Tonic GABAergic inhibition as a new way to regulate mesolimbic dopamine system

Dopamine (DA) neurons of the ventral tegmental area (VTA) are critical for decision-making and motivation and have also been implicated in the development of addictive behaviors. The activity of these neurons and the subsequent changes in DA concentrations in the target regions of the VTA are strictly regulated by both excitatory and inhibitory inputs. Among those inhibitory inputs, GABAergic transmission is mediated by phasic and tonic currents generated through different GABAA receptor subtypes. Although the phasic currents arising through the activation of synaptic GABAA receptors have been well described, much less is known about extrasynaptic GABAA receptors mediating tonic currents and modulating neuronal activity in the VTA. Here, pharmacologically selective receptor modulators, transgenic mouse models and brain slice electrophysiology were all exploited to probe the role of extrasynaptic GABAA receptors in mediating neuroplasticity in VTA DA neurons. Even though they possess distinct molecular sites of action, gaboxadol (THIP) and ganaxalone (GAN) enhanced tonic inhibition by selective targeting of the extrasynaptic δ subunit-containing GABAA receptors located on VTA GABA neurons. The tonic inhibition induced in these neurons appeared to be sufficient to disinhibit DA neurons and induce persistent neuroplasticity in the glutamate synapses on VTA DA neurons, which resulted from insertion of new GluA2 subunit-lacking AMPA receptors into the synapses. Screening of reward-related behaviors associated with VTA DA activity revealed that THIP failed to induce any reinforcement during self-administration either in mice or baboons. Moreover, both THIP and GAN produced conditioned place aversion in mice. The study performed in δ subunit-knockout mice further supported the proposal that tonic inhibition of the VTA GABA neurons contributes to conditioned aversive behavior and THIP- and GAN-induced neuroplasticity. The c-Fos mapping of brain regions, which could take part in THIP-induced aversive behavioral effects and/or neuroplasticity on VTA DA neurons, revealed the bed nucleus of stria terminalis (BNST), a part of the so-called extended amygdala circuitry, as a possible participant in mediating the aforementioned THIP-induced aversive effects. In summary, these studies demonstrate that tonic inhibition mediated by δ subunit-containing GABAA receptors appears to be a significant component of the inhibition in the VTA, and thus important for the control of motivated behavior.Ei saatavill

GABAA receptor drugs and neuronal plasticity in reward and aversion: focus on the ventral tegmental area.

Peer reviewe

Addiction-related interactions of pregabalin with morphine in mice and humans : reinforcing and inhibiting effects

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.Peer reviewe

GABAA receptor subtype involvement in addictive behaviour

GABAA receptors form the major class of inhibitory neurotransmitter receptors in the mammalian brain. This review sets out to summarise the evidence that variations in genes encoding GABAA receptor isoforms are associated with aspects of addictive behaviour in humans, while animal models of addictive behaviour also implicate certain subtypes of GABAA receptor. In addition to outlining the evidence for the involvement of specific subtypes in addiction, we summarise the particular contributions of these isoforms in control over the functioning of brain circuits, especially the mesolimbic system, and make a first attempt to bring together evidence from several fields to understanding potential involvement of GABAA Receptor Subtypes in addictive behaviour. While the weight of the published literature is on alcohol dependency, the underlying principles outlined are relevant across a number of different aspects of addictive behaviour

Conditioned Reward of Opioids, but not Psychostimulants, is Impaired in GABA-A Receptor δ Subunit Knockout Mice

Johdanto: Gamma-aminovoihappo (GABA) on aivojen yleinen inhibitorinen välittäjäaine. A-tyypin GABA-reseptorit (GABAAR) ovat inotrooppisia ja koostuvat useista eri alayksiköistä. Hermoliitoksien ulkopuolella olevat GABAA-reseptorit sisältävät yleensä δ-alayksikön, joka on kohde muun muassa neuroaktiivisille steroideille. Näitä hermoliitoksen ulkopuolisia GABAA-reseptoreita on havaittu muiden alueiden ohella muun muassa ventraalisessa tegmentumissa (VTA), jossa ne säätelevät välillisesti alueella olevia mesokortikolimbisiä dopamiiniratoja. Näiden ratojen projektiot accumbens-tumakkeeseen ovat tärkeässä asemassa palkkiokäyttäytymisessä ja riippuvuuksien synnyssä. VTA:n hermoliitosten ulkopuolisten GABAA-reseptorien aktivaatio esimerkiksi neuroaktiivisella steroidilla, ganaksolonilla, ja GABA-kohdan aktivaattorilla, gaboksadolilla, aiheuttaa koe-eläinmalleissa välttämiskäyttäytymistä. Vastaavaa välttämiskäyttäytymistä ei synny, mikäli δ-alayksikön sisältävät GABAAR on geneettisesti poistettu. Muiden lääke- ja huumausaineiden kohdalla ei tällä hetkellä tiedetä, miten vähentynyt hermoliitoksen ulkopuolinen inhibitio vaikuttaa alueiden toimintaan. Materiaalit ja menetelmät: Tutkimusasetelmassa käytimme koe-eläinmallia, josta δ-alayksikkö oli poistettu (δ-KO). Käytimme ehdollistettua paikka -testiä määrittääksemme morfiinin, metamfetamiinin ja mefedronin palkitsevuutta. Lisäksi tutkimme morfiinin vaikutusta kivuntuntemukseen käyttäen hännänkohotuskoetta ja kuuma levy -koetta. Tulokset: Huomasimme, että δ-KO hiirillä ei synny morfiinin aiheuttamaa ehdollistumista paikkaan, mutta toisaalta nämä hiiret ovat herkempiä morfiinin aiheuttamalle kivunlievitykselle hännänkohotustestissä. Stimulanttien kohdalla emme havainneet, että δ-alayksikön puute aiheuttaisi erilaista ehdollistumisvastetta. Diskussio: Lisätutkimukset ovat tarpeellisia, jotta voidaan tutkia, voisiko δ-GABAA-reseptoriantagonisteilla olla suotuisia vaikutuksia morfiinin palkitsevuuden vähentämisessä ja samalla kivunlievityksen tehostamisessa

Akt inhibitor MK2206 prevents influenza pH1N1 virus infection in vitro

The influenza pH1N1 virus caused a global flu pandemic in 2009 and continues manifestation as a seasonal virus. Better understanding of the virus-host cell interaction could result in development of better prevention and treatment options. Here we show that the Akt inhibitor MK2206 blocks influenza pH1N1 virus infection in vitro. In particular, at noncytotoxic concentrations, MK2206 alters Akt signaling and inhibits endocytic uptake of the virus. Interestingly, MK2206 is unable to inhibit H3N2, H7N9, and H5N1 viruses, indicating that pH1N1 evolved specific requirements for efficient infection. Thus, Akt signaling could be exploited further for development of better therapeutics against pH1N1 virus