Glycine blocks long-term potentiation of GABAergic synapses in the ventral tegmental area

Abstract

The mesocorticolimbic dopamine system, originating in the ventral tegmental area (VTA) are normally constrained by GABA-mediated synaptic inhibition. Accumulating evidence indicates that long-term potentiation of GABAergic synapses (LTPGABA) in VTA dopamine neurons plays an important role in the actions of drugs of abuse, including ethanol. We previously showed that a single infusion of glycine into the VTA of rats strongly reduces ethanol intake for 24 hours. In the current study, we examined the effect of glycine on the electrophysiological activities of putative dopamine VTA neurons in midbrain slices from ethanol-naïve rats. We report here that a 15 min exposure to 10 μM glycine prevented trains of high frequency stimulation from producing LTPGABA, which was rescued by the glycine receptor antagonist strychnine. Glycine also concentration-dependently decreased the frequency of spontaneous excitatory postsynaptic currents. By contrast, glycine pretreatment did not prevent potentiation of inhibitory postsynaptic currents during a continuous exposure to the nitric oxide donor, SNAP (S-nitroso-N-acetylpenicillamine), or a brief exposure to 10 μM glycine and 10 μM NMDA (N-methyl-D-aspartate), an agonist of NMDA-type glutamate receptors. Thus, the blockade of LTPGABA by glycine is probably resulted from suppressing glutamate release by activating the glycine receptors on the glutamatergic terminals. This effect of glycine may contribute to the reduction in ethanol intake induced by intra-VTA glycine observed in vivo.

Therapeutic Potential of Nonpsychoactive Cannabinoids by Targeting at Glycine Receptors

“…Finally, this idea is consistent with microscopic observation that the GlyRs at presynaptic terminals of calyceal synapses are composed of homomeric α1 subunits [23]. The presynaptic GlyRs have been the interest of recent research because they disinhibit GABAmediated synaptic inhibition of VTA dopaminergic neurons [20,34]. There is evidence suggesting that these receptors are involved in the reward mechanism of drugs of abuse [34].…”

“…Several lines of studies have provided consistent evidence to suggest that GlyRs are one primary target that mediates alcohol-induced behaviors in the brain [61][62][63][64][65]. Activation of VTA GlyRs reduces GABAergic transmission and increases the activity of dopaminergic neurons originated from VTA [20,34]. GlyRs in the nAc are involved in modulating both basal-and ethanol-induced dopamine output in the same brain region as local injection of strychnine can inhibit ethanol-induced DA release in nAc [48,66].…”

“…The presynaptic GlyRs have been the interest of recent research because they disinhibit GABAmediated synaptic inhibition of VTA dopaminergic neurons [20,34]. There is evidence suggesting that these receptors are involved in the reward mechanism of drugs of abuse [34].…”

The Glycine Receptor—A Functionally Important Primary Brain Target of Ethanol

“…Moreover, the effect was prevented by co‐application of strychnine. Further studies have suggested that this effect involves alterations in neuronal plasticity at GABA synapses (Guan and Ye, ).…”

Could GABA, with a side of glycine, control glutamate receptors?

“…For example, glycine can produce a biphasic modulation of the NO‐NMDAR pathway in the cerebellum, whereby low glycine concentration inhibits NO production and high glycine enhances it (Cabrera‐Pastor et al ., ). Within the VTA, glycine disrupts LTP GABA , although the authors attribute the effect to glycinergic receptors, owing to its sensitivity to strychnine (Guan & Ye, ). As a result, depending on the reach beyond the synapse, RMTg‐derived glycine might act cooperatively at NMDARs to modulate NO and its initiating role in LTP GABA .…”