Reduced inhibitory action of a GABA(B )receptor agonist on [(3)H]-dopamine release from rat ventral tegmental area in vitro after chronic nicotine administration

BACKGROUND: The activation of GABA(B )receptors in the ventral tegmental area (VTA) has been suggested to attenuate the rewarding properties of psychostimulants, including nicotine. However, the neurochemical mechanism that underlie this effect remains unknown. Since GABA(B )receptors modulate the release of several neurotransmitters in the mammalian brain, we have characterised the effect of the GABA(B )receptor agonist baclofen on the release of [(3)H]-dopamine ([(3)H]-DA) from VTA slices of naïve rats and of rats pre-treated with nicotine. RESULTS: In naïve rats, baclofen concentration-dependently inhibited the electrically evoked release of [(3)H]-DA from the isolated VTA (EC(50 )= 0.103 μM, 95% CI = 0.043–0.249), without affecting the basal [(3)H]-monoamine overflow. This effect was mediated by activation of GABA(B )receptors as it was blocked by the selective receptor antagonist CGP55845A. Chronic administration of nicotine (0.4 mg kg(-1), s.c., for 14 days) affected neither the basal nor the electrically evoked release of [(3)H]-DA from VTA slices. However, the inhibitory effect of baclofen (10 μM) on the stimulated [(3)H]-monoamine overflow was abolished in rats pre-treated with nicotine as compared to saline-injected controls. CONCLUSIONS: Our results demonstrate that GABA(B )receptor activation reduces the release of DA from the rat VTA. In addition, a reduced sensitivity of VTA GABA(B )receptors appears to develop after chronic exposure to nicotine. The resulting disinhibition of VTA DA neurones might therefore contribute to the sensitised dopaminergic responses observed in the rat mesocorticolimbic system following repeated administration of nicotine

GABAB receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

Functional GABAB receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on GABAB receptors [11, 72]) are formed from the heterodimerization of two similar 7TM subunits termed GABAB1 and GABAB2 [11, 71, 28, 72, 85]. GABAB receptors are widespread in the CNS and regulate both pre- and postsynaptic activity. The GABAB1 subunit, when expressed alone, binds both antagonists and agonists, but the affinity of the latter is generally 10-100-fold less than for the native receptor. Co-expression of GABAB1 and GABAB2 subunits allows transport of GABAB1 to the cell surface and generates a functional receptor that can couple to signal transduction pathways such as high-voltage-activated Ca2+ channels (Cav2.1, Cav2.2), or inwardly rectifying potassium channels (Kir3) [12, 11, 5]. The GABAB1 subunit harbours the GABA (orthosteric)-binding site within an extracellular domain (ECD) venus flytrap module (VTM), whereas the GABAB2 subunit mediates G protein-coupled signalling [11, 71, 40, 39]. The two subunits interact by direct allosteric coupling [63], such that GABAB2 increases the affinity of GABAB1 for agonists and reciprocally GABAB1 facilitates the coupling of GABAB2 to G proteins [71, 54, 39]. GABAB1 and GABAB2 subunits assemble in a 1:1 stoichiometry by means of a coiled-coil interaction between α-helices within their carboxy-termini that masks an endoplasmic reticulum retention motif (RXRR) within the GABAB1 subunit but other domains of the proteins also contribute to their heteromerization [5, 71, 15]. Recent evidence indicates that higher order assemblies of GABAB receptor comprising dimers of heterodimers occur in recombinant expression systems and in vivo and that such complexes exhibit negative functional cooperativity between heterodimers [70, 22]. Adding further complexity, KCTD (potassium channel tetramerization proteins) 8, 12, 12b and 16 associate as tetramers with the carboxy terminus of the GABAB2 subunit to impart altered signalling kinetics and agonist potency to the receptor complex [84, 3, 79] and are reviewed by [73]. The molecular complexity of GABAB receptors is further increased through association with trafficking and effector proteins [Schwenk et al., 2016, Nature Neuroscience 19(2): 233-42] and reviewed by [69]. Four isoforms of the human GABAB1 subunit have been cloned. The predominant GABAB1a and GABAB1b isoforms, which are most prevalent in neonatal and adult brain tissue respectively, differ in their ECD sequences as a result of the use of alternative transcription initiation sites. GABAB1a-containing heterodimers localise to distal axons and mediate inhibition of glutamate release in the CA3-CA1 terminals, and GABA release onto the layer 5 pyramidal neurons, whereas GABAB1b-containing receptors occur within dendritic spines and mediate slow postsynaptic inhibition [75, 89]. Only the 1a and 1b variants are identified as components of native receptors [11]. Additional GABAB1 subunit isoforms have been described in rodents and humans [55] and reviewed by [5]

GABAB receptors in GtoPdb v.2021.2

Functional GABAB receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on GABAB receptors [11, 71]) are formed from the heterodimerization of two similar 7TM subunits termed GABAB1 and GABAB2 [11, 70, 28, 71, 87]. GABAB receptors are widespread in the CNS and regulate both pre- and postsynaptic activity. The GABAB1 subunit, when expressed alone, binds both antagonists and agonists, but the affinity of the latter is generally 10-100-fold less than for the native receptor. Co-expression of GABAB1 and GABAB2 subunits allows transport of GABAB1 to the cell surface and generates a functional receptor that can couple to signal transduction pathways such as high-voltage-activated Ca2+ channels (Cav2.1, Cav2.2), or inwardly rectifying potassium channels (Kir3) [12, 11, 5]. The GABAB1 subunit harbours the GABA (orthosteric)-binding site within an extracellular domain (ECD) venus flytrap module (VTM), whereas the GABAB2 subunit mediates G protein-coupled signalling [11, 70, 40, 39]. The cryo-electron microscopy structures of the human full-length GABAB1-GABAB2 heterodimer have been solved in the inactive apo state, two intermediate agonist-bound forms and an active state in which the heterodimer is bound to an agonist and a positive allosteric modulator [81]. The positive allosteric modulator binds to the transmembrane dimerization interface and stabilizes the active state. Recent evidence indicates that higher order assemblies of GABAB receptor comprising dimers of heterodimers occur in recombinant expression systems and in vivo and that such complexes exhibit negative functional cooperativity between heterodimers [69, 22]. Adding further complexity, KCTD (potassium channel tetramerization proteins) 8, 12, 12b and 16 associate as tetramers with the carboxy terminus of the GABAB2 subunit to impart altered signalling kinetics and agonist potency to the receptor complex [86, 3, 79] and are reviewed by [72]. The molecular complexity of GABAB receptors is further increased through association with trafficking and effector proteins [80] and reviewed by [68]. The predominant GABAB1a and GABAB1b isoforms, which are most prevalent in neonatal and adult brain tissue respectively, differ in their ECD sequences as a result of the use of alternative transcription initiation sites. GABAB1a-containing heterodimers localise to distal axons and mediate inhibition of glutamate release in the CA3-CA1 terminals, and GABA release onto the layer 5 pyramidal neurons, whereas GABAB1b-containing receptors occur within dendritic spines and mediate slow postsynaptic inhibition [74, 91]. Amyloid precursor protein (APP) and soluble APP (sAPP) bind to the N- terminal sushi domain of the GABAB1a isoform to regulate axonal trafficking of GABAB receptors and release of neurotransmitters [76]