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Reviews in the Neurosciences Aug 2020In this review, a series of experiments is presented, in which γ-amino butyric acid (GABA)ergic and glutamatergic effects on dopamine function in the rat nigrostriatal... (Review)
Review
In this review, a series of experiments is presented, in which γ-amino butyric acid (GABA)ergic and glutamatergic effects on dopamine function in the rat nigrostriatal and mesolimbic system was systematically assessed after pharmacological challenge with GABAA receptor (R) and and N-methyl d-aspartate (NMDA)R agonists and antagonists. In these studies, [123I]iodobenzamide binding to the D2/3R was mesured in nucleus accumbens (NAC), caudateputamen (CP), substantia nigra/ventral tegmental area (SN/VTA), frontal (FC), motor (MC) and parietal cortex (PC) as well as anterior (aHIPP) and posterior hippocampus (pHIPP) with small animal SPECT in baseline and after injection of either the GABAAR agonist muscimol (1 mg/kg), the GABAAR antagonist bicuculline (1 mg/kg), the NMDAR agonist d-cycloserine (20 mg/kg) or the NMDAR antagonist amantadine (40 mg/kg). Muscimol reduced D2/3R binding in NAC, CP, SN/VTA, THAL and pHIPP, while, after amantadine, decreases were confined to NAC, CP and THAL. In contrast, d-cycloserine elevated D2/3R binding in NAC, SN/VTA, THAL, frontal cortex, motor cortex, PC, aHIPP and pHIPP, while, after bicuculline, increases were confined to CP and THAL. Taken together, similar actions on regional dopamine levels were exterted by the GABAAR agonist and the NMDAR antagonist on the one side and by the GABAAR antagonist and the NMDAR agonist on the other, with agonistic action, however, affecting more brain regions. Thereby, network analysis suggests different roles of GABAARs and NMDARs in the mediation of nigrostriatal, nigrothalamocortical and mesolimbocortical dopamine function.
Topics: Animals; Bicuculline; Dopamine; Humans; Muscimol; Nucleus Accumbens; Rats; Receptors, GABA-A; Receptors, N-Methyl-D-Aspartate
PubMed: 32619197
DOI: 10.1515/revneuro-2019-0112 -
ENeuro 2022Neurons express overlapping homeostatic mechanisms to regulate synaptic function and network properties in response to perturbations of neuronal activity....
Neurons express overlapping homeostatic mechanisms to regulate synaptic function and network properties in response to perturbations of neuronal activity. Endocannabinoids (eCBs) are bioactive lipids synthesized in the postsynaptic compartments to regulate synaptic transmission, plasticity, and neuronal excitability primarily through retrograde activation of presynaptic cannabinoid receptor type 1 (CB1). The eCB system is well situated to regulate neuronal network properties and coordinate presynaptic and postsynaptic activity. However, the role of the eCB system in homeostatic adaptations to neuronal hyperactivity is unknown. To address this issue, we used Western blotting and targeted lipidomics to measure adaptations in eCB system to bicuculline (BCC)-induced chronic hyperexcitation in mature cultured rat cortical neurons, and used multielectrode array (MEA) recording and live-cell imaging of glutamate dynamics to test the effects of pharmacological manipulations of eCB on network activities. We show that BCC-induced chronic hyperexcitation triggers homeostatic downscaling and a coordinated adaptation to enhance tonic eCB signaling. Hyperexcitation triggers first the downregulation of fatty acid amide hydrolase (FAAH), the lipase that degrades the eCB anandamide, then an accumulation of anandamide and related metabolites, and finally a delayed upregulation of surface and total CB1. Additionally, we show that BCC-induced downregulation of surface AMPA-type glutamate receptors (AMPARs) and upregulation of CB1 occur through independent mechanisms. Finally, we show that endocannabinoids support baseline network activities before and after downscaling and is engaged to suppress network activity during adaptation to hyperexcitation. We discuss the implications of our findings in the context of downscaling and homeostatic regulation of oscillatory network activities.
Topics: Animals; Rats; Endocannabinoids; Receptors, Cannabinoid; Arachidonic Acids; Polyunsaturated Alkamides; Glutamic Acid; Receptor, Cannabinoid, CB1; Cannabinoid Receptor Modulators
PubMed: 36316118
DOI: 10.1523/ENEURO.0276-22.2022 -
Frontiers in Endocrinology 2020Still circa 25% to 30% of patients with epilepsy cannot be efficiently controlled with available antiepileptic drugs so newer pharmacological treatment options have been...
Still circa 25% to 30% of patients with epilepsy cannot be efficiently controlled with available antiepileptic drugs so newer pharmacological treatment options have been continuously searched for. In this context, a group of endogenous or exogenous neurosteroids allosterically positively modulating GABA-A receptors may offer a promising approach. Among endogenous neurosteroids synthesized in the brain, allopregnanolone or allotetrahydrodeoxycorticosterone have been documented to exert anticonvulsant activity in a number of experimental models of seizures-pentylenetetrazol-, bicuculline- pilocarpine-, or 6 Hz-induced convulsions in rodents. Neurosteroids can also inhibit fully kindled seizures and some of them have been reported to counteract maximal electroshock-induced convulsions. An exogenous neurosteroid, alphaxalone, significantly elevated the threshold for maximal electroconvulsions in mice but it did not potentiate the anticonvulsive action of a number of conventional antiepileptic drugs against maximal electroshock-induced seizures. Androsterone not only elevated the threshold but significantly enhanced the protective action of carbamazepine, gabapentin and phenobarbital against maximal electroshock in mice, as well. Ganaxolone (a 3beta-methylated analog of allopregnanolone) needs special consideration for two reasons. First, it performed better than conventional antiepileptic drugs, diazepam or valproate, in suppressing convulsive and lethal effects of pentylenetetrazol in pentylenetetrazol-kindled mice. Second, ganaxolone has been evaluated in the randomized, double-blind, placebo-controlled phase 2 trial in patients with intractable partial seizures, taking maximally 3 antiepileptic drugs. The initial results indicate that add-on therapy with ganaxolone resulted in reduced seizure frequency with adverse effect being mainly mild to moderate. Possibly, ganaxolone may be also considered against catamenial seizures. Some positive effects of ganaxolone as an adjuvant were also observed in children with refractory seizures and its use may also prove efficient for the management of neonatal seizures associated with hypoxic injury. Neurosteroids positively modulating GABA-A receptor complex exert anticonvulsive activity in many experimental models of seizures. Their interactions with antiepileptic drugs seem ambiguous in mice. Initial clinical data indicate that ganaxolone may provide a better seizure control in patients with drug-resistant epilepsy.
Topics: Allosteric Regulation; Animals; Anticonvulsants; Epilepsy; GABA-A Receptor Agonists; Humans; Neurosteroids; Seizures; Treatment Outcome
PubMed: 33117274
DOI: 10.3389/fendo.2020.541802 -
Sleep Jan 2021The substantia nigra pars reticulata (SNR) is a major output nucleus of the basal ganglia. Animal studies have shown that lesions of the SNR cause hyposomnia and motor...
STUDY OBJECTIVES
The substantia nigra pars reticulata (SNR) is a major output nucleus of the basal ganglia. Animal studies have shown that lesions of the SNR cause hyposomnia and motor hyperactivity, indicating that the SNR may play a role in the control of sleep and motor activity.
METHODS
Eight 8- to 10-week-old adult male Sprague-Dawley rats were used. After 3 days of baseline polysomnographic recording, dialysates were collected from the lateral SNR across natural sleep-wake states. Muscimol and bicuculline were microinfused into the lateral SNR.
RESULTS
We found that GABA release in the lateral SNR is negatively correlated with slow wave sleep (SWS; R = -0.266, p < 0.01, n = 240) and positively correlated with waking (R = 0.265, p < 0.01, n = 240) in rats. Microinfusion of muscimol into the lateral SNR decreased sleep time and sleep quality, as well as eliciting motor hyperactivity in wake and increased periodic leg movement in SWS, while bicuculline infused into the lateral SNR increased sleep and decreased motor activity in SWS in rats. Muscimol infusion skewed the distribution of inter-movement intervals, with most between 10 and 20 s, while a flat distribution of intervals between 10 and 90 s was seen in baseline conditions.
CONCLUSIONS
Activation of the lateral SNR is important for inducing sleep and inhibiting motor activity prior to and during sleep, and thus to the maintenance of sleep. Abnormal function of the lateral SNR may cause hyposomnia and motor hyperactivity in quiet wake and in sleep.
Topics: Animals; GABA Antagonists; Male; Motor Activity; Pars Reticulata; Rats; Rats, Sprague-Dawley; Sleep; Substantia Nigra; gamma-Aminobutyric Acid
PubMed: 32808987
DOI: 10.1093/sleep/zsaa151 -
Neuron Nov 2023The neurotransmitter γ-aminobutyric acid (GABA) drives critical inhibitory processes in and beyond the nervous system, partly via ionotropic type-A receptors (GABARs)....
The neurotransmitter γ-aminobutyric acid (GABA) drives critical inhibitory processes in and beyond the nervous system, partly via ionotropic type-A receptors (GABARs). Pharmacological properties of ρ-type GABARs are particularly distinctive, yet the structural basis for their specialization remains unclear. Here, we present cryo-EM structures of a lipid-embedded human ρ1 GABAR, including a partial intracellular domain, under apo, inhibited, and desensitized conditions. An apparent resting state, determined first in the absence of modulators, was recapitulated with the specific inhibitor (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid and blocker picrotoxin and provided a rationale for bicuculline insensitivity. Comparative structures, mutant recordings, and molecular simulations with and without GABA further explained the sensitized but slower activation of ρ1 relative to canonical subtypes. Combining GABA with picrotoxin also captured an apparent uncoupled intermediate state. This work reveals structural mechanisms of gating and modulation with applications to ρ-specific pharmaceutical design and to our biophysical understanding of ligand-gated ion channels.
Topics: Humans; Receptors, GABA-A; Picrotoxin; Ligands; gamma-Aminobutyric Acid; Bicuculline; Binding Sites
PubMed: 37659407
DOI: 10.1016/j.neuron.2023.08.006 -
Experimental Physiology Mar 2022What is the central question of this study? Is there an interaction between histamine and the GABAergic system in modulation of anxiety in mice? What is the main finding...
NEW FINDINGS
What is the central question of this study? Is there an interaction between histamine and the GABAergic system in modulation of anxiety in mice? What is the main finding and its importance? There is a synergistic anxiogenic effect between histamine and bicuculline in mice. This effect may be due to a direct or an indirect effect of the histaminergic system on the GABAergic system.
ABSTRACT
It has been documented that both histaminergic and GABAergic systems participate in the neurobiology of anxiety behaviour. In the current research, we investigated the effects of the histaminergic system and GABA receptor agents on anxiety-related behaviours and their interaction using the elevated plus maze test in mice. Intraperitoneal (i.p.) administration of muscimol (0.12 and 0.25 mg/kg) increased the open arm time (OAT) (P < 0.001) without affecting the open arm entries (OAE) and locomotor activity, showing an anxiolytic effect. i.p. injection of bicuculline (0.5 and 1 mg/kg) decreased OAT (P < 0.001) but not OAE and locomotor activity, suggesting an anxiogenic behaviour. Intracerebroventricular (i.c.v.) microinjection of histamine (2.5 and 5 μg/mouse) resulted in a decline in OAT (P < 0.001) but not OAE and locomotor activity, indicating an anxiogenic response. Co-administration of histamine with GABAergic agents, muscimol (0.06 mg/kg; i.p.) and bicuculline (0.25 mg/kg; i.p.), decreased (P < 0.001) and increased (P < 0.05), respectively, the anxiogenic-like response to the effective dose (5 μg/mouse; i.c.v.) of histamine. In addition, co-treatment of effective doses of histamine (2.5 and 5 μg/mouse;i.c.v.) with an effective dose of muscimol (0.12 mg/kg; i.p.) and a non-effective dose of bicuculline (0.25 mg/kg; i.p.) significantly decreased OAT (P < 0.001), suggesting a likely interaction between the histaminergic and GABAergic systems in the regulation of anxiety. The results demonstrated a synergistic anxiogenic-like effect between histamine and bicuculline in mice. In conclusion, our results present an interaction between the histaminergic and GABAergic systems in anxiolytic/anxiogenic-like behaviours in the elevated plus maze test.
Topics: Animals; Anxiety; Elevated Plus Maze Test; GABA Agents; Histamine; Male; Maze Learning; Mice; Rats; Rats, Wistar; gamma-Aminobutyric Acid
PubMed: 35137999
DOI: 10.1113/EP090060 -
Frontiers in Systems Neuroscience 2022The ventral pallidum (VP) is central in the limbic Basal Ganglia circuit, controlling both appetitive (approach) and aversive (avoidance) motivated behaviors....
The ventral pallidum (VP) is central in the limbic Basal Ganglia circuit, controlling both appetitive (approach) and aversive (avoidance) motivated behaviors. Nevertheless, VP involvement in pathological aspects remains unclear, especially in the behavioral expression of different motivational dysfunctions. This study aimed to investigate how the VP contributes to the expression of abnormal behaviors opposite GABAergic dysfunctions. Opposite GABAergic dysfunctions were induced by injecting muscimol (a GABA agonist) and bicuculline (a GABA antagonist) into monkeys. We determined the effects of both substances on self-initiated behaviors in lab-chair and in free-moving home-cage contexts in six monkeys, and in two animals performing an approach-avoidance task in appetitive and aversive contexts. While the self-initiated behaviors induced by bicuculline injections in VP were characterized by compulsive behaviors such as repetitive grooming and self-biting, muscimol injections induced impulsive behaviors including limb movements in a lab-chair context and exploration behaviors in a free-moving context. More specific behavioral effects were observed in the approach-avoidance task. The muscimol injections induced premature responses and erroneous screen touches, which characterize impulsive and attention disorders, while the bicuculline injections into the VP increased passive avoidance (non-initiated action) and task-escape in an aversive context, suggesting an anxiety disorder. These results show that activating or blocking GABAergic transmission in the VP impairs motivated behaviors. Furthermore, the behavioral expressions produced by these opposite disturbances show that the VP could be involved in anxiety-driven compulsive disorders, such as OCD, as well as in impulsive disorders motivated by attention deficits or reward-seeking, as seen in ADHD or impulse control disorders.
PubMed: 36567755
DOI: 10.3389/fnsys.2022.1009626 -
Molecular Neurobiology May 2022Perineuronal nets (PNNs) are specialised extracellular matrix structures which preferentially enwrap fast-spiking (FS) parvalbumin interneurons and have diverse roles in...
Perineuronal nets (PNNs) are specialised extracellular matrix structures which preferentially enwrap fast-spiking (FS) parvalbumin interneurons and have diverse roles in the cortex. PNN maturation coincides with closure of the critical period of cortical plasticity. We have previously demonstrated that BDNF accelerates interneuron development in a c-Jun-NH-terminal kinase (JNK)-dependent manner, which may involve upstream thousand-and-one amino acid kinase 2 (TAOK2). Chondroitinase-ABC (ChABC) enzymatic digestion of PNNs reportedly reactivates 'juvenile-like' plasticity in the adult CNS. However, the mechanisms involved are unclear. We show that ChABC produces an immature molecular phenotype in cultured cortical neurons, corresponding to the phenotype prior to critical period closure. ChABC produced different patterns of PNN-related, GABAergic and immediate early (IE) gene expression than well-characterised modulators of mature plasticity and network activity (GABA-R antagonist, bicuculline, and sodium-channel blocker, tetrodotoxin (TTX)). ChABC downregulated JNK activity, while this was upregulated by bicuculline. Bicuculline, but not ChABC, upregulated Bdnf expression and ERK activity. Furthermore, we found that BDNF upregulation of semaphorin-3A and IE genes was TAOK mediated. Our data suggest that ChABC heightens structural flexibility and network disinhibition, potentially contributing to 'juvenile-like' plasticity. The molecular phenotype appears to be distinct from heightened mature synaptic plasticity and could relate to JNK signalling. Finally, we highlight that BDNF regulation of plasticity and PNNs involves TAOK signalling.
Topics: Bicuculline; Brain-Derived Neurotrophic Factor; Extracellular Matrix; Interneurons; Neuronal Plasticity; Parvalbumins
PubMed: 35233718
DOI: 10.1007/s12035-022-02772-z -
Frontiers in Pharmacology 2019Patients with liver cirrhosis may develop minimal hepatic encephalopathy (MHE) with mild cognitive impairment. Hyperammonemia is a main contributor to cognitive...
Patients with liver cirrhosis may develop minimal hepatic encephalopathy (MHE) with mild cognitive impairment. Hyperammonemia is a main contributor to cognitive impairment in MHE, which is mediated by neuroinflammation. GABAergic neurotransmission is altered in hyperammonemic rats. We hypothesized that, in hyperammonemic rats, (a) enhanced GABAergic tone would contribute to induce neuroinflammation, which would be improved by reducing GABAergic tone by chronic bicuculline treatment; (b) this would improve spatial learning and memory impairment; and (c) modulation of glutamatergic neurotransmission would mediate this cognitive improvement. The aim of this work was to assess the above hypotheses. Bicuculline was administrated intraperitoneally once a day for 4 weeks to control and hyperammonemic rats. The effects of bicuculline on microglia and astrocyte activation, IL-1β content, on membrane expression of AMPA and NMDA glutamate receptors subunits in the hippocampus and on spatial learning and memory as well as anxiety were assessed. Treatment with bicuculline reduces astrocyte activation and IL-1β but not microglia activation in the hippocampus of hyperammonemic rats. Bicuculline reverses the changes in membrane expression of AMPA receptor subunits GluA1 and GluA2 and of the NR2B (but not NR1 and NR2A) subunit of NMDA receptors. Bicuculline improves spatial learning and working memory and decreases anxiety in hyperammonemic rats. In hyperammonemia, enhanced activation of GABA receptors in the hippocampus contributes to some but not all aspects of neuroinflammation, to altered glutamatergic neurotransmission and to impairment of spatial learning and memory as well as anxiety, all of which are reversed by reducing activation of GABA receptors with bicuculline.
PubMed: 30858801
DOI: 10.3389/fphar.2019.00132 -
Nature Communications Apr 2021Spreading depression (SD) is an intense and prolonged depolarization in the central nervous systems from insect to man. It is implicated in neurological disorders such...
Spreading depression (SD) is an intense and prolonged depolarization in the central nervous systems from insect to man. It is implicated in neurological disorders such as migraine and brain injury. Here, using an in vivo mouse model of focal neocortical seizures, we show that SD may be a fundamental defense against seizures. Seizures induced by topical 4-aminopyridine, penicillin or bicuculline, or systemic kainic acid, culminated in SDs at a variable rate. Greater seizure power and area of recruitment predicted SD. Once triggered, SD immediately suppressed the seizure. Optogenetic or KCl-induced SDs had similar antiseizure effect sustained for more than 30 min. Conversely, pharmacologically inhibiting SD occurrence during a focal seizure facilitated seizure generalization. Altogether, our data indicate that seizures trigger SD, which then terminates the seizure and prevents its generalization.
Topics: 4-Aminopyridine; Animals; Bicuculline; Brain Stem; Cortical Spreading Depression; Depression; Female; Gene Knock-In Techniques; Kainic Acid; Male; Mice; Nervous System; Optogenetics; Penicillins; Potassium Channel Blockers; Seizures; Tetrodotoxin
PubMed: 33850125
DOI: 10.1038/s41467-021-22464-x