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Cocaine’s Effects On Brain Metabolism May Contribute To Abuse

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Many studies on cocaine addiction – and attempts to block its addictiveness – have focused on dopamine transporters, proteins that reabsorb the brain’s “reward” chemical once its signal is sent. Since cocaine blocks dopamine transporters from doing their recycling job, it leaves the feel-good chemical around to keep sending the pleasure signal. Now a new study conducted at the U.S. Department of Energy’s Brookhaven National Laboratory suggests that cocaine’s effects go beyond the dopamine system. In the study, cocaine had significant effects on brain metabolism, even in mice that lack the gene for dopamine transporters.

Magnetic resonance imaging (MRI) and positron emission tomography (PET) scans showing the effect of cocaine on brain metabolism in mice with normal levels of dopamine transporter proteins (DAT +/+) and mice lacking dopamine transporters (DAT -/-). Cocaine was compared with saline treatment (vehicle). Cocaine use blunted whole brain metabolism in both groups of mice (indicated by a reduced amount of yellow visible on the cocaine images), and had a particularly significant effect on the thalamus (TH) in DAT -/- mice. These results indicate that cocaine affects the brain in ways not modulated by its blockade of dopamine transporter proteins. (Credit: Image courtesy of DOE/Brookhaven National Laboratory)

“In dopamine-transporter-deficient mice, these effects on metabolism are clearly independent of cocaine’s effects on dopamine,” said Brookhaven neuroscientist Panayotis (Peter) Thanos, who led the research. “These metabolic factors may be a strong regulator of cocaine use and abuse, and may also suggest new avenues for addiction treatments.”

The scientists used positron emission tomography, or PET scanning, to measure brain metabolism in dopamine-transporter deficient mice (known as DAT knockouts) and in littermates that had normal dopamine transporter levels. In this technique, the scientists administer a radioactively labeled form of sugar (glucose) – the brain’s main “fuel” – and use the PET scanner to track its site-specific concentrations in various brain regions. They tested the mice before and after cocaine administration, and compared the results to mice treated with saline instead of the drug.

Before any treatment, mice lacking dopamine transporters had significantly higher metabolism in the thalamus and cerebellum compared with normal mice. This elevated metabolism may be linked to chronically high levels of dopamine in the DAT knockout mice. It also suggests that dopamine levels may play an important role in modulating glucose levels in these brain areas, which play important roles integrating sensory information, learning, and motor function.

Interestingly, DAT knockout mice have been suggested as an animal model for attention-deficit hyperactivity disorder (ADHD). Elevated metabolism due to persistent elevated dopamine levels may be a factor contributing to the symptoms of ADHD, Thanos said.

After the scientists administered cocaine, whole brain metabolism decreased in both groups of mice, but more significantly in normal mice than in DAT knockouts. The scientists were able to detect this reduction in metabolism in a wide range of brain regions in the normal mice, suggesting that these decreases in metabolism are somehow associated with the blockade of dopamine transporters by cocaine.

The scientists also observed a reduction in metabolism in the thalamus region in the DAT knockout mice. This effect may likely be due to the effect of cocaine on other neurotransmitter systems, for example, norepinepherine or serotonin.

In summary, cocaine exposure has an effect on regional brain activity, which is mostly driven by dopamine action and to a secondary degree norepinephrine or serotonin. These results also support the idea that the thalamus and the cerebellum play key roles in cocaine’s mechanism of effect on sensory input, learning, and motor function. This is particularly of interest in better understanding the mechanism of cocaine addiction as well as the neurobiology of ADHD.

Synapse. 2008 Feb 19;62(5):319-324 [Epub ahead of print]
The effects of cocaine on regional brain glucose metabolism is attenuated in dopamine transporter knockout mice.

Behavioral Neuropharmacology Lab, Medical Department, Brookhaven National Laboratory, Upton, New York 11973‐5000.

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 norepinephrineand 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 (muPET) 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 metabolismand 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. Synapse, 62:319-324, 2008. Published 2008 Wiley-Liss, Inc.


Written by huehueteotl

February 25, 2008 at 2:47 pm

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  1. I noticed that this is not the first time you write about this topic. Why have you chosen it again?

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    April 15, 2009 at 7:29 pm

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