Figure 1.

K_ATP channels found within the cell membrane of both pre- and postsynaptic neurons of the substantia nigra (SNr) and ventral tegumental area (VTA), as well as other brain regions. In the SNr and VTA, the majority of K_ATP neurons are dopaminergic and exert GABAergic inhibition on their postsynaptic targets. (a) Within these cells, under normal physiological conditions, K_ATP channels are closed and ligand-gated calcium channels are free to open allowing hypopolarisation of the cell membrane and tonic excitation. Connexin channels (Cx) are also open allowing for exchange of ions, metabolites, and second messengers to enable appropriate electrical coupling. (b) Under conditions of metabolic stress or hypoxia, ATP depletion causes K_ATP channels to open and Ca⁺ channels to close, hyperpolarising the cell membrane and conferring neuroprotective proprieties by inhibiting neuronal excitation. Inhibition of target cells is diminished due to reduction in GABA release, stimulating hypopolarisation in postsynaptic targets. Connexin channels are hypothesised to remain open under these conditions. (c) In the presence of low concentrations of mefloquine, K-ATP channels are inhibited and remain open in the absence of metabolic stress, causing potassium efflux from the cell and increased transport of sodium into the cell through this open cation pore. This sodium influx causes an initial hypopolarisation, increasing tonic firing and initially enhancing presynaptic GABA release. Increased activity of Na⁺ K⁺-ATPase transmembrane channels increases metabolic stress, ensuring that K_ATP channels remain open. GABA release is, initially, further enhanced by inhibition of cholinesterase (ChE) which results in accumulation of endogenous acetylcholine (ACh) in the presynaptic terminal. Continued exposure is likely to result in intracellular ATP depletion, and finally GABA depression, resulting in a loss of postsynaptic inhibition. In addition, mefloquine (Mf) blocks connexin channel transport, further dysregulating intra- and intercellular excitability, giving rise to additional neuropsychiatric symptoms such as focal cortical or limbic seizures. (d) Exposure to high levels of mefloquine, or continued long-term exposure, would result in complete inhibition of K_ATP channel closure, continued connexin channel blockade, and permanent dysregulation of postsynaptic inhibition by presynaptic GABAergic inhibition as well as exerting significant neuronal metabolic stress, finally resulting in metabolic cell death in the basal neuron and potentiating excitotoxic cell death target neurons in other brain regions. Adapted from Liss and Roeper [140].