articles
Reward Deficiency Syndrome
Kenneth Blum, John G. Cull, Eric R.
Braverman
and David E. Comings
cont.
Rat
During the past several decades research on the biological basis of
chemical dependency has been able to establish some of the brain regions and
neurotransmitters involved in reward. In particular it appears that the
dependence on alcohol, opiates and cocaine relies on a common set of
biochemical mechanisms (Cloninger 1983, Blum et al. 1989). A neuronal
circuit deep in the brain involving the limbic system and two regions called
the nucleus accumbens and the globus pallidus appears to be critical in the
expression of reward for people taking these drugs (Wise and Bozarth 1984).
Although each substance of abuse appears to act on different parts of this
circuit, the end result is the same: Dopamine is released in the nucleus
accumbens and the hippocampus (Koob and Bloom 1988). Dopamine appears to be
the primary neurotransmitter of reward at these reinforcement sites.
Although the system of neurotransmitters involved in the biology of reward is
complex, at least three other neurotransmitters are known to be involved at
several sites in the brain: serotonin in the hypothalamus, the enkephalins (opioid
peptides) in the ventral tegmental area and the nucleus accumbens, and the
inhibitory neurotransmitter GABA in the ventral tegmental area and the nucleus
accumbens (Stein and Belluzi 1986, Blum 1989). Interestingly, the glucose
receptor is an important link between the serotonergic system and the opioid
peptides in the hypothalamus. An alternative reward pathway involves the
release of norepinephrine in the hippocampus from neuronal fibers that
originate in the locus coeruleus.
In a normal person, these neurotransmitters work together in a cascade of
excitation or inhibition-between complex stimuli and complex responses-leading
to a feeling of well being, the ultimate reward (Cloninger 1983, Stein and
Belluzi 1986, Blum and Koslowski 1990). In the cascade theory of reward, a
disruption of these intercellular interactions results in anxiety, anger and
other "bad feelings" or in a craving for a substance that alleviates
these negative emotions. Alcohol, for example, is known to activate the
norepinephrine system in the limbic circuitry through an intercellular cascade
that includes serotonin, opioid peptides and dopamine. Alcohol may also act
directly through the production of neuroamines that interact with opioid
receptors or with dopaminergic systems (Alvaksinen et al. 1984; Blum
and Kozlowski 1990). In the cascade theory of reward, genetic anomalies,
prolonged stress or long-term abuse of alcohol can lead to a self-sustaining
pattern of abnormal cravings in both animals and human beings.
Limbic System
Support for the cascade theory can be derived from a series of experiments
on strains of rats that prefer alcohol to water. Compared to normal rats, the
alcohol-preferring rats have fewer serotonin neurons in the hypothalamus,
higher levels of enkephalin in the hypothalamus (because less is released),
more GABA neurons in the nucleus accumbens (which inhibit the release of
dopamine), a reduced supply of dopamine in the nucleus accumbens and a lower
density of dopamine D2 receptors in certain areas of the limbic system
(Russell, Lanin and Taljaard 1988; McBride et al. 1990; Zhou et al.
1990; McBride et al. 1993).
These studies suggest a four-part cascade in which there is a reduction in
the amount of dopamine released in a key reward area in the alcohol-preferring
rats. The administration of substances that increase the supply of serotonin
at the synapse or that directly stimulate dopamine D2 receptors reduce craving
for alcohol (McBride et al. 1993). For example, D2 receptor agonists
reduce the intake of alcohol among rats that prefer alcohol, whereas D2
dopamine-receptor antagonist increase the drinking of alcohol in these inbred
animals (Dyr et al. 1993).
Support for the cascade theory of alcoholism in human beings is found in a
series of clinical trials. When amino-acid precursors of certain
neurotransmitters (serotonin and dopamine) and a drug that promotes enkephalin
activity were given to alcoholic subjects, the individuals experienced fewer
cravings for alcohol, a reduced incidence of stress, an increased likelihood
of recovery and a reduction in relapse rates (Brown et al. 1990; Blum
and Tractenberg 1988; Blum, Briggs and Tractenberg 1989). Furthermore, the
notion that dopamine is the "final common pathway" for drugs such as
cocaine, morphine and alcohol is supported by recent studies by Jordi Ortiz
and his associates at Yale University School of Medicine and the University of
Connecticut Health Services Center. These authors demonstrated that the
chronic use of cocaine, morphine or alcohol results in several biochemical
adaptations in the limbic dopamine system. They suggest that these adaptations
may result in changes in the structural and functional properties of the
dopaminergic system.
We believe that the biological substrates of reward that underlie the
addiction to alcohol and other drugs are also the basis for impulsive,
compulsive and addictive disorders comprising the reward deficiency syndrome.
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