The GABAergic system is the main inhibitory neurotransmitter system in the central nervous system (CNS) of vertebrates. Signalling of the transmitter γ‐aminobutyric acid (GABA) via GABA type A ...receptor channels or G‐protein‐coupled type B receptors is implicated in multiple CNS functions. Recent findings have implicated the GABAergic system in immune cell functions, inflammatory conditions and diseases in peripheral tissues. Interestingly, the specific effects may vary between immune cell types, with stage of activation and be altered by infectious agents. GABA/GABA‐A receptor‐mediated immunomodulatory functions have been unveiled in immune cells, being present in T lymphocytes and regulating the migration of Toxoplasma‐infected dendritic cells. The GABAergic system may also play a role in the regulation of brain resident immune cells, the microglial cells. Activation of microglia appears to regulate the function of GABAergic neurotransmission in neighbouring neurones through changes induced by secretion of brain‐derived neurotrophic factor. The neurotransmitter‐driven immunomodulation is a new but rapidly growing field of science. Herein, we review the present knowledge of the GABA signalling in immune cells of the periphery and the CNS and raise questions for future research.
Abstract We studied the possible activation of a neuropeptide FF2 receptor (NPFF2R) by kisspeptins, neuropeptides derived from the mouse and human metastin or Kiss-1 precursor. The hypothesis was ...that the human kisspeptins, which share the C-terminal dipeptide RF-NH2 with NPFF, might activate the NPFF2R, as has previously been shown for two related peptides, prolactin-releasing peptide and RF-amide-related peptide. Using two-electrode voltage clamp of Xenopus oocytes, we found that 100 nM NPFF strongly activated the human NPFF2R expressed together with rat GIRK1/4 inward rectifier potassium channels, and that 100 nM hKisspeptin-13 and hKisspeptin-8 had about 25% relative efficacy to that of NPFF. The current response induced by hKisspeptin-13 was proportional to its concentration (1–500 nM). The corresponding mouse peptides resulted in low activation only. When hNPFF2R was expressed in Chinese hamster ovary (CHO) cells, NPFF and its stable analog (1DMe)Y8Fa induced guanosine 5′-(γ-35 Sthio)-triphosphate (GTP-γ-35 S) binding with EC50 values of 13±4 and 16±4 nM, respectively. hKisspeptin-13 induced the binding with an EC50 value of 110±50 nM, whereas mKisspeptin-13 induced very modestly activation with an EC50 value>2 μM. The results suggest that, besides regulation of reproduction, kisspeptins have a potential to mediate physiological effects on, for example autonomic regulation and nociception in man via the NPFF2R pathways.
Abstract A single administration of benzodiazepine-site ligands of the inhibitory GABAA receptors has been shown to lead to persistently potentiated AMPA receptor-mediated responses in dopaminergic ...neurons of the ventral tegmental area (VTA). This plasticity has been suggested to be a common property of different kinds of addictive drugs. We now wanted to test if the plasticity induced by diazepam would also affect behaviors elicited by other drugs of abuse. Activity and plasticity of the VTA dopaminergic neurons are known to be essential for the initiation and/or sensitization of the psychomotor responses to morphine and amphetamine. The effect of diazepam pre-treatment (a single dose of 5 mg/kg) was studied 24–72 h later in behaving C57BL/6J mice on locomotor activity induced by acute and repeated administration of morphine (5 mg/kg) and amphetamine (2.5 mg/kg). The pre-treatment attenuated the locomotor-activating effect of morphine. On the other hand, it reduced the amphetamine-induced locomotor sensitization in male mice in N-methyl- d -aspartate (NMDA) receptor-dependent manner. The acute amphetamine effect was not affected. The results indicate that benzodiazepine-induced neural plasticity transiently reduces the sensitivity to psychomotor stimulation by opioids and stimulants.
γ -Aminobutyric acid (GABA) type A receptors mediate fast inhibitory synaptic transmission and have been implicated in responses to sedative/hypnotic agents (including neuroactive steroids), anxiety, ...and learning and memory. Using gene targeting technology, we generated a strain of mice deficient in the δ subunit of the GABA type A receptors. In vivo testing of various behavioral responses revealed a strikingly selective attenuation of responses to neuroactive steroids, but not to other modulatory drugs. Electrophysiological recordings from hippocampal slices revealed a significantly faster miniature inhibitory postsynaptic current decay time in null mice, with no change in miniature inhibitory postsynaptic current amplitude or frequency. Learning and memory assessed with fear conditioning were normal. These results begin to illuminate the novel contributions of the δ subunit to GABA pharmacology and sedative/hypnotic responses and behavior and provide insights into the physiology of neurosteroids.
The loop diuretic furosemide is known to antagonize the function of γ‐aminobutyric acid type A (GABA
A
) receptors. The purpose of the present study was to examine the direct interaction of ...furosemide with the GABA
A
receptors by autoradiography and ligand binding studies with native rat and human receptors and with recombinant receptors composed of rat subunits.
Autoradiography with
35
S‐
t
‐butylbicyclophosphorothionate (
35
S‐TBPS) as a ligand indicated that furosemide (0.1–1 m
m
) reversed the 5 μ
m
GABA‐induced inhibition of binding only in the cerebellar granule cell layer of rat brain sections. In all other regions studied, notably also in the hippocampal and thalamic areas, furosemide failed to antagonize GABA. Furosemide 1 m
m
decreased
35
S‐TBPS binding only in a limited number of brain regions, but facilitation of the GABA‐inhibition of the binding was much more widespread.
In well‐washed rat cerebellar, but not cerebrocortical, membranes, furosemide enhanced the
35
S‐TBPS binding over basal level in the absence of added GABA. The GABA
A
antagonist, SR 95531, and the convulsant, Ro 5–4864, blocked this furosemide‐induced increase. Both interactions with the furosemide enhancement are likely to be allosteric, since furosemide affected the binding of
3
H‐SR 95531 and
3
H‐Ro 5–4864 identically in the cerebellar and cerebrocortical membranes. Maximal GABA‐antagonism induced by furosemide in cerebellar membranes was further increased by SR 95531 but not by Ro 5–4864, indicating additive antagonism only for SR 95531. In human cerebellar receptors, only GABA antagonism by furosemide, but not the enhancement without added GABA, was observed.
In recombinant GABA
A
receptors, furosemide antagonism of GABA‐inhibition of
35
S‐TBPS binding depended only on the presence of α6 and β2/3 subunits, irrespective of the presence or absence of γ2 or δ subunits.
In α6β3γ2 receptors, clozapine reversed the enhancement of
35
S‐TBPS binding by furosemide in the absence of GABA. However, it failed to affect the GABA‐antagonism of furosemide, suggesting that the enhancement of basal binding and the GABA antagonism might represent two different allosteric actions of furosemide.
In conclusion, the present results indicate that furosemide is a subtype‐selective GABA
A
antagonist with a mode of action not shared by several other antagonists, which makes furosemide a unique compound for development of potential GABA
A
receptor subtype‐specific and ‐selective ligands.
British Journal of Pharmacology
(1997)
120
, 741–748; doi:
10.1038/sj.bjp.0700922
Medications used for the treatment of diseases also affect oral health. We investigated how having/not having periodontitis at baseline in 1985 was associated with purchases of medicines in the long ...term. The study paradigm is in the oral health-systemic health connections. We hypothesized that periodontitis links to purchases of medicines later in life. The study cohort consisted of 3,276 individuals from the greater Stockholm area, Sweden. Of them, 1,655 were clinically examined at baseline. Patients were followed-up for >35 years, using the national population and patient registers. The burden of systemic diseases and purchases of medicines were statistically analyzed comparing patients with (
= 285) and without (
= 1,370) periodontitis. The results showed that patients with periodontitis had purchased more of certain medications than non-periodontitis patients. Periodontitis patients purchased significantly more drugs used in diabetes (
= 0.035), calcium channel blockers (
= 0.016), drugs acting on the renin-angiotensin system (
= 0.024), and nervous system drugs (
= 0.001). Hence, patients with periodontitis indeed had purchased specific medications statistically significantly more than the periodontally healthy ones. This indicates that periodontitis, over time, might increase the risk for systemic diseases with the subsequent need for medication.
The nonsteroidal anti-inflammatory drug (NSAID) niflumic acid, a fenamate in structure, has many molecular targets, one of them being specific subtypes of the main inhibitory ligand-gated anion ...channel, the GABA
receptor. Here, we report on the effects of other fenamates and other classes of NSAIDs on brain picrotoxinin-sensitive GABA
receptors, using an autoradiographic assay with
STBPS as a ligand on mouse brain sections. We found that the other fenamates studied (flufenamic acid, meclofenamic acid, mefenamic acid and tolfenamic acid) affected the autoradiographic signal at low micromolar concentrations in a facilitatory-like allosteric fashion, i.e., without having affinity to the
STBPS binding site. Unlike niflumic acid that shows clear preference for inhibiting cerebellar granule cell layer GABA
receptors, the other fenamates showed little brain regional selectivity, indicating that their actions are not receptor-subtype selective. Of the non-fenamate NSAIDs studied at 100 μM concentration, diclofenac induced the greatest inhibition of the binding, which is not surprising as it has close structural similarity with the potent fenamate meclofenamic acid. Using two-electrode voltage-clamp assays on Xenopus oocytes, the effect of niflumic acid was found to be dependent on the β subunit variant and the presence of γ2 subunit in rat recombinant α1β and α1βγ2 GABA
receptors, with the β1 allowing the niflumic acid inhibition and β3 the stimulation of the receptor-mediated currents. In summary, the fenamate NSAIDs constitute an interesting class of compounds that could be used for development of potent GABA
receptor allosteric agonists with other targets to moderate inflammation, pain and associated anxiety/depression.
The gabapentinoid pregabalin is a rapid‐acting anxiolytic and analgesic, possibly suitable in supervised opioid detoxification. However, clinicians have been cautious in using it because of its ...unknown addictive risk and rising number of mortalities after pregabalin self‐medication in opioid abusers. Here, we studied interactions of pregabalin and morphine on reward functions of the dopamine system in mice and the efficacy of pregabalin on withdrawal in opioid addicts. After the treatment of mice with pregabalin and morphine, we used electrophysiology to study neuroplasticity in midbrain slices, self‐administration and conditioned place preference tests to investigate the rewarding potential of pregabalin and naloxone‐precipitated morphine withdrawal to evaluate opioid withdrawal symptoms. Further, we ran a pilot single‐blind, randomized, controlled trial (34 heroin addicts) to evaluate the efficacy and safety of pregabalin in the treatment of opioid withdrawal syndrome. Pregabalin alone did not induce glutamate receptor neuroplasticity of dopamine neurons in the ventral tegmental area, but pre‐treatment with pregabalin suppressed morphine‐induced neuroplasticity, hyperlocomotion and morphine self‐administration. Pregabalin administration after chronic morphine exposure failed to induce any rewarding effects. Instead, pregabalin suppressed withdrawal symptoms in both morphine‐treated mice and opioid addicts and was well tolerated. Intriguingly, pregabalin administration after a low dose of morphine strongly facilitated ventral tegmental area neuroplasticity and led to increased conditioned place preference. Pregabalin appears to have the efficacy to counteract both reinforcing and withdrawal effects of opioids, but it also has a potentiating effect when given to mice with existing opioid levels.
In this translational study, we investigated the interactions of pregabalin and morphine on reward functions of the dopamine system in mice and the efficacy of pregabalin on withdrawal in opioid addicts. In mice, acute pregabalin suppressed morphine‐induced long‐term potentiation in the dopamine neurons and withdrawal signs, but pregabalin after morphine administration facilitated this long‐term potentiation and rewarding behavior. Chronic experience of morphine in the past did not change the rewarding effects of pregabalin. In humans, pregabalin suppressed withdrawal signs and was well tolerated.
The cellular architecture of the ventral tegmental area (VTA), the main hub of the brain reward system, remains only partially characterized. To extend the characterization to inhibitory neurons, we ...have identified three distinct subtypes of somatostatin (Sst)-expressing neurons in the mouse VTA. These neurons differ in their electrophysiological and morphological properties, anatomical localization, as well as mRNA expression profiles. Importantly, similar to cortical Sst-containing interneurons, most VTA Sst neurons express GABAergic inhibitory markers, but some of them also express glutamatergic excitatory markers and a subpopulation even express dopaminergic markers. Furthermore, only some of the proposed marker genes for cortical Sst neurons were expressed in the VTA Sst neurons. Physiologically, one of the VTA Sst neuron subtypes locally inhibited neighboring dopamine neurons. Overall, our results demonstrate the remarkable complexity and heterogeneity of VTA Sst neurons and suggest that these cells are multifunctional players in the midbrain reward circuitry.
PDF
