Cocaine Harms Brain"s Pleasure Center
Updated June 10, 2015.
Jan. 1, 2003
ANN ARBOR, MI -- New research results strongly suggest that cocaine bites the hand that feeds it, in essence, by harming or even killing the very brain cells that trigger the "high" that cocaine users feel.
This first-ever direct finding of cocaine-induced damage to key cells in the human brain's dopamine "pleasure center" may help explain many aspects of cocaine addiction, and perhaps aid the development of anti-addiction drugs.
It also could help scientists understand other disorders involving the same brain cells, including depression.
The results are the latest from research involving postmortem brain tissue samples from cocaine abusers and control subjects, performed at the University of Michigan Health System and the VA Ann Arbor Healthcare System. The paper will appear in the January issue of the American Journal of Psychiatry.
"This is the clearest evidence to date that the specific neurons cocaine interacts with don't like it and are disturbed by the drug's effects," says Karley Little, M.D., associate professor of psychiatry at the U-M Medical School and chief of the VAHS Affective Neuropharmacology Laboratory. "The questions we now face are: Are the cells dormant or damaged, is the effect reversible or permanent, and is it preventable?"
Little and his colleagues report results from 35 known cocaine abusers and 35 non-drug users of about the same age, sex, race and causes of death. Using brain samples normally removed during autopsy, the researchers measured several indicators of the health of the subjects' dopamine brain cells, which release a pleasure-signaling chemical called dopamine.
The cells interact directly with cocaine.
The team looked at levels of a protein called VMAT2, as well as VMAT2's binding to a selective radiotracer molecule, and overall dopamine level. In all three, cocaine users' levels were significantly lower than control subjects. Levels tended to be lowest in cocaine users with depression.
The paper gives the most conclusive evidence yet that dopamine neurons are harmed by cocaine use, because it uses three molecular measures that provide a trustworthy assessment of dopamine neuron health.
Dopamine, Little explains, triggers the actions required to repeat previous pleasures. It's not only involved in drug users' "high" -- it helps drive us to eat, work, feel emotions, and reproduce. Normally, when something pleasurable happens, dopamine neurons pump the chemical into the gaps between themselves and related brain cells. Dopamine finds its way to receptors on neighboring cells, triggering signals that help set off pathways to different feelings or sensations.
Then, the dopamine is normally brought back into its home cell, entering through a gateway in the membrane called a transporter. While our brain waits for another pleasurable stimulus -- a good meal, a smile from a friend, a kiss -- dopamine lies waiting inside the neuron, sequestered in tiny packets called vesicles. VMAT2 acts as a pump to pull returning dopamine into vesicles.
When it comes time for another dopamine release, the vesicles merge with the cell membrane, dumping their contents into the gap, or synapse, and the pleasure signaling process begins again.
Dopamine neurons in the brain's pleasure center die off at a steady rate over a person's lifetime. Severe damage is a hallmark of Parkinson's disease, causing its loss of movement control. "As the words themselves suggest, there's an intimate connection between motion and emotion," says Little. "Emotion puts you in motion -- they're pre-activity preparations. It's not surprising that the basal ganglia, where these dopamine neurons are, is very active in 'emotional states.'"
When first taken, cocaine has a disruptive effect on the brain's dopamine system: It blocks the transporters that return dopamine to its home cell once its signaling job is done. With nowhere to go, dopamine builds up in the synapse and keeps binding with other cells' receptors, sending pleasure signals over and over again. This helps cause the intense "high" cocaine users feel.
Since the dopamine system helps us recognize pleasurable experiences and seek to repeat them, cocaine's long-term dopamine effects likely contribute to the craving addicts feel, and the decreased motivation, stunted emotion and uncomfortable withdrawal they face.
In recent years, many researchers have come to suspect that chronic cocaine use causes the brain to adapt to the drug's presence by altering the molecules involved in dopamine release and reuptake, and in the genetic instructions needed to make those molecules. Little and his colleagues are studying the effects of long-term cocaine use on the brain at a molecular level, in an attempt to explain the effects seen in cocaine users and addicts.
Jan. 1, 2003
ANN ARBOR, MI -- New research results strongly suggest that cocaine bites the hand that feeds it, in essence, by harming or even killing the very brain cells that trigger the "high" that cocaine users feel.
This first-ever direct finding of cocaine-induced damage to key cells in the human brain's dopamine "pleasure center" may help explain many aspects of cocaine addiction, and perhaps aid the development of anti-addiction drugs.
It also could help scientists understand other disorders involving the same brain cells, including depression.
The results are the latest from research involving postmortem brain tissue samples from cocaine abusers and control subjects, performed at the University of Michigan Health System and the VA Ann Arbor Healthcare System. The paper will appear in the January issue of the American Journal of Psychiatry.
"This is the clearest evidence to date that the specific neurons cocaine interacts with don't like it and are disturbed by the drug's effects," says Karley Little, M.D., associate professor of psychiatry at the U-M Medical School and chief of the VAHS Affective Neuropharmacology Laboratory. "The questions we now face are: Are the cells dormant or damaged, is the effect reversible or permanent, and is it preventable?"
Little and his colleagues report results from 35 known cocaine abusers and 35 non-drug users of about the same age, sex, race and causes of death. Using brain samples normally removed during autopsy, the researchers measured several indicators of the health of the subjects' dopamine brain cells, which release a pleasure-signaling chemical called dopamine.
The cells interact directly with cocaine.
The team looked at levels of a protein called VMAT2, as well as VMAT2's binding to a selective radiotracer molecule, and overall dopamine level. In all three, cocaine users' levels were significantly lower than control subjects. Levels tended to be lowest in cocaine users with depression.
The paper gives the most conclusive evidence yet that dopamine neurons are harmed by cocaine use, because it uses three molecular measures that provide a trustworthy assessment of dopamine neuron health.
Dopamine, Little explains, triggers the actions required to repeat previous pleasures. It's not only involved in drug users' "high" -- it helps drive us to eat, work, feel emotions, and reproduce. Normally, when something pleasurable happens, dopamine neurons pump the chemical into the gaps between themselves and related brain cells. Dopamine finds its way to receptors on neighboring cells, triggering signals that help set off pathways to different feelings or sensations.
Then, the dopamine is normally brought back into its home cell, entering through a gateway in the membrane called a transporter. While our brain waits for another pleasurable stimulus -- a good meal, a smile from a friend, a kiss -- dopamine lies waiting inside the neuron, sequestered in tiny packets called vesicles. VMAT2 acts as a pump to pull returning dopamine into vesicles.
When it comes time for another dopamine release, the vesicles merge with the cell membrane, dumping their contents into the gap, or synapse, and the pleasure signaling process begins again.
Dopamine neurons in the brain's pleasure center die off at a steady rate over a person's lifetime. Severe damage is a hallmark of Parkinson's disease, causing its loss of movement control. "As the words themselves suggest, there's an intimate connection between motion and emotion," says Little. "Emotion puts you in motion -- they're pre-activity preparations. It's not surprising that the basal ganglia, where these dopamine neurons are, is very active in 'emotional states.'"
When first taken, cocaine has a disruptive effect on the brain's dopamine system: It blocks the transporters that return dopamine to its home cell once its signaling job is done. With nowhere to go, dopamine builds up in the synapse and keeps binding with other cells' receptors, sending pleasure signals over and over again. This helps cause the intense "high" cocaine users feel.
Since the dopamine system helps us recognize pleasurable experiences and seek to repeat them, cocaine's long-term dopamine effects likely contribute to the craving addicts feel, and the decreased motivation, stunted emotion and uncomfortable withdrawal they face.
In recent years, many researchers have come to suspect that chronic cocaine use causes the brain to adapt to the drug's presence by altering the molecules involved in dopamine release and reuptake, and in the genetic instructions needed to make those molecules. Little and his colleagues are studying the effects of long-term cocaine use on the brain at a molecular level, in an attempt to explain the effects seen in cocaine users and addicts.
