A Possible Mechanism Underlying the Effectiveness of Acupuncture in the Treatment of Drug Addiction

Chae Ha Yang; Bong Hyo Lee; Sung Hoon Sohn


Evid Based Complement Alternat Med. 2008;5(3):257-266. 

In This Article

Physiological Basis of Drug Addiction

Role of Dopamine

The mesolimbic dopamine system originates in the ventral tegmental area (VTA) and projects to regions that include the nucleus accumbens and prefrontal cortex. Dopamine is believed to be the final common pathway for drugs such as cocaine, morphine and alcohol. The neurobiological substrate for self-administration of all addictive drugs by animals and drug abuse in humans is believed to, in some way, involve the dopamine system of the nucleus accumbens, a primitive structure that is one of the brain's important pleasure centers. Dopamine is believed by many to be directly responsible for the exhilarating rush that reinforces the desire to take drugs in drug addicts and plays a pivotal role in the development of drug addiction. These drugs of abuse-induced changes in brain levels of dopamine are associated with feelings of well being and pleasure and provide positive reinforcement; contributing to the continued drug abuse.[20–22] Furthermore, repeated drug administration produces sensitization of extracellular dopamine levels in the nucleus accumbens and behavioral sensitization in rats, as evidenced by an enhanced locomotor response and increased dopamine release in brain.[23,24] Conversely, withdrawal from chronic drug administration produced a reduction in dopamine outflow in the nucleus accumbens.[25–27] As suggested by many studies, drug-induced dopamine depletion in the mesolimbic system may represent the mechanism, at least in part, underlying dysphoria and anhedonia that accompanies drug withdrawal and might also contribute to the intense drug craving experienced by addicts.[28,29] These withdrawal-negative affects are largely associated with negative reinforcement.

Although it is generally believed that the same neural systems are involved in drug reward and drug-associated learning, there are two different theories that have opposite views on the role of brain reward pathways in mediating drug-seeking behavior. One theory suggests that drug seeking is triggered by drug-like, proponent processes that activate reward pathways in a manner similar to acute effects of drug itself.[30,31] Another theory suggests that drug-opposite or opponent processes induce drug seeking by producing a hypofunctional state of reward pathways which leads to dysphoria or anxiety during withdrawal.[32] Yin and Yang theory may explain these seemingly opposite proponent and opponent theories underlying drug addiction and relapse to drug seeking. Koob and Moal Le[33] proposed a conceptual framework of allostasis which focused on abnormal changes in reward function that lead to excessive drug taking and drug seeking in prolonged withdrawal. The allostasis model has been proposed for brain changes that occur during the development of addiction process and explains the persistent vulnerability to relapse long after drug taking has ceased. During the course of addiction, counter-adaptive processes such as opponent process that are usually part of normal homeostatic limitation of reward function fails to return to normal range and it is hypothesized to form an allostatic state. The allostasis model shares a similar concept on reward with Yin and Yang theory, from the standpoint of understanding that both theories explain the homeostasis and balance between positive and negative impact on drug addiction.

Modulation of Dopamine Neuron by GABA and Opioids

The firing activity of dopamine neuron is controlled by the intrinsic activity of the neuron as well as the inhibitory and excitatory input, which it receives from other brain structures as well as from local GABA interneurons in the VTA. GABA can interact with either GABAA or GABAB receptors present in the VTA. While GABAergic neurons are known to dampen dopamine neurons via inhibitory GABAA or GABAB receptors in the VTA dopamine neurons,[34,35] recent findings suggest that GABAB receptors play a predominant role in attenuating the reinforcing effects of the drugs through a modulation of dopamine transmission. For example, it has been shown that the GABAB antagonist SCH 50911 blocked gamma-vinyl GABA's inhibition of cocaine-induced increases in dopamine in the nucleus accumbens.[36] A similar conclusion was obtained in another study in which GABAB receptor agonist baclofen dose dependently reduced heroin-induced dopamine release in the nucleus accumbens and inhibited heroin self-administration behavior.[37] Therefore, it is highly likely that GABAB receptor stimulation is sufficient to dampen nucleus accumbens dopamine release induced by abused drugs. Chronic cocaine or amphetamine is associated with altered GABAB receptor function after withdrawal.[38] Importantly, the observed increase in GABAB heteroreceptor function would be expected to lead to decreased dopamine and glutamate release in the VTA, and may therefore contribute to the reward deficits associated with psychostimulant withdrawal.[38] Moreover, chronic administration of ethanol enhanced the baseline activity of VTA GABA neurons underlying the decrease in accumbal dopamine release associated with withdrawal from chronic ethanol.[39] It has been shown that probability of GABA release in the VTA area is increased during withdrawal from morphine.[40] In contrast, chronic exposure to cocaine decreased the functional coupling of GABAB receptors to G-proteins in the VTA in rats, suggesting that cocaine sensitization implicates the enhanced extracellular dopamine levels in the nucleus accumbens.[41] There is some direct support for this finding in studies of in vivo microdialysis showing that endogenous GABA release was reduced in the striatum of rats sensitized to cocaine.[42] Taken together, these results suggest that neurochemical and behavioral sensitization may imply a decreased ability of GABAB receptors to inhibit dopaminergic activity.

Activation of μ- and κ-opioid receptors is known to exert opposite modulation of dopamine neuron in the mesolimbic dopamine system.[43,44] The μ-opioid receptors are selectively expressed on inhibitory GABA interneurons in the VTA. Activation of μ-receptors hyperpolarizes these GABAergic neurons, causing a disinhibition of the dopamine neurons.[45] As a consequence, this leads to the increased accumbal dopamine release. Conversely, κ-receptor is located on presynaptic dopaminergic nerve terminals in the nucleus accumbens. The κ-receptor agonist inhibits the dopaminergic neuron directly, resulting in the decrease of accumbal dopamine release.[46] Supporting the notion that suppression of GABAergic input onto dopaminergic neurons in the VTA contributes to μ-opioid receptor modulation of cocaine reinforcement, μ-opioid receptor knockout mice showed the reduced cocaine self-administration and increased GABAergic input to VTA dopaminergic neurons.[47] A role for κ-receptor in dopamine release in the nucleus accumbens was extended by the observation that inhibition of κ-opioid receptor by κ-opioid receptor knockout and the κ-opioid receptor antagonist norbinaltorphimine produced ethanol-induced elevation of extracellular dopamine in the nucleus accumbens, respectively.[48,49] Also, recent work has shown that blockade of κ-opioid receptor increased alcohol drinking in two bottle choice paradigm, suggesting that κ-opioid receptor may be particularly important for the blockade of the reinforcing effect of ethanol via inhibition of dopaminergic neuron.[50]


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