012). In fact, the mesoaccumbal dopamine system possesses both the transcript and protein for GABAB receptors, and GABAB receptors act as heteroreceptors on dopaminergic and glutamatergic neurons in the ventral tegmental area (Bowery et al., 1987; Liang et al., 2000; Wirtshafter and Sheppard, 2001). A tonic modulation of the excitability of tegmental dopamine neurons has been identified, and GABAB antagonism enhances drug of abuse-induced increase of firing frequency (Erhardt et al., 2002), while activation of tegmental GABAB receptors results in a decreased dopamine release in the nucleus accumbens and prefrontal cortex. In the ventral tegmental area, a PAM enhances the GABAB receptor-mediated inhibition of dopaminergic neuron firing activity (Chen et al., 2005), while intraventral tegmental area or intra-nucleus accumbens administration of baclofen, with a stronger effect observed in the ventral tegmental area (Brebner et al., 2000; Shoaib et al., 1998), attenuated cocaine self-administration. Moreover, microinjections of baclofen into the ventral tegmental area resulted in a dose-dependent suppression of alcohol-seeking behavior in rats (Leite-Morris and Czachowski, 2006). Neurochemical studies indicate that endogenously released GABA inhibits dopaminergic and glutamatergic neuronal activity in other brain areas enriched in GABAB receptors (Fig. 1). For example, in animals treated repeatedly with cocaine, intra-prefrontal cortex baclofen injection increased glutamate levels in the nucleus accumbens and the ventral tegmental area (Jayaram and Steketee,

Table 8 GABAB receptor PAMs and reinstatement of drug-seeking behavior. Drug of abuse (training dose; route of administration; schedule of reinforcement) Drug-induced Cocaine (0.5 mg/kg/infusion for 14 days), FR5 Cue-induced Alcohol 10% v/v oral SA RR20 Cocaine (0.5 mg/kg/infusion for 14 days), FR5 Nicotine (0.03 mgkg/infusion, for 14 days), FR5

Reinstatement

Species (sex)


Change

References

Cocaine (10 mg/kg, ip)

Rats Wistar (male)

CGP7930 (10, 30 mg/kg, ip)

Y

Filip and Frankowska, 2007

experimental chamber tone þ light light

Male rats Long-Evans

GS39783 (5, 10, 20 mg/side VTA)

Y

Leite-Morris et al., 2008

Rats Wistar (male) Rats Wistar (male)

CGP7930 (10, 30 mg/kg, ip) BHF177 (2.5, 5, 10, 20, 40 mg/kg, po)

Y Y

Filip and Frankowska, 2007 Vlachou et al., 2011a

Y e reduction. FR e fixed ratio. VTA e ventral tegmental area. Effective doses are marked in bold.



9

In molecular analyses, chronic GABAB-positive modulation counteracted long-lasting DeltaFosB (a marker of cell activation to drugs of abuse) accumulation in the mesolimbic system in response to chronic nicotine (Mombereau et al., 2007) or chronic cocaine (Lhuillier et al., 2007), and it reduced the expression of cAMPresponse element-binding-protein (CREB) and dopamine-andcAMP-regulated-phosphoprotein of 32 kD (DARPP-32) in the nucleus accumbens of rats exposed to cocaine (Lhuillier et al., 2007). These findings seem to indicate the specificity of GABAB receptors in the molecular events generated by long-term drug exposure. There remain many open questions related to the neurochemical mechanism of GABAB receptor PAM activity, and additional studies are required to localize interactions between these ligands and drugs of abuse at the neuronal, neurochemical and molecular levels. 5. Conclusions

Fig. 1. Hypothetical output pathways whereby the GABAB receptors stimulation may inhibit mezolimbic dopamine pathways (green lines) to attenuate drugs of abuserelated reward processes. Only major projections are shown. Blue lines indicate inhibitory GABA-ergic pathways, whereas red lines indicates excitatory glutamate (Glu)-ergic connections. GABAB receptors are marked as blue symbols. Please refer ‘Neurochemical mechanisms’ in Section 4 for detailed explanation. STR, striatum; PFC, prefrontal cortex; VTA, ventral tegmental area. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

2004). The neuronal distribution of GABAB receptors in the prefrontal cortex linked to drug of abuse-induced behaviors is unknown, and further studies are required to identify whether receptors located on the presynaptic terminals of glutamatergic nerve endings and/or on the cell bodies (Margeta-Mitrovic et al., 1999) or on GABA neurons (Calver et al., 2002) control drug seeking (for review see: Kalivas and McFarland, 2003; Rebec and Sun, 2005; Schmidt et al., 2005; See, 2005). It should be noted that in the hippocampal CA1 area, a PAM selectively enhances the baclofen-induced modulation of synaptic inhibition resulting from the activation of presynaptic autoreceptors located on the inhibitory GABA terminals, without inducing significant effects on the presynaptic heteroreceptors on excitatory glutamatergic terminals (Chen et al., 2006). Because the ventral CA subfields of the hippocampus play an important role in the relapse to cue-induced and cocaine-primed reinstatement (Rogers and See, 2007), it is tempting to speculate that the inhibitory effects of CGP 7930 toward cocaine-seeking behavior may be linked to the activation of GABAB presynaptic autoreceptors in this brain region.

Extensive behavioral research in recent years indicates that PAMs of GABAB receptors may have a therapeutic index and mimic the clinically approved drug baclofen to suppress the intake, reward and motivation and seeking behavior associated with drugs of abuse (Tyacke et al., 2010). GABAB receptor PAMs may also show efficacy to control depression and anxiety responses, but whether these drugs regulate the anxiety, depression and other impulsiveness and/or aggression that often occur in addiction or specifically control reward, motivation or seeking, remains an open question. GABAB receptor PAMs seem to have a better pharmacological profile than orthosteric agonists at GABAB receptor sites as they, at doses that block the addictive properties of drugs, do not evoke hypothermia, sedation, myorelaxation, amnesia or tolerance after repeated treatment (Cryan and Kaupmann, 2005; Filip et al., 2007; Gjoni and Urwyler, 2009; Koek et al., 2010; Lehmann et al., 2003; Maccioni et al., 2007, 2008, 2009, 2010a). On the other hand, the influence of GABAB receptor PAMs on food intake is inconclusive as these drugs either do not influence (Filip and Frankowska, 2007; Vlachou et al., 2011a), decrease (Paterson et al., 2008; Perdona et al., 2011) or enhance (Ebenezer, 2012) food behavior and/or reinstatement of food seeking. Whether GABAB receptor PAMs control motivational and conditioned aspects of consumption behaviors requires further analyses. More studies are also needed in order to characterize the rewarding and aversive stimulus effects of GABAB receptor PAMs given alone (see: Mombereau et al., 2007) as well as their efficacy after repeated administration and effects on withdrawal. Apart from the above-unanswered preclinical queries, the most fundamental questions remaining are (i) whether GABAB receptor PAMs will be sufficient for therapeutic efficacy and (ii) if any PAM targeting GPCR allosteric sites do function as a therapeutic agent. So far, only cinacalcet, being a calciumimetic agent increasing the sensitivity of the calcium-sensing receptor (CaSR) to extracellular calcium is an example of marketed PAMs (Conn et al., 2009). Therefore, using the approved therapeutic the GABAB receptor agonist (baclofen as a muscle relaxer/an antispastic agent) or agonist/partial agonist (GHB as a blocker of excessive daytime sleepiness/cataplexy) (Kothare and Kaleyias, 2010) with tolerable side-effects might be still a good choice for control of substance use disorders. Of note, both of them were proposed for the treatment of cocaine addiction (baclofen) or alcoholism (baclofen, GHB). On the other hand, limitation of GHB use are its euphoric, anabolic, sedative, and amnestic properties that lead to rapid development of addiction in patients (Teter and Guthrie, 2001). It should also be mentioned that some GABAB receptor PAMs (e.g., CGP7930) function as “allosteric agonists” and exert differential effects on intracellular receptor signaling, which alter in vivo


10


effects (Urwyler, 2011). As yet, it is unknown whether multiple, distinct allosteric binding sites exist within the GABAB receptor structure and how their pharmacological activation influences drug addiction. Another open question is if and how GABAB receptor PAMs influence the GABAB receptors associated with KCTD as GABAB2 subunit contains a binding site for these ligands and the auxiliary subunits. To conclude, a new approach to the problem of drug abuse and addiction involving PAM manipulation of GABAB receptors may constitute an attractive alternative therapy; however, clinical translation of such effects is now warranted.

Acknowledgments Supported by the Institute of Pharmacology, Polish Academy of Science.

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