Targeting GABAB receptors

Alterations to the GABAB receptor system have been linked to autism, bipolar disorder, major depression, and schizophrenia [1] GABAB receptors exhibit decreased expression in bipolar disorder, major depressive disorder (MDD) and schizophrenia, and have been proposed as promising treatment targets for these neuropsychiatric disorders as well as anxiety and addiction.

Activation of the pre-synaptic GABAB-Rs inhibits neurotransmitter release through multiple targets including inactivation of voltage-dependent calcium channels, gating of potassium conductance to shunt pre-synaptic action potentials, reduction of vesicle priming or interaction with the exocytosis machinery. Released GABA also signals onto post-synaptic GABAB-Rs located on dendritic shaft and spines. Activation of these receptors generates slow (100-150 ms) inhibitory potentials via the opening of G-protein activated-inward rectifying potassium channels. [2]

GABAB receptors regulate hippocampal excitability and presynaptic GABAB and group II metabotropic glutamate (mGlu2/3) receptors exert marked inhibitory control over corticostriatal glutamate release in the dorsolateral striatum [3] An interplay between mGluR5 and GABAB receptors has also been reported [4] with GABAB receptor agonism inhibiting presynaptic release of glutamate and thus blockade of downstream signaling of mGluR5

More recently, the extent of cross-talk and regulation between GABAB and glutamate receptors has been uncovered:

Cross-talk and regulation between glutamate and GABAB receptors.

Brain function depends on co-ordinated transmission of signals from both excitatory and inhibitory neurotransmitters acting upon target neurons. NMDA, AMPA and mGluR receptors are the major subclasses of glutamate receptors that are involved in excitatory transmission at synapses, mechanisms of activity dependent synaptic plasticity, brain development and many neurological diseases. In addition to canonical role of regulating presynaptic release and activating postsynaptic potassium channels, GABAB receptors also regulate glutamate receptors. There is increasing evidence that metabotropic GABAB receptors are now known to play an important role in modulating the excitability of circuits throughout the brain by directly influencing different types of postsynaptic glutamate receptors. Specifically, GABAB receptors affect the expression, activity and signaling of glutamate receptors under physiological and pathological conditions. Conversely, NMDA receptor activity differentially regulates GABAB receptor subunit expression, signaling and function. In this review I will describe how GABAB receptor activity influence glutamate receptor function and vice versa. Such a modulation has widespread implications for the control of neurotransmission, calcium-dependent neuronal function, pain pathways and in various psychiatric and neurodegenerative diseases.

The GABAB receptor system has been shown to have substantial interactions with the serotonergic system and neurotrophic factors, such as BDNF. Blockade, or loss of function, of GABAB receptors causes an antidepressant-like phenotype [5].  Manipulation of GABAB receptors can modify behaviors relevant to depression and anxiety – the GABAB receptor positive allosteric modulator CGP 7930 and the antagonist SCH 50911 show both antidepressant and anxiolytic profiles, while the GABAB receptor agonists (baclofen and SKF 97541) reportedly produce effects that are characteristic of antidepressant drugs [6].  A cognition enhancer that upregulates GABAB receptor densities in the cortex displays potent antidepressant activity [7]. Likewise, alterations in GABABR signaling play a role in the rapid antidepressant activity of NMDA antagonists [8].

” …a recent review of nonclinical data has suggested that pharmacological blockade or genetic knockout of GABAB receptors induces antidepressant-like behavioral effects in a variety of nonclinical rodent MDD models, including chronic mild stress, learned helplessness, and forced swim, while GABAB-receptor activation either blocks the effects of known antidepressants or induces a depressive-like phenotype. Although there are no clinical investigations of GABAB-receptor antagonists in MDD that could be identified at this time, a clinical experiment demonstrated that GABAB-receptor activation using baclofen induced symptom exacerbation in the majority of a very small MDD patient sample that reversed upon baclofen withdrawal.” [link]

GABAB-receptor agonists at low concentrations increase the firing frequency of VTA-DA neurons, while high concentrations reduce the firing frequency: baclofen, a GABAB agonist, at low concentrations, causes a disinhibition of DA neurons, increases DA levels and thus facilitates reinforcement learning. [9] In humans, stimulation of cortical GABAB receptors in the fronto-parietal network leads to better attentional allocation in reinforcement learning. [10] Chronic baclofen desensitizes GABAB-mediated G-protein activation and stimulates phosphorylation of kinases in mesocorticolimbic rat brain. [11]

(R)-baclofen reverses social deficits and reduces repetitive behavior in two mouse models of autism [12] and has shown efficacy in treating autistic children in phase II trials.

GABAB receptors appear to be particularly important in contributing to the learning and/or memory of conditioned aversive stimuli [13]. Presynaptic GABAB receptors inhibit postsynaptic LTP in the basolateral amygdala (BLA) and thereby prevent fear generalisation. Postsynaptic GABAB receptors modulate the acquisition or consolidation of fear conditioning. Neither baclofen nor BHF177 had any selective effects on fear memory retrieval in contextual and cued fear conditioning or spatial learning and memory tests [14]

Enhanced GABAB signalling, preferably by positive allosteric modulation, improves PPI deficits in animal models [15]

Positive allosteric modulation of GABAB receptors ameliorates sensorimotor gating in rodent models.

Converging evidence points to the involvement of γ-amino-butyric acid B receptors (GABABRs) in the regulation of information processing. We previously showed that GABABR agonists exhibit antipsychotic-like properties in rodent models of sensorimotor gating deficits, as measured by the prepulse inhibition (PPI) of the acoustic startle reflex. The therapeutic potential of these agents, however, is limited by their neuromuscular side effects; thus, in this study, we analyzed whether rac-BHFF, a potent GABABR-positive allosteric modulator (PAM), could counter spontaneous and pharmacologically induced PPI deficits across various rodent models. We tested the antipsychotic effects of rac-BHFF on the PPI deficits caused by the N-methyl-D-aspartate glutamate receptor antagonist dizocilpine, in Sprague-Dawley rats and C57BL/6 mice. Furthermore, we verified whether rac-BHFF ameliorated the spontaneous PPI impairments in DBA/2J mice. rac-BHFF dose-dependently countered the PPI deficits across all three models, in a fashion akin to the GABABR agonist baclofen and the atypical antipsychotic clozapine; in contrast with these compounds, however, rac-BHFF did not affect startle magnitude. The present data further support the implication of GABABRs in the modulation of sensorimotor gating and point to their PAMs as a novel promising tool for antipsychotic treatment, with fewer side effects than GABABR agonists.

Anecdotally (from a single case study), acute administration of either baclofen or phenibut resulted in a reduction in the intensity of auditory hallucinations in a patient with clozapine resistant schizophrenia and further studies are warranted.

“Harte and O’Connor (2005) demonstrate that a reduction in the mPFC GABAB receptor-mediated inhibitory tone is associated with a disinhibition of PFC-mediated corticofugal glutamate drive onto both mesolimbic dopamine and GABA-containing neurons in the VTA while local intra-mPFC perfusion with the selective GABAB receptor agonist baclofen reverses this effect. Baclofen has been clinically tested as a possible antipsychotic and while it alone is not beneficial it has been proposed that cortical GABAB receptor activation may be a useful treatment in schizophrenia when co-administered with conventional neuroleptics” [16]

GABAB-mediated effects may play a role in the unique effectiveness of clozapine:

“The GABAB receptor potentially represents a novel treatment target for schizophrenia. Clozapine has unique efficacy for the treatment of refractory schizophrenia (Lieberman et al., 2005) which is likely unrelated to D2-receptor antagonism given its low D2 receptor occupancy (Kapur et al., 1999). Further support for the theory that clozapine’s antipsychotic mechanism is independent of dopamine antagonism is that clozapine effectively treats drug-induced psychosis in Parkinson’s disease without significant worsening of motor function (Pollak et al., 2004). Our results suggest that clozapine’s unique efficacy may be related to the magnitude of GABAB potentiation not seen with any other typical or atypical antipsychotic (Daskalakis et al., 2008, Liu et al., 2009 and Frank et al., 2014). To clarify the role of GABAB in schizophrenia pathophysiology, future work may use GABAB receptor agonists as an adjunct to non-clozapine antipsychotics in order to determine if targeting of GABAB enhances treatment response. If this were to demonstrate increased cortical silent period (i.e. GABAB potentiation) without an improved response rate, then an alternate mechanism likely underlies clozapine’s unique efficacy.” [17]

GABAB agonists and PAMs are unique as anti-abuse therapies because of their impact against multiple addictive drugs [18]

GABAB-Rs play a key role in the modulation of GABAergic synaptogenesis and plasticity:
GABAB-Rs modulate GABAergic synaptogenesis and plasticity. The activation of GABAB-Rs induces the formation of diacylglycerol (DAG), activation of protein kinase C (PKC), and the opening of L-type voltage-dependent Ca2+ channels (L-VDCC). The intracellular Ca2+ rise triggers the secretion of BDNF which acting on TrkB-Rs modulate the formation and efficacy of developing GABAergic synapses [source]

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