Possible Interaction: Heroin and Gamma-Aminobutyric Acid

“Chemogenetic and optogenetic manipulations of VTA DA or GABA neurons establish a causal link to heroin reinforcement.”

“Likewise, heroin occluded the self-inhibition of VTA GABA neurons.”

“ Heroin also reduced IC-evoked post-stimulus spike discharges, a manifestation of gap-junction-mediated electrical coupling between VTA GABA neurons.”

“The baseline firing rate of VTA GABA neurons significantly increased (239%) following the acquisition of heroin self-administration behavior and transiently increased during each response for heroin (105%), but decreased (49%) following heroin, similar to non-contingent heroin.”

“Using cerebellar membranes, the corresponding IC50 values were 5.3 and 4.8 μM. These … effects were reversed by the potent GABAA receptor blocker R5135 (10 nM), suggesting that H and M allosterically increase the … of GABAA receptors for GABA and MUS by binding to … in GABAA receptor complexes.”

“Concentrations of the inhibitory amino acid GABA in ventral pallidal dialysates were significantly reduced within the first 10 min of heroin self‐administration (0.02 mg per infusion; FR‐1), and remained ≈ 65% of presession baseline levels for the remainder of the 3‐h self‐administration session.”

“Thus, heroin self‐administration is associated with both decreased GABA efflux and a late phase increase in glutamate efflux in the ventral pallidum.”

“ Heroin has been hypothesized to activate opiate receptors and inhibit γ‐aminobutyric acid ( GABA ) release from inhibitory GABAergic interneurons which, in turn, activates dopamine projection cells.”

“Taken together, these experiments, for the first time, demonstrate that pharmacological elevation of mesolimbic GABA concentration blocks heroin reinforcement by activating GABA(B) receptors, supporting the GABAergic hypothesis of opiate reinforcement and the incorporation of GABA agents in opiate abuse treatment.”

“These findings indicate that gamma-vinyl GABA can interfere with the synergistic effects produced by the combination of an indirect dopamine releaser ( heroin ) and a dopamine reuptake blocker (cocaine).”

“ Heroin elevates dopamine levels in forebrain by blocking inhibitory GABA interneurons near the ventral tegmental area, leading to activation of mesocorticolimbic dopaminergic neurons (Nakagawa 2008, Steidl 2011).”