Adenosine and ATP-sensitive potassium channels modulate dopamine release in the anoxic turtle (Trachemys scripta) striatum

Abstract

Excessive dopamine (DA) is known to cause hypoxic/ischemic damage to mammalian brain. The freshwater turtle Trachemys scripta, however, maintains basal striatal DA levels in anoxia. We investigated DA balance during early anoxia when energy status in the turtle brain is compromised. The roles of ATP-sensitive potassium (K(ATP)) channels and adenosine (AD) receptors were investigated as these factors affect DA balance in mammalian neurons. Striatal extracellular DA was determined by microdialysis with HPLC in the presence or absence of the specific DA transport blocker GBR-12909, the K(ATP) blocker 2,3-butanedione monoxime, or the nonspecific AD receptor blocker theophylline. We found that in contrast to long-term anoxia, blocking DA reuptake did not significantly increase extracellular levels in 1-h anoxic turtles. Low DA levels in early anoxia were maintained instead by activation of K(ATP) channels and AD receptors. Blocking K(ATP) resulted in a 227% increase in extracellular DA in 1-h anoxic turtles but had no effect after 4 h of anoxia. Similarly, blocking AD receptors increased DA during the first hour of anoxia but did not change DA levels at 4-h anoxia. Support for the role of K(ATP) channels in DA balance comes from normoxic animals treated with K(ATP) opener; infusing diazoxide but not adenosine into the normoxic turtle striatum resulted in an immediate DA decrease to 14% of basal values within 1.5 h. Alternative strategies to maintain low extracellular levels may prevent catastrophic DA increases when intracellular energy is compromised while permitting the turtle to maintain a functional neuronal network during long-term anoxia.

Controlling anoxic tolerance in adult Drosophila via the cGMP–PKG pathway

“…Facultative anaerobes are evolutionarily adapted to withstand long periods without oxygen; anoxia survival tolerance of at least several hours has been established in the fruit fly D. melanogaster (Wingrove and O'Farrell, 1999;Haddad, 2006) while some turtles can withstand anoxia for days to months (Ultsch, 2006). These anoxia-tolerant organisms, in contrast to mammalian systems, enter a state of deep reversible hypometabolism, thereby losing neural function but maintaining a balance between energy requirements and supply by suppressing energy-demanding functions, including the release of excitatory neurotransmitters (Milton et al, 2002;Milton and Lutz, 2005) and ion flux (Sick et al, 1982;Perez-Pinzon et al, 1992;Bickler et al, 2000), which together suppress electrical activity (Fernandes et al, 1997;Gu and Haddad, 1999). Anoxia tolerance then permits survival of extended anoxia without neuronal deficit (Haddad, 2006;Kesaraju et al, 2009).…”

No oxygen? No problem! Intrinsic brain tolerance to hypoxia in vertebrates

“…However, NMDA-receptor (NMDAR)-dependent excitotoxicity is also suppressed by δ-opioid receptors (Pamenter and Buck, 2008) which exist at surprisingly high density in the turtle brain (Xia and Haddad, 2001), and aid resistance to glutamate and hypoxic stress in mammals (Zhang et al, 2000). AMPA receptor currents, meanwhile, are also reduced by activation of mitochondrial ATP-dependent K + channels (Zivkovic and Buck, 2010), which in turn also reduce glutamate and dopamine release in early anoxia (Milton and Lutz, 2005;Milton et al, 2002). In longer anoxic exposures, glutamate release is suppressed by adenosine and GABA (Thompson et al, 2007).…”

“…In longer anoxic exposures, glutamate release is suppressed by adenosine and GABA (Thompson et al, 2007). Adenosine in turn affects channel arrest (Pék and Lutz, 1997;Pérez-Pinzón et al, 1993), dopamine release (Milton and Lutz, 2005;Milton et al, 2002), NMDAR currents (Buck and Bickler, 1998) and cerebral blood flow (Hylland et al, 1994). …”

Alleviating Brain Stress: What Alternative Animal Models Have Revealed About Therapeutic Targets For Hypoxia and Anoxia

“…The 52% decrease in anoxic AMPA receptor currents, for example, is abolished by mitochondial K ATP (mK ATP ) antagonists [31], as is the 50% decrease in anoxic NMDAR currents [32]. The reduced efflux of K + in early anoxia is also mediated in part by the opening of K ATP channels [33], and blocking K ATP together with adenosine receptor blockade increases both Glu and DA release in the early anoxic turtle brain [26,27]. As ATP demand is suppressed to meet reduced energy delivery, however, ATP levels return to basal, K ATP channels close and other mechanisms function to maintain reduced brain function, including the aforementioned GABA increases [34] and an upregulation of protective pathways.…”