The effects of cocaine on regional brain glucose metabolism is attenuated in dopamine transporter knockout mice

Abstract

Cocaine's ability to block the dopamine transporter (DAT) is crucial for its reinforcing effects. However the brain functional consequences of DAT blockade by cocaine are less clear since they are confounded by its concomitant blockade of norepinephrine and serotonin transporters. To separate the dopaminergic from the non-dopaminergic effects of cocaine on brain function we compared the regional brain metabolic responses to cocaine between dopamine transporter deficient (DAT −/− ) mice with that of their DAT +/+ littermates. We measured regional brain metabolism (marker of brain function) with 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) and microPET (μPET) before and after acute cocaine administration (i.p. 10 mg/kg). Scans were conducted 2 weeks apart. At baseline DAT −/− mice had significantly greater metabolism in thalamus and cerebellum than DAT +/+ . Acute cocaine decreased whole brain metabolism and this effect was greater in DAT +/+ (15%) than in DAT −/− mice (5%). DAT +/+ mice showed regional decreases in the olfactory bulb, motor cortex, striatum, hippocampus, thalamus and cerebellum whereas DAT −/− mice showed decreases only in thalamus. The differential pattern of regional responses to cocaine in DAT −/− and DAT +/+ suggests that most of the brain metabolic changes from acute cocaine are due to DAT blockade. Cocaine-induced decreases in metabolism in thalamus (region with dense noradrenergic innervation) in DAT −/− suggest that these were mediated by cocaine's blockade of norepinephrine transporters. The greater baseline metabolism in DAT −/− than DAT +/+ mice in cerebellum (brain region mostly devoid of DAT) suggests that dopamine indirectly regulates activity of these brain regions.

Substance-specific and shared transcription and epigenetic changes in the human hippocampus chronically exposed to cocaine and alcohol

“…The main dysfunctions involved in the pathological processes are suppressed oxidative stress defense, altered membrane ion permeability, and, particularly, depleted ATP synthesis resulting from the inhibition of components of the oxidative phosphorylation pathway. Via brain imaging such as autoradiography and PET, negative effects of cocaine on glucose metabolism and energy state have been repeatedly observed in various brain regions, including hippocampal formation, in humans (10), nonhuman primates (11), mice (13), and rats (12). Prolonged cocaine exposure also lead to more widespread and more severe inhibition of glucose metabolism in various brain regions (12).…”

The Role of Guanfacine as a Therapeutic Agent to Address Stress-Related Pathophysiology in Cocaine-Dependent Individuals

“…For example, cocaine use impinges functionally (Goldstein et al, 2009) structurally (Franklin et al, 2002; Lim, Choi, Pomara, Wolkin, & Rotrosen, 2002) and metabolically (Thanos, Michaelides, Benveniste, Wang, & Volkow, 2008; Volkow, Fowler, Wang, & Swanson, 2004) upon regulatory prefrontal executive control systems of the brain as well as memory-related cortico-striatal and hippocampal regions (Rabbitt, 1997; L. Roberts, Robbins, & Weiskrantz, 1998).…”

Large-Scale, Ion-Current-Based Proteomic Investigation of the Rat Striatal Proteome in a Model of Short- and Long-Term Cocaine Withdrawal

“…Third, more than ten proteins involved in glucose metabolism also displayed differential expression in WD1. Several studies have reported that cocaine inhibits regional/global glucose metabolism in various mammalian subjects including human cocaine users 53 , non-human primates 54 , and rodents 55 . We hypothesize that the increased glucose metabolism proteins observed might serve to rescue the deterioration of energy production caused by chronic cocaine exposure.…”