ReviewTherapeutic potential of GABAB receptor ligands in drug addiction, anxiety, depression and other CNS disorders
Introduction
γ-Aminobutyric acid and the inhibitory GABAergic neurons were discovered by Flory and Bazemore in 1957 (Florey, 1991). GABA is considered to be a major inhibitory neurotransmitter in the CNS and serves various functions in neuronal and non neuronal tissues. GABA mediates its function via, ionotropic (GABAA and GABAC) and metabotropic GABAB receptors. GABAergic ionotropic receptors are ligand gated ion channels, involved in fast synaptic transmission, whereas metabotropic GABAB receptors belong to the superfamily of G-protein coupled receptors (GPCRs) and are responsible for the neuromodulatory effect of GABA (Cytril et al., 2009, Eduardo, 2012). Neurons are excited by the glutamate and inhibited by the GABA, over or under activation of either of these two systems or both has been implicated in the pathophysiology of neuropsychiatric and neurodegenerative disorders (Princivalle et al., 2002, Enna and Bowery, 2004, Oblak et al., 2010). Herein, we have discussed the role of GABAB receptor in various neuropsychiatric and neurodegenerative disorders.
Section snippets
Structure
GABAB receptors were discovered at the end of the 1970s by the Bowery's research team and were cloned in 1997 (Kaupmann et al., 1997). As shown in Fig. 1, GABAB receptor has two subunits GABABR1 and GABABR2, having molecular weight of 130 and 110 kDa respectively. Both the subunits have a long extracellular N-terminus, seven transmembrane domains and a short intracellular carboxy terminus forming a loop responsible for linking the two subunits (Filip and Frankowska, 2008). These subunits are
Agonists
The discovery of the exogenous GABAB receptor ligand, baclofen, i.e., p-chlorophenyl-GABA, was a milestone in the characterization of these receptors. Baclofen was synthesized by Heinrich Keberle in 1962, 30 years before a GABAB receptor was cloned (Froestl, 2010). Baclofen is a lipophilic GABA derivative and possesses a high affinity and strong intrinsic activity for GABAB receptors. Baclofen is an optically active compound, and its R isomer shows a three times greater affinity/efficacy for GABA
Role of GABAB receptors ligands in various CNS disorders
Baclofen, a GABAB receptor agonist, is the only available drug marketed for multiple neurological disorders associated with motor dysfunction (Bettler et al., 2010). Baclofen is used as antispastic and muscle relaxant in patients suffering from multiple sclerosis (Sachais et al., 1977, Greene, 1992, Dario and Tomei, 2004, Franek et al., 2004). It is administered intrathecally in severe cases of spasticity and Stiffman syndrome (Ho and Shih, 2012). Further, it is being used to treat cerebral
Summary and future prospective
GABA, as a major inhibitory transmitter, plays a vital role in neuronal functions by regulating neuronal excitability and neurotransmitter release. GABAB receptors play a crucial role in mediating the effects of GABAergic neuronal transmission and the availability of auto- and hetero-GABAB receptors, suggests their neuromodulatory role. Various strategies, such as agonism, antagonism and in recent years, positive allosteric modulation of GABAB receptors, have been suggested to be beneficial in
Acknowledgment
Authors are thankful to Mr. Parveeen Garg; chairman, ISF College of Pharmacy, Moga (Punjab) for valuable financial support and encouragement.
References (129)
- et al.
Cannabinoid (CB(1)), GABA(A) and GABA(B) receptor subunit changes in the globus pallidus in Huntington's disease
J Chem Neuroanat
(2009) - et al.
Reversal of scopolamine-induced amnesia by the GABAB receptor antagonist CGP 35348 in the mouse
Brain Res Cogn Brain Res
(1993) - et al.
GABAA and GABAB receptor site distribution in the rat central nervous system
Neuroscience
(1987) - et al.
GABAB receptor subunits, R1 and R2, in brainstem catecholamine and serotonin neurons
Brain Res
(2003) - et al.
125I-CGP 64213 binding to GABA(B) receptors in the brain of monkeys: effect of MPTP and dopaminomimetic treatments
Exp Neurol
(2000) - et al.
Unbalance of CB1 receptors expressed in GABAergic and glutamatergic neurons in a transgenic mouse model of Huntington's disease
Neurobiol Dis
(2012) - et al.
Ischaemia differentially regulates GABAB receptor subunits in organotypic hippocampal slice cultures
Neuropharmacology
(2009) - et al.
Don't worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression
Trends Pharmacol Sci
(2005) - et al.
GABAB receptor alterations as indicators of physiological and pharmacological function
Biochem Pharmacol
(2004) Chemistry and pharmacology of GABAB receptor ligands
Adv Pharmacol
(2010)
SGS742: the first GABAB receptor antagonist in clinical trials
Biochem Pharmacol
Cholinergic system function and cognition in mild cognitive impairment
Neurobiol Aging
Demonstration of a tandem pair of complement protein modules in GABAB receptor 1a
FEBS Lett
GABAB receptor antagonist SGS742 improves spatial memory and reduces protein binding to the cAMP response element (CRE) in the hippocampus
Neuropharmacology
The role of the GABA(B) receptor and calcium channels in a Drosophila model of Parkinson's disease
Neurosci Lett
Baclofen attenuates conditioned locomotion to cues associated with cocaine administration and stabilizes extracellular glutamate levels in rat nucleus accumbens
Neuroscience
Evaluation of the anxiolytic-like profile of the GABAB receptor positive modulator CGP7930 in rodents
Neuropharmacology
Allosteric modulation of G-protein coupled receptors
Eur J Pharm Sci
Ghrelin receptor antagonist attenuates nicotine-induced locomotor stimulation, accumbal domain release and conditioned place preference in mice
Drug Alcohol Depend
Changes in GABA(B) receptor mRNA expression in the rodent basal ganglia and thalamus following lesion of the nigrostriatal pathway
Neuroscience
Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity
Brain Res Brain Res Rev
Synergistic combinatorial stroke therapy: a quantal bioassay of a GABA agonist and a glutamate antagonist
Exp Neurol
Cost of disorders of the brain in Europe
Eur J Neurol
Decreased GABAB receptor function in the cerebellum and brain stem of hypoxic neonatal rats: role of glucose, oxygen and epinephrine resuscitation
J Biomed Sci
Mechanism underlying selective regulation of G protein-gated inwardly rectifying potassium channels by the psychostimulant-sensitive sorting nexin 27
PNAS
Modulation of cell surface GABAB receptors by desensitization, trafficking and regulated degradation
World J Biol Chem
Hippocampal levels of phosphorylated protein kinase a (phosphor-S96) are linked to spatial memory enhancement by SGS742
Hippocampus
Molecular structure and physiological functions of GABAB receptors
Neuron
GABAB receptor autoradiography in hippocampal sclerosis associated with human temporal lobe epilepsy
Br J Pharmacol
Alterations in GABAergic biomarkers in the autism brain: research findings and clinical implications
Anat Rec (Hoboken)
Characterization of COR627 and COR628, two novel positive allosteric modulators of the GABAB receptor
J Pharmacol Exp Ther
Non-monoaminergic approaches in search of novel antidepressants
Clin Neuropsychiatry
GABAB receptor modulation of voltage-sensitive calcium channels in spines and dendrites
J Neurosci
Metabotropic glutamate 1 (mGlu1) receptor antagonists enhance GABAergic neurotransmission: a mechanism for the attenuation of post-ischemic injury and epileptiform activity?
Neuropharmacology
5-HT1A and beyond: the role of serotonin and its receptors in depression and the antidepressant response
Hum Psychopharmacol
GABAB receptors and depression: current status
Behavioral characterization of the novel GABAB receptor-positive modulator GS39783 (N, N'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine): anxiolytic-like activity without side effects associated with baclofen or benzodiazepines
J Pharmacol Exp Ther
Metabotropic receptors for glutamate and GABA in pain
Brain Res Rev
A benefit–risk assessment of baclofen in severe spinal spasticity
Drug Saf
GABAB receptor antagonist-mediated antidepressant-like behavior is serotonin-dependent
JPET
Contributions of calcium-dependent and calcium-independent mechanisms to presynaptic inhibition at a cerebellar synapse
J Neurosci
Neurotransmitters decrease the calcium conductance activated by depolarization of embryonic chick sensory neurons
J Physiol (Lond)
A physiological role for GABAB receptors in the central nervous system
Nature
GABAB receptors: structure, functions, and clinical implications
Neurology
Baclofen antagonizes nicotine-, cocaine-, and morphine-induced dopamine release in the nucleus accumbens of rat
Synapse
Expression of GABAB receptors is altered in brains of subjects with autism
Cerebellum
mRNA and protein levels for GABAAα4, α5, β1 and GABABR1 receptors are altered in brains from subjects with autism
J Autism Dev Disord
Acute and long-term changes in the mesolimbic dopamine pathway after systemic or local single nicotine injections
Eur J Neurosci
GABAB receptors in drug addiction
Pharmacol Rep
GABA: history and perspectives
Can J Physiol Pharmacol
Cited by (100)
Mechanistic and therapeutic relationships of traumatic brain injury and γ-amino-butyric acid (GABA)
2024, Pharmacology and TherapeuticsGenetic mutation of TRPV2 induces anxiety by decreasing GABA-B R2 expression in hippocampus
2022, Biochemical and Biophysical Research CommunicationsGABAkines – Advances in the discovery, development, and commercialization of positive allosteric modulators of GABA<inf>A</inf> receptors
2022, Pharmacology and TherapeuticsCitation Excerpt :GABAB receptors act through activation of pertussis toxin-sensitive G proteins (Knight & Bowery, 1996) resulting in a prolonged decrease in neuronal excitability through the inhibition of adenylyl cyclase and voltage-gated Ca2+ channels, as well as the opening of G protein-coupled inward rectifying K+ channels (Bettler, Kaupmann, Mosbacher, & Gassmann, 2004; Gassmann & Bettler, 2012). GABAB receptors have been implicated in pathophysiological mechanisms of multiple neuronal processes and have been proposed as a drug target for a range of disorders including spasticity, pain, cough, bladder dysfunction, drug addiction, and epilepsy (Enna, 1997; Kumar, Sharma, Kumar, & Deshmukh, 2013). Substantial effort has been devoted to the discovery of compounds for GABABRs, but the compounds generally suffered from lack of efficacy, non-drug-like pharmacokinetic profiles, and side effects at sub-efficacious doses (Evenseth, Gabrielsen, & Sylte, 2020).