γ-Hydroxybutyrate (GHB) induces GABAB receptor independent intracellular Ca2+ transients in astrocytes, but has no effect on GHB or GABAB receptors of medium spiny neurons in the nucleus accumbens

The Neurobiological Mechanisms of Gamma-Hydroxybutyrate Dependence and Withdrawal and Their Clinical Relevance: A Review

“…GHB does not lack a direct effect on the GABAergic neurons and glutamatergic pathways in the NAc, but it reduces the activity of the NAc through an indirect pathway producing cortical and limbic inputs outside the NAc. GHB is suggested to cause an elevation of the astrocytic Ca 2+ -dependent neuronal signals within the NAc, which explains the rapid rewarding effect of GHB [62]. Several factors contribute to the potential GHB dependence liability, for instance the self-medication role in sleep regulation, the high rewarding euphoric state, and the anxiolytic and depression-modulating effect.…”

“…GHB in nano- to micromolar concentrations [58] exerts effects via the GHBR high-affinity site, and is suggested to be counteracted by the GHBR antagonist NCS-382 [56]. Some studies have stated, in contrast, that pretreatment with NCS-382 potentiated, rather than antagonized, a GHB-induced sedative hypnotic effect [59], which was offset by others who questioned the antagonistic properties of NCS-382 on GHBR since it failed to block the effect of GHB on hypomotility and sedation/hypnosis [60,61,62]. The involvement of GHBR was confirmed when the specific GHBR agonist c-hydroxyvaleric acid was proved to mimic the sedative effects of GHB without binding to the GABA B R [58,63].…”

“…GHB shares with other drugs of abuse the ability to reduce the excitability of the NAc neurons, which contribute to its abuse potential [55,81]. Conversely, GHB differs as it has no direct GABA B R-mediated effect on the medium spiny neurons of the NAc, as stated by Molnár et al [62]. Thus, the reduced activity of NAc observed after systemic GHB administration [81] is related to an indirect effect of the cortical and limbic inputs outside the NAc.…”

“…There, GHB activates post- and presynaptic GABA B Rs, hence hyperpolarizing cells and decreasing their glutamate-mediated synaptic responses [108], and then merging into the NAc and increasing the release of dopamine into the reward-mediating NAc area [85]. This is in addition to a GHB main cellular effect in the NAc, executed via a repetitive transient elevation of astrocytic Ca 2+ -independent neuronal signalling [62,109]. This in turn leads to neuronal hyperpolarization and suppresses baseline excitatory synaptic activity [110], a reaction which has been proven to be mediated by a putative novel GHB agonist-specific and succinate-sensitive but NCS-382-insensitive receptor in the astrocytic target [109].…”

“…This in turn leads to neuronal hyperpolarization and suppresses baseline excitatory synaptic activity [110], a reaction which has been proven to be mediated by a putative novel GHB agonist-specific and succinate-sensitive but NCS-382-insensitive receptor in the astrocytic target [109]. This ability of GHB achieved at a lower dose than the concentration necessary to activate GABA B R [55,62] is a powerful means for the rapid modulation of network activity, which can explain the rapid process and intense reward dependence effect of GHB.…”