Involvement of Dopamine Receptors in Binge Methamphetamine-Induced Activation of Endoplasmic Reticulum and Mitochondrial Stress Pathways

Abstract

Single large doses of methamphetamine (METH) cause endoplasmic reticulum (ER) stress and mitochondrial dysfunctions in rodent striata. The dopamine D1 receptor appears to be involved in these METH-mediated stresses. The purpose of this study was to investigate if dopamine D1 and D2 receptors are involved in ER and mitochondrial stresses caused by single-day METH binges in the rat striatum. Male Sprague-Dawley rats received 4 injections of 10 mg/kg of METH alone or in combination with a putative D1 or D2 receptor antagonist, SCH23390 or raclopride, respectively, given 30 min prior to each METH injection. Rats were euthanized at various timepoints afterwards. Striatal tissues were used in quantitative RT-PCR and western blot analyses. We found that binge METH injections caused increased expression of the pro-survival genes, BiP/GRP-78 and P58IPK, in a SCH23390-sensitive manner. METH also caused up-regulation of ER-stress genes, Atf2, Atf3, Atf4, CHOP/Gadd153 and Gadd34. The expression of heat shock proteins (HSPs) was increased after METH injections. SCH23390 completely blocked induction in all analyzed ER stress-related proteins that included ATF3, ATF4, CHOP/Gadd153, HSPs and caspase-12. The dopamine D2-like antagonist, raclopride, exerted small to moderate inhibitory influence on some METH-induced changes in ER stress proteins. Importantly, METH caused decreases in the mitochondrial anti-apoptotic protein, Bcl-2, but increases in the pro-apoptotic proteins, Bax, Bad and cytochrome c, in a SCH23390-sensitive fashion. In contrast, raclopride provided only small inhibition of METH-induced changes in mitochondrial proteins. These findings indicate that METH-induced activation of striatal ER and mitochondrial stress pathways might be more related to activation of SCH23390-sensitive receptors.

The TNF-α/Nf-κB Signaling Pathway has a Key Role in Methamphetamine–Induced Blood–Brain Barrier Dysfunction

“…9,23 Additionally, this binge protocol has been widely used in animal studies and is well characterized by striatal toxicity. 42 However, little is known about the effect of this METH regimen on BBB function. Nevertheless, Urrutia et al 10 showed that a similar METH binge protocol (3 × 4 mg/kg) induced BBB disruption in mouse striatum at 1, 12, and 24 hours after METH treatment, observed by extravasation of Immunoglobulin G (150 kDa).…”

Single and Binge Methamphetamine Administrations Have Different Effects on the Levels of Dopamine D2 Autoreceptor and Dopamine Transporter in Rat Striatum

“…This was an expected result, as METH neurotoxicity occurs after regimens that result in a relatively long presence of METH in the brain, such as multiple injections of the drug (4 × 5–10 mg/kg) or a massive single dose of METH (30–60 mg/kg) [11]. Binge and massive single doses of METH induce hyperthermia that lasts longer than 4 h [40,41]; therefore, our data suggest that short-lasting hyperthermia does not lead to neurotoxicity to DAergic terminals.…”

Amphetamine-related drugs neurotoxicity in humans and in experimental animals: Main mechanisms

“…At the molecular level, D 1 -like receptors blockade decreasesDA-induced oxidation and cytotoxicity mediatedby the activation of extracellular-signalregulated kinase (ERK) and c-Jun N-terminal kinases (JNK) (Chen et al, 2004). In addition,SCH-23390 completely blocked METH-induced expression of endoplasmic reticulum stress-related proteins (ATF3, ATF4, CHOP/Gadd153, HSPs and caspase 12), inhibitedMETH-induced increase in pro-survival genes in response to endoplasmic reticulum stress (includingBIP/GRP-78 and P58IPK) and increased expression of the mitochondrial anti-apoptotic protein Bcl-2 in the striatum (Beauvais et al, 2011). However, as SCH-23390 does not distinguish between D 1 andD 5 receptors (Moratalla et al, 1996b) and, as mentioned above, interacs with 5-HT receptors (Kvernmo et al, 2006), it was not clear exactly which receptor subtypes were involved in METH-induced neurotoxicity.…”