ABSTRACT
BACKGROUND: Positive allosteric modulators (PAMs) of the GABAB receptor constitute a new class of GABAB-receptor ligands. GABAB PAMs reproduce several pharmacological effects of the orthosteric GABAB receptor agonist, baclofen, although displaying a better safety profile. AIMS: This paper reviews the reducing or, frequently, even suppressing effects of all GABAB PAMs tested to date on multiple alcohol-related behaviours in laboratory rodents exposed to validated experimental models of human alcohol use disorder. RESULTS: Acute or repeated treatment with CGP7930, GS39783, BHF177, rac-BHFF, ADX71441, CMPPE, COR659, ASP8062, KK-92A, and ORM-27669 reduced excessive alcohol drinking, relapse- and binge-like drinking, operant alcohol self-administration, reinstatement of alcohol seeking, and alcohol-induced conditioned place preference in rats and mice. CONCLUSIONS: These effects closely mirrored those of baclofen; notably, they were associated to remarkably lower levels of tolerance and toxicity. The recent transition of ASP8062 to clinical testing will soon prove whether these highly consistent preclinical data translate to AUD patients.
Subject(s)
Alcoholism , Animals , Mice , Rats , Alcohol Drinking/drug therapy , Alcoholism/drug therapy , Baclofen/pharmacology , Baclofen/therapeutic use , GABA-B Receptor Agonists/pharmacology , GABA-B Receptor Agonists/therapeutic use , Receptors, GABA-BABSTRACT
BACKGROUND: Dysfunctional sensory gating in anxiety disorders, indexed by the failure to inhibit the P50 event-related potential (ERP) to repeated stimuli, has been linked to deficits in the major inhibitory neurotransmitter γ-aminobutyric acid (GABA). AIMS/METHODS: This study, conducted in 30 healthy volunteers, examined the acute effects of GABAA (lorazepam: 1 mg) and GABAB receptor (baclofen: 10 mg) agonists on P50 measures of auditory sensory gating within a paired-stimulus (S1-S2) paradigm and assessed changes in gating in relation to self-ratings of anxiety. RESULTS: Compared to placebo, lorazepam reduced ERP indices of sensory gating by attenuating response to S1. Although not directly impacting P50 inhibition, baclofen-induced changes in gating (relative to placebo) were negatively correlated with trait but not state anxiety. CONCLUSIONS: These preliminary findings support the involvement of GABA in sensory gating and tentatively suggest a role for GABAB receptor signaling in anxiety-associated gating dysregulation.
Subject(s)
Anxiety , Baclofen , GABA-B Receptor Agonists , Lorazepam , Receptors, GABA-B , Sensory Gating , Humans , Male , Female , Adult , Baclofen/pharmacology , Lorazepam/pharmacology , GABA-B Receptor Agonists/pharmacology , Anxiety/metabolism , Young Adult , Sensory Gating/drug effects , Receptors, GABA-B/metabolism , Receptors, GABA-B/drug effects , GABA-A Receptor Agonists/pharmacology , Healthy Volunteers , Double-Blind Method , Evoked Potentials, Auditory/drug effects , Evoked Potentials, Auditory/physiology , Receptors, GABA-A/metabolism , Receptors, GABA-A/drug effects , AdolescentABSTRACT
The anterior retrosplenial cortex (aRSC) integrates multimodal sensory information into cohesive associative recognition memories. Little is known about how information is integrated during different learning phases (i.e., encoding and retrieval). Additionally, sex differences are observed in performance of some visuospatial memory tasks; however, inconsistent findings warrant more research. We conducted three experiments using the 1-h delay object-in-place (1-h OiP) test to assess recognition memory retrieval in male and female Long-Evans rats. (i) We found both sexes performed equally in three repeated 1-h OiP test sessions. (ii) We showed infusions of a mixture of muscimol/baclofen (GABAA/B receptor agonists) into the aRSC ~15-min prior to the test phase disrupted 1-h OiP in both sexes. (iii) We assessed the role of aRSC ionotropic glutamate receptors in 1-h OiP retrieval using another squad of cannulated rats and confirmed that infusions of either the competitive AMPA/Kainate receptor antagonist CNQX (3 mM) or competitive NMDA receptor antagonist AP-5 (30 mM) (volumes = 0.50 uL/side) significantly impaired 1-h OiP retrieval in both sexes compared to controls. Taken together, findings challenge reported sex differences and clearly establish a role for aRSC ionotropic glutamate receptors in short-term visuospatial recognition memory retrieval. Thus, modulating neural activity in the aRSC may alleviate some memory processing impairments in related disorders.
Subject(s)
Muscimol , Rats, Long-Evans , Recognition, Psychology , Animals , Male , Female , Rats , Recognition, Psychology/drug effects , Recognition, Psychology/physiology , Muscimol/pharmacology , GABA-A Receptor Agonists/pharmacology , Baclofen/pharmacology , Memory, Short-Term/drug effects , Memory, Short-Term/physiology , Receptors, Ionotropic Glutamate/metabolism , Receptors, Ionotropic Glutamate/antagonists & inhibitors , Mental Recall/drug effects , Mental Recall/physiology , Excitatory Amino Acid Antagonists/pharmacology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/metabolism , Sex Characteristics , GABA-B Receptor Agonists/pharmacologyABSTRACT
Altered reactivity and responses to auditory input are core to the diagnosis of autism spectrum disorder (ASD). Preclinical models implicate Ï-aminobutyric acid (GABA) in this process. However, the link between GABA and auditory processing in humans (with or without ASD) is largely correlational. As part of a study of potential biosignatures of GABA function in ASD to inform future clinical trials, we evaluated the role of GABA in auditory repetition suppression in 66 adults (n = 28 with ASD). Neurophysiological responses (temporal and frequency domains) to repetitive standard tones and novel deviants presented in an oddball paradigm were compared after double-blind, randomized administration of placebo, 15 or 30 mg of arbaclofen (STX209), a GABA type B (GABAB) receptor agonist. We first established that temporal mismatch negativity was comparable between participants with ASD and those with typical development (TD). Next, we showed that temporal and spectral responses to repetitive standards were suppressed relative to responses to deviants in the two groups, but suppression was significantly weaker in individuals with ASD at baseline. Arbaclofen reversed weaker suppression of spectral responses in ASD but disrupted suppression in TD. A post hoc analysis showed that arbaclofen-elicited shift in suppression was correlated with autistic symptomatology measured using the Autism Quotient across the entire group, though not in the smaller sample of the ASD and TD group when examined separately. Thus, our results confirm: GABAergic dysfunction contributes to the neurophysiology of auditory sensory processing alterations in ASD, and can be modulated by targeting GABAB activity. These GABA-dependent sensory differences may be upstream of more complex autistic phenotypes.
Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Adult , Humans , Auditory Perception/physiology , GABA-B Receptor Agonists/pharmacology , GABA-B Receptor Agonists/therapeutic use , gamma-Aminobutyric AcidABSTRACT
Previous studies have demonstrated the role of γ-aminobutyric acid type B (GABAB) receptors in skin-related conditions and pain. However, most studies have focused on the main effects of GABAB on the central nervous system. Therefore, this study has aimed to determine the potential topical anti-inflammatory and anti-proliferative effects of baclofen cream in an inflammatory skin disease model. The effects of the baclofen cream were evaluated using acute and chronic models of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin inflammation in mouse ears. Histological and immunohistochemical evaluations were performed using an ear oedema assay. The effect of baclofen on keratinocyte proliferation was assessed in PAM212, the murine keratinocyte cell line. The results demonstrate that a single topical application of 5% baclofen, 7.5% baclofen, and 1% dexamethasone each inhibited acute TPA-induced ear oedema (58.94 ± 6.14%, 47.73 ± 11.26%, and 87.33 ± 4.59%, respectively). These results were confirmed by histological analysis. In the chronic model, baclofen (5%) and dexamethasone (1%) each inhibited ear oedema and the maximum inhibitory effect was reached at the end of the experiment (9th day of TPA application) with a percentage inhibition of 54.60 ± 6.15% for baclofen and 71.68 ± 3.45% for dexamethasone, when compared to the vehicle. These results were confirmed by histological analysis. Baclofen and dexamethasone also reduced proliferating cell nuclear antigen expression by 62.01 ± 6.65% and 70.42 ± 6.11%, respectively. However, baclofen did not inhibit keratinocyte proliferation in PAM212 cells. In conclusion, these results demonstrate that baclofen exhibits notable topical antiproliferative and anti-inflammatory properties and could be a potential therapeutic alternative for treating inflammatory and proliferative skin diseases.
Subject(s)
Dermatitis , Skin Diseases , Animals , Mice , Baclofen/pharmacology , Baclofen/therapeutic use , GABA-B Receptor Agonists/pharmacology , GABA-B Receptor Agonists/therapeutic use , Skin Diseases/drug therapy , Anti-Inflammatory Agents/adverse effects , Inflammation/drug therapy , Dexamethasone/therapeutic use , Edema/chemically induced , Edema/drug therapy , Edema/metabolism , Tetradecanoylphorbol Acetate/therapeutic useABSTRACT
Mephedrone is a psychoactive drug that increases dopamine, serotonin and noradrenaline levels in the central nervous system via interaction with transporters or monoamines. The aim of the presented study was to assess the role of the GABA-ergic system in the expression of mephedrone-induced reward. For this purpose, we conducted (a) a behavioral evaluation of the impact of baclofen (a GABAB receptors agonist) and GS39783 (a positive allosteric modulator of GABAB receptors) on the expression of mephedrone-induced conditioned place preference (CPP) in rats, (b) an ex vivo chromatographic determination of the GABA level in the hippocampi of rats subchronically treated with mephedrone and (c) an in vivo evaluation of GABA hippocampal concentration in rats subchronically administered with mephedrone using magnetic resonance spectroscopy (MRS). The results show that GS39783 (but not baclofen) blocked the expression of CPP induced by (20 mg/kg of) mephedrone. The behavioral effect was consistent with chromatographic analysis, which showed that mephedrone (5 and 20 mg/kg) led to a decrease in GABA hippocampal concentration. Altogether, the presented study provides a new insight into the involvement of the GABA-ergic system in the rewarding effects of mephedrone, implying that those effects are at least partially mediated through GABAB receptors, which suggests their potential role as new targets for the pharmacological management of mephedrone use disorder.
Subject(s)
GABA-B Receptor Agonists , Reward , Rats , Animals , GABA-B Receptor Agonists/pharmacology , Baclofen/pharmacology , Receptors, GABA-B/metabolismABSTRACT
Alcohol use despite negative consequences is a core phenomenon of alcohol addiction. We recently used alcohol self-administration that is resistant to footshock punishment as a model of this behavior, and found that activity of PKCδ + GABAergic neurons in the central amygdala (CeA) is a determinant of individual susceptibility for punishment resistance. In the present study, we examined whether activation of GABAB receptors in CeA can attenuate the activity of PKCδ + neurons in this region, and whether this will result in suppression of punishment- resistant alcohol self-administration in the minority of rats that show this behavior. Systemic administration of the clinically approved GABAB agonist baclofen (1 and 3 mg/kg) dose- dependently reduced punishment-resistant alcohol self-administration. Bilateral microinjections of baclofen into CeA (64 ng in 0.3 µl/side) reduced the activity of PKCδ + neurons, as measured by Fos expression. This manipulation also selectively suppressed punished alcohol self-administration in punishment-resistant rats. Expression analysis indicated that virtually all CeA PKCδ + neurons express the GABAB receptor. Using in vitro electrophysiology, we found that baclofen induced hyperpolarization of CeA neurons, reducing their firing rate in response to depolarizing current injections. Together, our findings provide a potential mechanism that contributes to the clinical efficacy of baclofen in alcohol addiction. Therapeutic use of baclofen itself is limited by problems of tolerance and need for dose escalation. Our findings support a mechanistic rationale for developing novel, improved alcohol addiction medications that target GABAB receptors, and that lack these limitations, such as e.g., GABAB positive allosteric modulators (PAM:s).
Subject(s)
Alcoholism , Central Amygdaloid Nucleus , Rats , Animals , Baclofen , Alcoholism/drug therapy , Punishment , Central Amygdaloid Nucleus/metabolism , Receptors, GABA-B/metabolism , Ethanol , Neurons/metabolism , GABA-B Receptor Agonists/pharmacology , GABA-B Receptor Agonists/therapeutic useABSTRACT
Promoting remyelination is considered as a potential neurorepair strategy to prevent/limit the development of permanent neurological disability in patients with multiple sclerosis (MS). To this end, a number of clinical trials are investigating the potential of existing drugs to enhance oligodendrocyte progenitor cell (OPC) differentiation, a process that fails in chronic MS lesions. We previously reported that oligodendroglia express GABAB receptors (GABAB Rs) both in vitro and in vivo, and that GABAB R-mediated signaling enhances OPC differentiation and myelin protein expression in vitro. Our goal here was to evaluate the pro-remyelinating potential of GABAB R agonist baclofen (Bac), a clinically approved drug to treat spasticity in patients with MS. We first demonstrated that Bac increases myelin protein production in lysolecithin (LPC)-treated cerebellar slices. Importantly, Bac administration to adult mice following induction of demyelination by LPC injection in the spinal cord resulted in enhanced OPC differentiation and remyelination. Thus, our results suggest that Bac repurposing should be considered as a potential therapeutic strategy to stimulate remyelination in patients with MS.
Subject(s)
Multiple Sclerosis , Remyelination , Animals , Baclofen/metabolism , Baclofen/pharmacology , Baclofen/therapeutic use , Cell Differentiation , Central Nervous System/metabolism , GABA-B Receptor Agonists/metabolism , GABA-B Receptor Agonists/pharmacology , GABA-B Receptor Agonists/therapeutic use , Lysophosphatidylcholines/metabolism , Mice , Mice, Inbred C57BL , Multiple Sclerosis/pathology , Myelin Sheath/metabolism , Oligodendroglia/metabolismABSTRACT
Baclofen is a GABAB receptor agonist with proposed use as a treatment for alcohol use disorder (AUD). In preclinical studies, racemic baclofen decreases alcohol consumption in both mice and rats; however, there is a significant disparity in the efficacy of the drug across species. We previously demonstrated that baclofen is enantioselective, with the racemic enantiomer successfully reducing binge-like alcohol consumption during Drinking-in-the-Dark (DID) in C57BL/6J (B6) mice, as well as 24-h consumption during two-bottle choice (2BC) preference drinking in replicate 1 High Alcohol Preferring (HAP) mice. Here we extend these findings by investigating the effects of racemic baclofen on the acquisition and maintenance of alcohol consumption, locomotor activity, and saccharin drinking in two different mouse genotypes and drinking paradigms. Adult male and female B6 mice were allowed free access to 20% (v/v) alcohol for 2 h daily in a 14-day DID procedure. Adult male and female replicate 2 HAP (HAP2) mice were allowed 24-h access to 10% (v/v) alcohol versus tap water in a 2BC procedure for 14 days. Systemic injections of baclofen (0.0 or 3.0 mg/kg) were given 3 h into the dark cycle on days 1-5 in alcohol acquisition experiments and days 6-10 in alcohol maintenance experiments. We found that racemic baclofen significantly reduces acquisition of DID and 2BC alcohol drinking in male and female B6 and HAP2 mice, whereas it only significantly reduces the maintenance of DID alcohol intake in B6 mice. Racemic baclofen did not alter home cage locomotor activity but did alter saccharin intake, suggesting it may have nonspecific effects. The current data add to literature suggesting that smaller doses of racemic baclofen may be an effective treatment of AUD. Future work should focus on the longitudinal efficacy of racemic baclofen in high-drinking mouse genotypes to further investigate whether it is effective for those with a genetic predisposition to AUD.
Subject(s)
Alcoholism , Baclofen , Alcohol Drinking/drug therapy , Alcohol Drinking/genetics , Alcoholism/drug therapy , Animals , Baclofen/pharmacology , Baclofen/therapeutic use , Ethanol , Female , GABA-B Receptor Agonists/pharmacology , GABA-B Receptor Agonists/therapeutic use , Male , Mice , Mice, Inbred C57BL , Rats , Saccharin , WaterABSTRACT
The systemic use of GABAB orthosteric agonist baclofen might be limited due to its detrimental properties: sedation and motor impairment. In contrast, GABAB positive allosteric modulators produce less adverse effects. Using BHF-177 as a starting point, we found a new active scaffold: the 6-aryl-quinazoline scaffold. Further elaborating the scaffold, we identified several in vitro and in vivo active compounds.
Subject(s)
GABA-B Receptor Agonists , Receptors, GABA-B , Allosteric Regulation , Baclofen , GABA-B Receptor Agonists/pharmacology , Quinazolines/pharmacologyABSTRACT
Cognitive deficits and impaired sensory processing are hallmarks of several neurodevelopmental and neuropsychiatric disorders. N-methyl-d-aspartate receptor (NMDAR) hypofunction contributes to these deficits by disrupting the excitation-to-inhibition balance in neuronal networks. Although preclinical data suggest that the activation of gamma-Aminobutyric acid B receptors (GABAB R) may restore excitation-to-inhibition balance and rescues some behavioral deficits, GABAB R agonists have failed to meet their clinical study endpoints, suggesting more complex interactions at play. Here, we studied the effects of Baclofen (a GABAB R agonist) and MK-801 (a non-competitive NMDAR antagonist) on the neurophysiology of limbic-auditory circuits in freely-moving rats. The pharmacological effects were assessed using resting-state EEG, auditory-evoked oscillation, and mismatch negativity paradigms. MK-801 elevated resting-state oscillatory power, mainly in the gamma and higher frequency ranges, and impaired auditory-evoked responses. Baclofen partially normalized resting-state oscillations but failed to rescue auditory-evoked oscillatory abnormalities. Coherence analysis indicated that NMDAR hypofunction alters the functional coupling of limbic and thalamocortical circuits in several frequency bands. Baclofen normalized only a fraction of MK-801-induced abnormalities (e.g., theta coherence between frontal cortex and amygdala) while reducing delta-theta and augmenting gamma coherence in thalamocortical circuits. Finally, we report that Baclofen intensified the MK-801-induced deficits in auditory mismatch responses. In summary, while Baclofen partially normalizes MK-801-induced gamma abnormalities, it either fails to rescue or exacerbates deficits in other phenotypes like functional coupling and auditory processing. We hope that the presented complex interactions between pharmacologically induced NMDAR hypofunction and GABABR agonism inspire a new understanding of the therapeutic potential around GABAergic modulation.
Subject(s)
Dizocilpine Maleate , Schizophrenia , Animals , Baclofen/toxicity , Disease Models, Animal , Dizocilpine Maleate/pharmacology , GABA-B Receptor Agonists/pharmacology , Perception , Rats , Receptors, N-Methyl-D-Aspartate , Schizophrenia/chemically inducedABSTRACT
Literature data suggest that activation and blockade of the GABAB receptor may produce similar effects on several reward-related behaviours. Accordingly, the present study was designed to investigate whether treatment with the GABAB receptor antagonist, SCH 50911, reproduced the suppressing effect of the GABAB receptor agonist, baclofen, and several positive allosteric modulators of the GABAB receptor on operant oral alcohol self-administration in rats. To this end, Sardinian alcohol-preferring (sP) rats were trained to lever-respond for alcohol (15% v/v) under the fixed ratio (FR) 4 (FR4) schedule of reinforcement. Once lever-responding had stabilized, rats were exposed to test sessions preceded by treatment with SCH 50911 (0, 25, 50, and 100 mg/kg; i.p.). Two independent experiments were conducted, differing solely in the set of rats used. Selectivity of SCH 50911 effect on alcohol self-administration was assessed by evaluating the effect of SCH 50911 (0, 25, 50, and 100 mg/kg; i.p.) on self-administration of a sucrose solution (0.7% w/v) in sP rats exposed to the FR4 schedule. In both 'alcohol' experiments, treatment with SCH 50911 reduced lever-responding for alcohol and amount of self-administered alcohol. SCH 50911 effect was characterized by large interindividual variability, with several instances of dose-unrelated reductions, and frequent occurrence of complete suppression of lever-responding for alcohol. Similar data were collected in the 'sucrose' experiment. These results extend to alcohol self-administration with the notion that activation and blockade of GABAB receptor may produce unidirectional effects on reward-related behaviours; these similarities are discussed in terms of differential contribution of pre- and postsynaptic GABAB receptors.
Subject(s)
Alcohol Drinking , Baclofen/pharmacology , GABA-B Receptor Agonists/pharmacology , GABA-B Receptor Antagonists/pharmacology , Morpholines/pharmacology , Receptors, GABA-B/metabolism , Reinforcement, Psychology , Alcohol Drinking/metabolism , Alcohol Drinking/psychology , Animals , Behavior, Animal/drug effects , Dose-Response Relationship, Drug , Models, Animal , Rats , Self Administration/psychologyABSTRACT
BACKGROUND: Baclofen, a clinically available GABAB receptor agonist, produces non-opioid analgesia in multiple models of pain but has not been tested for effects on bladder nociception. METHODS: A series of experiments examined the effects of systemic and spinally administered baclofen on bladder nociception in female anesthetized rats. Models of bladder nociception included those which employed neonatal and adult bladder inflammation to produce bladder hypersensitivity. RESULTS: Cumulative intraperitoneal dosing (1-8 mg/kg IP) and cumulative intrathecal dosing (10-160 ng IT) of baclofen led to dose-dependent inhibition of visceromotor responses (VMRs) to urinary bladder distension (UBD) in all tested models. There were no differences in the magnitude of the analgesic effects of baclofen as a function of inflammation versus no inflammation treatments. Hemodynamic (pressor) responses to UBD were similarly inhibited by IT baclofen as well as UBD-evoked excitatory responses of spinal dorsal horn neurons. The GABAB receptor antagonist, CGP 35,348, antagonized the antinociceptive effects of IT baclofen on VMRs in all tested models but did not affect the magnitude of the VMRs by itself suggesting no tonic GABAB activity was present in this preparation. Tolerance to a seven day continuous IT infusion of baclofen was not observed. CONCLUSIONS: These data provide support for a clinical trial of baclofen as a non-opioid treatment of human bladder pain.
Subject(s)
Baclofen/pharmacology , GABA-B Receptor Agonists/pharmacology , Nociception/drug effects , Urinary Bladder/drug effects , Urinary Bladder/physiology , Animals , Baclofen/administration & dosage , Female , GABA-B Receptor Agonists/administration & dosage , Injections, Spinal , Rats , Rats, Sprague-DawleyABSTRACT
Non-alcoholic steatohepatitis (NASH) is a rising health challenge, with no approved drugs. We used a computational drug repositioning strategy to uncover a novel therapy for NASH, identifying a GABA-B receptor agonist, AZD3355 (Lesogaberan) previously evaluated as a therapy for esophageal reflux. AZD3355's potential efficacy in NASH was tested in human stellate cells, human precision cut liver slices (hPCLS), and in vivo in a well-validated murine model of NASH. In human stellate cells AZD3355 significantly downregulated profibrotic gene and protein expression. Transcriptomic analysis of these responses identified key regulatory nodes impacted by AZD3355, including Myc, as well as MAP and ERK kinases. In PCLS, AZD3355 down-regulated collagen1α1, αSMA and TNF-α mRNAs as well as secreted collagen1α1. In vivo, the drug significantly improved histology, profibrogenic gene expression, and tumor development, which was comparable to activity of obeticholic acid in a robust mouse model of NASH, but awaits further testing to determine its relative efficacy in patients. These data identify a well-tolerated clinical stage asset as a novel candidate therapy for human NASH through its hepatoprotective, anti-inflammatory and antifibrotic mechanisms of action. The approach validates computational methods to identify novel therapies in NASH in uncovering new pathways of disease development that can be rapidly translated into clinical trials.
Subject(s)
Drug Repositioning , GABA-B Receptor Agonists/therapeutic use , Liver/drug effects , Non-alcoholic Fatty Liver Disease/drug therapy , Phosphinic Acids/therapeutic use , Propylamines/therapeutic use , Adult , Aged , Animals , Cell Line , Disease Models, Animal , Female , GABA-B Receptor Agonists/pharmacology , Humans , Liver/metabolism , Liver/pathology , Male , Mice , Mice, Inbred C57BL , Middle Aged , Non-alcoholic Fatty Liver Disease/metabolism , Non-alcoholic Fatty Liver Disease/pathology , Phosphinic Acids/pharmacology , Propylamines/pharmacologyABSTRACT
RATIONALE: Pre-clinical evidence implicates the GABAergic system in mediating the reinforcing effects of alcohol and offers a therapeutic target for alcohol use disorder (AUD). The orthosteric GABAB receptor agonist baclofen decreases alcohol self-administration in animals and alcohol use in humans; however side effects limit its utility. Pre-clinical evidence shows positive allosteric GABAB receptor modulators also decrease alcohol self-administration without untoward side effects. OBJECTIVES: We assessed the impact of the novel GABAB-positive allosteric modulator ASP8062 and baclofen on operant alcohol self-administration and their potential non-specific effects. METHODS: The effects of ASP8062 (1 - 10 mg/kg, PO) and baclofen (0.3 - 3 mg/kg, IP) were evaluated in male and female rats lever pressing for alcohol (10%, w/v) under a fixed ratio 2 schedule of reinforcement. On the fourth consecutive day of vehicle, ASP8062 or baclofen administration, active and inactive lever presses, reinforcers earned, head entries, and estimated alcohol consumed were analyzed. Locomotor activity was assessed in separate groups of rats following dosing. RESULTS: Both ASP8062 and baclofen decreased alcohol self-administration and amount consumed (g/kg) in male and female rats. ASP8062 decreased operant alcohol self-administration to a greater extent in male rats, whereas baclofen was more efficacious in female rats. ASP8062 did not alter locomotor activity in either sex, whereas baclofen (3.0 mg/kg) decreased activity in male rats yet (1.0 mg/kg) increased activity in female rats. CONCLUSIONS: ASP8062 decreases alcohol reinforcement like baclofen but without non-specific effects which are influenced by sex. Results support further development of ASP8062 as a potential treatment for AUD in humans.
Subject(s)
Pyrimidines , Receptors, GABA-B , Allosteric Regulation , Animals , Baclofen/pharmacology , Conditioning, Operant , Female , GABA-B Receptor Agonists/pharmacology , Male , Morpholines , Rats , Rats, Sprague-Dawley , Self AdministrationABSTRACT
Cognitive flexibility is a prefrontal cortex-dependent neurocognitive process that enables behavioral adaptation in response to changes in environmental contingencies. Electrical vagus nerve stimulation (VNS) enhances several forms of learning and neuroplasticity, but its effects on cognitive flexibility have not been evaluated. In the current study, a within-subjects design was used to assess the effects of VNS on performance in a novel visual discrimination reversal learning task conducted in touchscreen operant chambers. The task design enabled simultaneous assessment of acute VNS both on reversal learning and on recall of a well-learned discrimination problem. Acute VNS delivered in conjunction with stimuli presentation during reversal learning reliably enhanced learning of new reward contingencies. Enhancement was not observed, however, if VNS was delivered during the session but was not coincident with presentation of to-be-learned stimuli. In addition, whereas VNS delivered at 30 HZ enhanced performance, the same enhancement was not observed using 10 or 50 Hz. Together, these data show that acute VNS facilitates reversal learning and indicate that the timing and frequency of the VNS are critical for these enhancing effects. In separate rats, administration of the norepinephrine reuptake inhibitor atomoxetine also enhanced reversal learning in the same task, consistent with a noradrenergic mechanism through which VNS enhances cognitive flexibility.
Subject(s)
Reversal Learning , Vagus Nerve Stimulation , Adrenergic Uptake Inhibitors , Animals , Atomoxetine Hydrochloride/pharmacology , Baclofen/pharmacology , Conditioning, Operant/drug effects , Conditioning, Operant/physiology , Discrimination Learning/drug effects , Discrimination Learning/physiology , GABA-B Receptor Agonists/pharmacology , Male , Rats , Rats, Inbred BN , Reversal Learning/drug effects , Reversal Learning/physiologyABSTRACT
Repetitive transcranial magnetic stimulation (rTMS) is a promising, innovative, and non-invasive therapy used clinically. Efficacy of rTMS has been demonstrated to ameliorate psychiatric disorders and neuropathic pain through neuromodulation of affected neural circuits. However, little is known about the mechanisms and the specific neural circuits via which rTMS facilitates these functional effects. The aim of this study was to begin revealing the mechanisms by which rTMS may tap into existing neural circuits, by using a well characterized spinal motor circuit - the phrenic circuit. Here we hypothesized that rTMS can be used to enhance phrenic motoneuron excitability in anesthetized Sprague Dawley rats. Multiple acute rTMS protocols were used revealing 10 Hz rTMS protocol induced a robust, long-lasting increase in phrenic motoneuron excitability, functionally evaluated by diaphragm motor evoked potentials (59.1 ± 21.1 % of increase compared to baseline 60 min after 10 Hz protocol against 6.0 ± 5.8 % (p = 0.007) for Time Control, -5.8 ± 7.4 % (p < 0.001) for 3 Hz, and 5.2 ± 12.5 % (p = 0.008) for 30 Hz protocols). A deeper analyze allowed to discriminate "responder" and "non-responder" subgroups among 10 Hz rTMS treated animals. Intravenous injections of GABAA and GABAB receptor agonists prior to 10 Hz rTMS treatment, abolished the enhanced phrenic motoneuron excitability, suggesting GABAergic input plays a mechanistic role in rTMS-induced phrenic excitability. These data demonstrate that a single high frequency rTMS protocol at 10 Hz increases phrenic motoneuron excitability, mediated by a local GABAergic "disinhibition". By understanding how rTMS can be used to affect neural circuits non-invasively we can begin to harness the therapeutic potential of this neuromodulatory strategy to promote recovery after disease or injury to the central nervous system.
Subject(s)
Evoked Potentials, Motor/physiology , GABA-A Receptor Agonists/pharmacology , GABA-B Receptor Agonists/pharmacology , Motor Neurons/physiology , Nerve Net/physiology , Phrenic Nerve/physiology , Transcranial Magnetic Stimulation , Animals , Diaphragm/drug effects , Diaphragm/physiology , Evoked Potentials, Motor/drug effects , Female , Motor Neurons/drug effects , Nerve Net/drug effects , Nerve Net/metabolism , Phrenic Nerve/drug effects , Phrenic Nerve/metabolism , Rats , Rats, Sprague-DawleyABSTRACT
MK-801 (dizocilpine) is a potent non-competitive N-methyl-[D]-aspartate (NMDA) receptor antagonist that affects cognitive function, learning, and memory. As we know, NMDA receptors are significantly involved in memory function, as well as GABA (Gamma-Aminobutyric acid) receptors. In this study, we aimed to discover the effect of GABA-B receptors in the basolateral amygdala (BLA) on MK-801-induced memory impairment. We used 160 male Wistar rats. The shuttle box was used to evaluate passive avoidance memory and locomotion apparatus was used to evaluate locomotor activity. MK-801 (0.125, 0.25, and 0.5 µg/rat), baclofen (GABA-B agonist, 0.0001, 0.001, and 0.01 µg/rat) and phaclofen (GABA-B antagonist, 0.0001, 0.001, and 0.01 µg/rat) were injected intra-BLA, after the training. The results showed that MK-801 at the dose of 0.5 µg/rat, baclofen at the doses of 0.001 and 0.01 µg/rat, and phaclofen at the doses of 0.001 and 0.01 µg/rat, impaired passive avoidance memory. Locomotor activity did not alter in all groups. Furthermore, the subthreshold dose of both baclofen (0.0001 µg/rat) and phaclofen (0.0001 µg/rat) restored the impairment effect of MK-801 (0.5 µg/rat) on memory. Also, both baclofen (0.0001 µg/rat) potentiated the impairment effect of MK-801 (0.125 µg/rat) and phaclofen (0.0001 µg/rat) potentiated the impairment effect of MK-801 (0.125 and 0.25 µg/rat) on passive avoidance memory. In conclusion, our results indicated that BLA GABA-B receptors can alter the effect of NMDA inactivation on passive avoidance memory.
Subject(s)
Avoidance Learning/drug effects , Basolateral Nuclear Complex/drug effects , Behavior, Animal/drug effects , Excitatory Amino Acid Antagonists/pharmacology , GABA-B Receptor Agonists/pharmacology , GABA-B Receptor Antagonists/pharmacology , Memory Disorders/chemically induced , Memory Disorders/drug therapy , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Animals , Baclofen/analogs & derivatives , Baclofen/pharmacology , Disease Models, Animal , Dizocilpine Maleate/pharmacology , Excitatory Amino Acid Antagonists/administration & dosage , GABA-B Receptor Agonists/administration & dosage , GABA-B Receptor Antagonists/administration & dosage , Male , Rats , Rats, WistarABSTRACT
Allosteric modulators of G protein coupled receptors (GPCRs), including GABABRs (GABABRs), are promising therapeutic candidates. While several positive allosteric modulators (PAM) of GABABRs have been characterized, only recently the first negative allosteric modulator (NAM) has been described. In the present study, we report the characterization of COR758, which acts as GABABR NAM in rat cortical membranes and CHO cells stably expressing GABABRs (CHO-GABAB). COR758 failed to displace the antagonist [3H]CGP54626 from the orthosteric binding site of GABABRs showing that it acts through an allosteric binding site. Docking studies revealed a possible new allosteric binding site for COR758 in the intrahelical pocket of the GABAB1 monomer. COR758 inhibited basal and GABABR-stimulated O-(3-[35Sthio)-triphosphate ([35S]GTPγS) binding in brain membranes and blocked the enhancement of GABABR-stimulated [35S]GTPγS binding by the PAM GS39783. Bioluminescent resonance energy transfer (BRET) measurements in CHO-GABAB cells showed that COR758 inhibited G protein activation by GABA and altered GABABR subunit rearrangements. Additionally, the compound altered GABABR-mediated signaling such as baclofen-induced inhibition of cAMP production in transfected HEK293 cells, agonist-induced Ca2+ mobilization as well as baclofen and the ago-PAM CGP7930 induced phosphorylation of extracellular signal-regulated kinases (ERK1/2) in CHO-GABAB cells. COR758 also prevented baclofen-induced outward currents recorded from rat dopamine neurons, substantiating its property as a NAM for GABABRs. Altogether, these data indicate that COR758 inhibits G protein signaling by GABABRs, likely by interacting with an allosteric binding-site. Therefore, COR758 might serve as a scaffold to develop additional NAMs for therapeutic intervention.
Subject(s)
GABA Modulators/chemistry , GABA Modulators/pharmacology , GABA-B Receptor Antagonists/chemistry , GABA-B Receptor Antagonists/pharmacology , Receptors, GABA-B/physiology , Allosteric Regulation/drug effects , Allosteric Regulation/physiology , Animals , Bioluminescence Resonance Energy Transfer Techniques/methods , CHO Cells , Cricetulus , Dose-Response Relationship, Drug , GABA-B Receptor Agonists/chemistry , GABA-B Receptor Agonists/pharmacology , Humans , Male , Rats , Rats, Sprague-Dawley , gamma-Aminobutyric Acid/chemistry , gamma-Aminobutyric Acid/pharmacologyABSTRACT
Resilience is the capacity to maintain normal psychological and physical functions in the face of stress and adversity. Understanding how one can develop and enhance resilience is of great relevance to not only promoting coping mechanisms but also mitigating maladaptive stress responses in psychiatric illnesses such as depression. Preclinical studies suggest that GABA(B) receptors (GABA(B1) and GABA(B2)) are potential targets for the treatment of major depression. In this study, we assessed the functional role of GABA(B) receptors in stress resilience and vulnerability by using a chronic unpredictable stress (CUS) model in mice. As the medial prefrontal cortex (mPFC) plays a key role in the top-down modulation of stress responses, we focused our study on this brain structure. Our results showed that only approximately 41.9% of subjects exhibited anxiety- or despair-like behaviors after exposure to CUS. The vulnerable mice showed higher c-Fos expression in the infralimbic cortex (IL) subregion of the mPFC when exposed to a social stressor. Moreover, the expression of GABA(B1) but not GABA(B2) receptors was significantly downregulated in IL subregion of susceptible mice. Finally, we found that intra-IL administration of baclofen, a GABA(B) receptor agonist, rapidly relieved the social avoidance symptoms of the "stress-susceptible" mice. Taken together, our results show that the GABA(B1) receptor within the IL may play an important role in stress resilience and vulnerability, and thus open an avenue to develop novel, personalized approaches to promote stress resilience and treat stress-related psychiatric disorders.