Methamphetamine blocks exercise effects on Bdnf and Drd2 gene expression in frontal cortex and striatum

Abstract

Exposure to drugs of abuse can produce many neurobiological changes which may lead to increased valuation of rewards and decreased sensitivity to their costs. Many of these behavioral alterations are associated with activity of D2-expressing medium spiny neurons in the striatum. Additionally, Bdnf in the striatum has been shown to play a role in flexible reward-seeking behavior. Given that voluntary aerobic exercise can affect the expression of these proteins in healthy subjects, and that exercise has shown promise as an anti-addictive therapy, we set out to quantify changes in D2 and Bdnf expression in methamphetamine-exposed rats given access to running wheels. Sixty-four rats were treated for two weeks with an escalating dose of methamphetamine or saline, then either sacrificed, housed in standard cages, or given free access to a running wheel for 6 weeks prior to sacrifice. Rats treated with methamphetamine ran significantly greater distances than saline-treated rats, suggesting an augmentation in the reinforcement value of voluntary wheel running. Transcription of Drd2 and Bdnf was assessed via RT-qPCR. Protein expression levels of D2 and phosphorylation of the TrkB receptor were measured via western blot. Drd2 and Bdnf mRNA levels were impacted independently by exercise and methamphetamine, but exposure to methamphetamine prior to the initiation of exercise blocked the exercise-induced changes seen in rats treated with saline. Expression levels of both proteins were elevated immediately after methamphetamine, but returned to baseline after six weeks, regardless of exercise status.

Steep effort discounting of a preferred reward over a freely-available option in prolonged methamphetamine withdrawal in male rats

“…Rats were pretreated with d -methamphetamine hydrochloride (Sigma, St. Louis, MO), using a subchronic escalating regimen (Thompson et al 2015) that is known to protect DA systems from neurotoxicity following subsequent binge exposures (Segal et al 2003). In experiment 1, rats were given three daily injections (separated by 3.25 h) of methamphetamine (“mAMPH”, n = 11; 0.1–6.0 mg free base/kg, s.c., escalating in 0.1 mg/kg increments up to 2.1 mg/kg, then in 0.2 mg/kg increments from 2.1 mg/kg to 6.0 mg/kg) or physiological saline solution (“SAL”, n = 12; 1 ml/kg, s.c.) for 2 weeks.…”

“…We have previously reported that rats, when assessed after acute methamphetamine withdrawal, are more willing to expend effort for valued natural rewards such as food and exercise (Stolyarova et al 2015; Thompson et al 2015). Similarly, rats exposed to and withdrawn from a variety of drugs, including the psychostimulants amphetamine, MDMA, and cocaine, show increased lever pressing behavior for sucrose pellets in a progressive ratio task relative to saline-treated animals (Olausson et al 2006).…”

The neural basis of reversal learning: An updated perspective

“…Experience with reward events may calibrate the impact of subsequent events on D2 receptor signaling; events that may be negative or suboptimal by comparison, as in the case of acute drug-withdrawal (Thompson et al, 2015a). More generally, this role is consistent with the idea that dopamine tone scales the performance of previously learned behavior and that poor reward conditions, as experienced in early reversal learning, are characterized by weaker dopamine signaling, co-occurring with D2 receptor activation (Cagniard et al, 2006, Calabresi et al, 2007).…”

The neurobiological mechanisms of physical exercise in methamphetamine addiction

“…However, prior exercise in running wheels provided no protection against METH‐induced damage to striatal DA terminals in male rats . Changes in BDNF levels are also associated to reward‐seeking behavior . Hilburn et al newly found that serum BDNF levels in METH‐dependent humans were related to the number of abstinent days since last abuse, but not related to craving and substance use history.…”

“…Voluntary aerobic exercise (wheel running) increases BDNF exon IV transcription in rat hippocampus . However, METH exposure prior to initiation of aerobic exercise (6 weeks of voluntary wheel running) prevented the increases in both cortical and striatal BDNF seen in saline‐treated animals that exercised . The impact of physical exercise on BDNF levels in METH addicts warrants further evaluation because it was recently demonstrated that patients with serum BDNF levels ≤1251.0 pg/mL had higher risk of depression symptoms during METH withdrawal .…”