Dopamine Receptors and the Persistent Neurovascular Dysregulation Induced by Methamphetamine Self-Administration in Rats

Abstract

Recently abstinent methamphetamine (Meth) abusers showed neurovascular dysregulation within the striatum. The factors that contribute to this dysregulation and the persistence of these effects are unclear. The current study addressed these knowledge gaps. First, we evaluated the brains of rats with a history of Meth selfadministration following various periods of forced abstinence. Micro-computed tomography revealed a marked reduction in vessel diameter and vascular volume uniquely within the striatum between 1 and 28 days after Meth self-administration. Microvessels showed a greater impairment than larger vessels. Subsequently, we determined that dopamine (DA) D2 receptors regulated Meth-induced striatal vasoconstriction via acute noncontingent administration of Meth. These receptors likely regulated the response to striatal hypoxia, as hypoxia inducible factor 1a was elevated. Acute Meth exposure also increased striatal levels of endothelin receptor A and decreased neuronal nitric oxide synthase. Collectively, the data provide novel evidence that Meth-induced striatal neurovascular dysregulation involves DA receptor signaling that results in vasoconstriction via endothelin receptor A and nitric oxide signaling. As these effects can lead to hypoxia and trigger neuronal damage, these findings provide a mechanistic explanation for the selective striatal toxicity observed in the brains of Meth-abusing humans.

Methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxypyrovalerone (MDPV) induce differential cytotoxic effects in bovine brain microvessel endothelial cells

“…However, different studies have reported that METH, MDMA, and MDPV all induce similar effects on the vasculature [41-45]. For instance, in association with NO signaling [17] METH induces cerebral blood vessel vasoconstriction [42] and a reduction in cerebral blood flow [43] . MDMA induces coronary [45] and peripheral [46] vasoconstriction, whereas MDPV also induces peripheral [41] and integumentary vasoconstriction, as well as an increase in brain temperature, effects that suggest vasoconstriction of cerebral blood vessels [44].…”

Cerebrovascular Injury After Serial Exposure to Chronic Stress and Abstinence from Methamphetamine Self-Administration

“…Therefore, the less severe stress exposure employed in the current study could explain why stress did not alter Meth self-administration. Additionally, the absence of stress induced potentiation of Meth self-administration could be due to the unrestricted access to Meth that was allowed in this study compared to other studies where the duration of access to the drug is limited each day 34 , 35 . The lack of drug availability during the time the animal is not in the operant chamber could trigger withdrawal-associated processes that promote craving and increase drug administration in the stressed group 36 .…”

Traumatic brain injury and methamphetamine: A double-hit neurological insult

“…Dopaminergic neurons cause vasomotor changes in brain microvasculature [74]. In METH users, dopamine receptor activation largely accounts for cerebral vasoconstriction [75], with a marked reduction in regional blood flow in the insular cortex [76,77]. A decrease in striatal and cortical perfusion is maintained in abstinent users [57,78].…”