Methamphetamine-Induced Brain Injury and Alcohol Drinking

Abstract

A majority of methamphetamine (Meth) abusers also abuse alcohol but the neurochemical consequences of this co-abuse are unknown. Individually, alcohol and Meth cause inflammation and long-term alterations in dopamine and serotonin signaling within the brain. Experiments were conducted to identify if serial exposure to alcohol and Meth has neurochemical consequences that are greater than after either drug alone. Male Sprague Dawley rats voluntarily drank 10% ethanol (EtOH) every other day for 4 weeks and were then exposed to a binge injection regimen of Meth (10 mg/kg injected every 2 h, for a total of 4 injections). EtOH drinking and preference increased over the 4 weeks and caused inflammation evidenced by increases in serum and brain lipopolysaccharide (LPS) and brain cyclooxygenase-2 (COX-2) 24 h after the last day of drinking. Meth alone depleted dopamine and serotonin in the striatum, as well as serotonin in the prefrontal cortex when measured 1 week later. In contrast, EtOH drinking alone did not affect dopamine and serotonin content in the striatum and prefrontal cortex, but prior EtOH drinking followed by injections of Meth enhanced Meth-induced depletions of dopamine, serotonin, as well as dopamine and serotonin transporter immunoreactivities in a manner that was correlated with the degree of EtOH consumption. Cyclooxygenase inhibition by ketoprofen during EtOH drinking blocked the increases in LPS and COX-2 and the enhanced decreases in dopamine and serotonin produced by Meth. Therefore, prior EtOH drinking causes an increase in inflammatory mediators that mediate a synergistic interaction with Meth to cause an enhanced neurotoxicity.

Serial exposure to ethanol drinking and methamphetamine enhances glutamate excitotoxicity

“…The current study expands upon previous findings by Blaker and Yamamoto () reporting a role for inflammation in the enhanced dopamine toxicity observed after the serial exposure to ethanol (EtOH)+Meth. Because inflammation may promote glutamate‐mediated excitotoxicity and contribute to neuronal damage after either drug alone, the current study investigated the role of glutamate signaling in mediating enhanced dopamine depletions after EtOH + Meth.…”

“…Rats increased EtOH intake over 28 days (Fig. 2) and despite consuming lower amounts than we have published (Blaker and Yamamoto, 2018), EtOH drinking resulted in decreased GLAST in the striatum at 24 h. In contrast, GLT-1 was unaffected by EtOH drinking (Fig. 3).…”

“…The proteolytic cleavage of spectrin results in breakdown products of different molecular weights and in the case of caspase‐3 activation, causes the cleavage of spectrin into a 120 kDa breakdown product (Pike et al ). The finding that the serial exposure to EtOH drinking and Meth‐induced increases in the appearance of a 120 kDa spectrin breakdown product suggests caspase‐3 mediated spectrin proteolysis as a consequence of the co‐exposure to EtOH and Meth and a contributor to the synergistic effects of EtOH and Meth on striatal dopamine depletions (Blaker and Yamamoto ). Although we did not observe caspase‐3‐mediated proteolysis with either EtOH drinking alone or Meth alone, EtOH‐induced neuron death and acute Meth‐induced spectrin proteolysis have previously been observed (Warren et al ; Staszewski and Yamamoto ; Warren et al ; Halpin et al ).…”

“…After the initial acclimation period, rats were individually housed in order to accurately measure 10% EtOH intake per rat. As described in Blaker and Yamamoto (), rats were allowed access to two bottles of water or access to one bottle of 10% EtOH and a second bottle of water every other day for a total period of 28 days, and ad libitum access to food. On the days without EtOH access, a second water bottle was placed on the cage permitting access to two bottles at all times.…”

“…A mechanism underlying the toxic effects of alcohol includes inflammation derived from the gastrointestinal (GI) tract, liver, and brain (Vall es et al 2004;Wang et al 2010;Massey and Arteel 2012;Bishehsari et al 2017;Leclercq et al 2017) whereas the neurotoxic effects of Meth are mediated by neuroinflammation and excitotoxicity (Stephans and Yamamoto 1994;Battaglia et al 2002;Mark et al 2004;Thomas and Kuhn 2005). Enhanced dopamine toxicity has been observed after the serial exposure to alcohol and Meth in the striatum that may be mediated by neuroinflammation via increases in cyclooxygenase-2 from alcohol drinking (Blaker and Yamamoto, 2018) but this requires further investigation. Although neuroinflammation can promote glutamate-mediated excitotoxicity that in turn, contributes to neuronal injury (Lawrence et al 1998;Stroemer and Rothwell 1998;Allan et al 2000;Ye et al 2013), the contribution of glutamate signaling to enhanced dopamine neurotoxicity after the serial exposure to alcohol and Meth is unknown.…”