Addiction and Reward Circuitry in the Brain

Elizabeth Howell, MD


March 29, 2004

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Roy A. Wise, PhD,[1] Chief of the Behavioral Neuroscience Branch of the Intramural Research Program of the National Institute on Drug Abuse, Bethesda, Maryland, spoke on brain reward circuitry and addiction at the American Society of Addiction Medicine's 2003 State-of-the-Art conference. He highlighted the dopamine hypothesis of reward, which postulates that the actions of drugs of abuse are rewarding as a consequence of activation of dopamine in the mesolimbic dopamine system. This dopamine reward hypothesis was based on studies by Yokel and Wise[2,3,4] of the effects of pimozide on amphetamine self-administration. They found that animals would self-administer amphetamine up to a certain point; when previously self-administering animals were given dopamine antagonists, such as pimozide, the self-administration would initially increase as they worked harder for amphetamine and eventually extinguish as the levels of dopamine antagonist increased. This same pattern occurs with amphetamine, cocaine, food, and electrical stimulation of the brain. In a model using intravenous self-administration, with lever pressing to get a drug injection, basal dopamine levels in the nucleus accumbens (Nacc) are driven up by the self-administration of heroin.[5]

How do we identify sites in the reward circuitry where different drugs activate the system? Dr. Wise summarized work demonstrating that rates of intracranial self-administration of endomorphin-1 (which has the greatest selectivity for the mu opioid receptor) into the dopamine cell bodies of the ventral tegmental area (VTA) differ from the anterior and posterior VTAs. The rewarding effects of endomorphin-1 are much more pronounced in the posterior VTA. Cocaine and amphetamine trigger reward at the Nacc; however, cocaine also has rewarding actions in the frontal cortex and the olfactory tubercle.

Dopamine is not the whole story; GABA-containing cells also receive input from and send input to the dopamine system. Morphine and heroin trigger reward by disinhibiting the VTA dopamine cells inhibiting GABA release from neighboring neurons. Nicotine triggers reward at cholinergic synapses in VTA, where it activates dopamine neurons projecting to Nacc. Phencyclidine (PCP) is an example of a drug that does not activate the dopamine system; it triggers reward in NACC by blocking the glutamate (NMDA) receptors on the GABAergic neurons, but bypasses the dopamine circuitry. Cannabis (delta-9-tetrahydrocannabinol) is preferentially self-administered into the posterior VTA and inhibits these cells through the CB-1 receptor.

Dr. Wise then discussed the differences between the dopamine reward hypothesis and the dopamine transporter (DAT) hypothesis, which is restricted to cocaine and amphetamine only -- not with opioids, food, brain stimulation, etc. The DAT hypothesis is based largely on correlational evidence. A number of psychomotor stimulants have rewarding properties, and the strength of their rewarding properties is more closely linked to their affinities for the DAT than for other binding sites in the brain. However, mice without DAT, known as DAT knockout (DAT-KO) mice, still self-administer cocaine. Cocaine blocks not only DAT, but also the norepinephrine and serotonin transporters. The various transporters are promiscuous; the DAT is not specific for dopamine, and the norepinephrine and serotonin transporters both transport dopamine. Therefore, dopamine uptake does not depend on the presence of DAT; in fact, the norepinephrine transporters in the frontal cortex have more affinity for dopamine than the DATs do. Neurotransmitter transport depends on which transporters are present, their relative densities, and their relative affinities in different parts of the brain. Norepinephrine transporters continue to transport dopamine, and cocaine still elevates dopamine in the Nacc, the prefrontal cortex, and the olfactory tubercle in DAT-KO mice.

According to Dr. Wise, DAT-KO studies reinforce the dopamine reward hypothesis, and falsify the DAT hypothesis. In DAT-KO mice, other transporters begin to play a significant role in the reward process. Selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, and serotonin norepinephrine reuptake inhibitors, such as nisoxetine, cause conditioned place preference (an indirect measure of drug reinforcement) in DAT-KO mice. As an aside, he also noted that the SSRIs are not selective for serotonin; they are selective for the serotonin transporter, but the transporter is not selective for serotonin.

Implications for Medication Treatments

Drugs that block dopamine receptors and drugs that stimulate dopamine receptors have been considered as potential medications for addiction, but these drugs affect the reward system too strongly. How could the system be controlled more subtly? One way might be to affect the circuitry that sends input to the reward system. In vivo brain microdialysis studies of cocaine self-administration provide clues about the effects of glutamate, GABA, and acetylcholine on the dopamine reward system. For example, VTA glutamate increases to 170% of normal levels during initial cocaine self-administration, then decreases to baseline in the presence of cocaine. This VTA glutamate spike also occurs with saline and, thus, is not due to the effects of cocaine alone; apparently, glutamate is signaling the dopamine system to expect cocaine. During cocaine self-administration, GABA increases in the Nacc shell, but not in the VTA or in the prefrontal cortex; acetylcholine increases in the VTA, presumably stimulating dopamine neurons, and stays up as long as dopamine is increased at the next synapse in the Nacc. These and other intriguing findings may lead to more effective medications for the treatment of addiction.

  1. Wise RA. Brain reward circuitry and addiction. Program and abstracts of the American Society of Addiction Medicine 2003 The State of the Art in Addiction Medicine; October 30-November 1, 2003; Washington, DC. Session I.

  2. Yokel RA, Wise RA. Increased lever pressing for amphetamine after pimozide in rats: implications for a dopamine theory of reward. Science. 1975;187:547-549. Abstract

  3. Yokel RA, Wise RA. Attenuation of intravenous amphetamine reinforcement by central dopamine blockade in rats. Psychopharmacology (Berl). 1976;48:311-318. Abstract

  4. Wise RA. Brain reward circuitry: insights from unsensed incentives. Neuron. 2002;36:229-240. Abstract

  5. Vaccarino FJ, Bloom FE, Koob GF. Blockade of nucleus accumbens opiate receptors attenuates intravenous heroin reward in the rat. Psychopharmacology (Berl). 1985;86:37-42. Abstract


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