Chronic Methamphetamine Effects on Brain Structure and Function in Rats

Abstract

Methamphetamine (MA) addiction is a growing epidemic worldwide. Chronic MA use has been shown to lead to neurotoxicity in rodents and humans. Magnetic resonance imaging (MRI) studies in MA users have shown enlarged striatal volumes and positron emission tomography (PET) studies have shown decreased brain glucose metabolism (BGluM) in the striatum of detoxified MA users. The present study examines structural changes of the brain, observes microglial activation, and assesses changes in brain function, in response to chronic MA treatment. Rats were randomly split into three distinct treatment groups and treated daily for four months, via i.p. injection, with saline (controls), or low dose (LD) MA (4 mg/kg), or high dose (HD) MA (8 mg/kg). Sixteen weeks into the treatment period, rats were injected with a glucose analog, [18F] fluorodeoxyglucose (FDG), and their brains were scanned with micro-PET to assess regional BGluM. At the end of MA treatment, magnetic resonance imaging at 21T was performed on perfused rats to determine regional brain volume and in vitro [3H]PK 11195 autoradiography was performed on fresh-frozen brain tissue to measure microglia activation. When compared with controls, chronic HD MA-treated rats had enlarged striatal volumes and increases in [3H]PK 11195 binding in striatum, the nucleus accumbens, frontal cortical areas, the rhinal cortices, and the cerebellar nuclei. FDG microPET imaging showed that LD MA-treated rats had higher BGluM in insular and somatosensory cortices, face sensory nucleus of the thalamus, and brainstem reticular formation, while HD MA-treated rats had higher BGluM in primary and higher order somatosensory and the retrosplenial cortices, compared with controls. HD and LD MA-treated rats had lower BGluM in the tail of the striatum, rhinal cortex, and subiculum and HD MA also had lower BGluM in hippocampus than controls. These results corroborate clinical findings and help further examine the mechanisms behind MA-induced neurotoxicity.

Increased expression of proenkephalin and prodynorphin mRNAs in the nucleus accumbens of compulsive methamphetamine taking rats

“…The inability to quit taking methamphetamine is probably related to persistent neuroadaptive changes in brain regions thought to be responsible for rewarding effects of drugs and cognitive processes that regulate habitual behaviors23. These neuroadaptations are thought to include altered synaptic plasticity, transcriptional alterations, and epigenetic changes in mesostriatal and mesocorticolimbic projection areas such as the nucleus accumbens (NAc)456.…”

Chronic oral methylphenidate treatment increases microglial activation in rats

“…Previously, we found that chronic MP, provided at doses that mimic the pharmacokinetic profile of treated patients, results in a myriad of effects on physiology (including skeletal development) (Komatsu et al 2012; Uddin et al 2018; Robison et al 2017b; Thanos et al 2015), behavior (Robison et al 2017b;Thanos et al 2015), and neurochemistry (Robison et al 2017a) in normal rats, with some effects persisting beyond the end of treatment. There is a concerning gap in knowledge, however, as to whether chronic MP treatment could result in significant brain inflammation, as has been shown following chronic administration of related psychostimulants (Cadet et al 2005; Thanos et al 2016a). …”

“…Due to an increase in cytokines and chemokines, excess dopamine has been shown to induce an inflammatory response in the brain, which could lead to an induction of microgliosis (Jang et al 2012). Therefore, one possible consequence of MP treatment that has not been fully explored is its ability to trigger inflammatory and neurodegenerative processes, as has been shown to result from chronic administration of related psychostimulants (Gonçalves et al 2010;Thanos et al 2016a;Cubells et al 1994; Cadet et al 2005). …”

Neurotoxic Doses of Chronic Methamphetamine Trigger Retrotransposition of the Identifier Element in Rat Dorsal Dentate Gyrus

“…METH is a widely-abused central nervous system (CNS) psychostimulant, which reduces hippocampal volume and induces apoptosis in the hippocampus in experimental animals and humans, particularly when administered at high doses [22,23,24,25,26]. METH also affects adult neurogenesis in the hippocampus [22,27,28].…”