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

Chae Ha Yang; Bong Hyo Lee; Sung Hoon Sohn

Disclosures

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

In This Article

Acupuncture and the Negative Reinforcing Effect of Abused Drugs

Role of the Mesolimbic Dopamine System in Acupuncture

Although there is a lack of well-controlled experiments investigating the effect of acupuncture on drug abuse, including ethanol, a few studies using animal models have provided evidence that acupuncture can play an important role in reducing negative reinforcing effects of drug.

Electroacupuncture at the specific point ST36 effectively reduced the increase in alcohol-drinking behavior and enhanced the striatal dopamine level in rats challenged with immobilization stress.[70] While ethanol has diverse effects in the brain, ethanol has been shown to increase the firing rates of mesolimbic dopamine neurons by modulating GABAA receptors located on GABAergic neurons in the VTA.[71] Ethanol has stimulatory, euphoric, sedation, anxiolytic and muscle relaxant effects. Even though all these diverse effects probably cannot be related to one specific single neurotransmitter, dopamine seems to be involved in most of the effects. During ethanol withdrawal, brain stimulation reward thresholds were elevated compared to pre-drug baseline.[72] This elevation in reward threshold may reflect an anhedonia state and as such it may be homologous to the anhedonia reported by alcohol-dependent patients.[73,74] A likely neurochemical mechanism involved in this withdrawal state would be some hypoactivity of dopamine functioning. It has also been shown that withdrawal from chronic ethanol administration can produce a reduction in dopamine outflow in the nucleus accumbens.[75] Based on the earlier facts, these results, combined with observations of dopamine levels in the striatum, suggest that the suppression of alcohol-drinking behavior by electroacupuncture may be mediated by the increase of striatal dopamine levels.

Recent studies have shown that acupuncture attenuated alcohol withdrawal syndrome and Fos-like immunoreactivity (FLI) in the striatum and the nucleus accumbens core of rats. During 3 days of cessation following chronic administration of ethanol, rats showed a significant increase in alcohol withdrawal syndrome, such as hypermotility, tail rigidity, grooming and tremor and increase in FLI in the dopamine terminal areas in the brain, reflecting the expected increases in neuronal excitability. Treatment of acupuncture at Zusanli or Sanyinjiao points during withdrawal period inhibited AWS and also prevented the expected increase in FLI of rats exposed to chronic ethanol. These results suggest that acupuncture may be effective in suppressing alcohol withdrawal syndrome by modulating post-synaptic neural activation in the striatum and nucleus accumbens core.[76] Similar to these results, a recent study showed that electroacupuncture decreased both c-Fos gene expression in the central nucleus of the amygdala and withdrawal signs in morphine-withdrawn rats.[77] Amygdala and nucleus accumbens play an important role for the motivational effect of opiate withdrawal. Given that the increase of c-Fos gene expression in the central nucleus of amygdala is associated with the negative motivational impact on drug addiction, one possibility is that acupuncture could help to normalize neuronal activation and thereby reverse withdrawal signs.

Acupuncture and Cerebral Endogenous Opioid System

The 'Incentive-sensitization theory' proposes that enhanced mesocorticolimbic dopamine neurotransmission is currently recognized as a common target of the dependence-producing properties of opioids, psychostimulants and alcohol.[78] Previous work has suggested cerebral β-endorphin system may be involved in reward. Additionally, cerebral β-endorphin originates in the arcuate nucleus of the mediobasal hypothalamus and projects to limbic structures such as the VTA and the nucleus accumbens, seems to be responsible for the reinforcing effects of abused drugs.[79] A hypothetical model has been proposed for possible interactions between the endogenous opioid reward system and the release of dopamine from the nucleus accumbens. VTA GABA interneurons connect to VTA dopamine neurons and likely inhibit them. Activation of presynaptic μ-opioid receptors on these GABAergic interneurons decreases the firing rate of VTA GABA neurons, leading to an increase in release of dopamine in the nucleus accumbens, whereas presynaptic κ-opioid receptors in the nucleus accumbens directly inhibit dopamine release in the nucleus accumbens. β-endorphin released from fibers ascending from the arcuate nucleus of the hypothalamus stimulates μ-receptors in the VTA, thereby disinhibiting VTA dopamine neurons. Also, it activates δ-opioid receptors in the nucleus accumbens. Thus, β-endorphin increases dopamine release in the nucleus accumbens (Fig. 1).[80] Several experiments have investigated the effect of electroacupuncture on endogenous opioid system. These opioid-related studies, using animal models, have provided evidence that low-frequency electroacupuncture can activate enkephalinergic and β-endorphinergic neurons in the nucleus arcuatus of the hypothalamus.[81,82] Accordingly, it seems reasonable to propose that electroacupuncture may help to enhance the release of dopamine in the nucleus accumbens via δ-opioid receptors in the nucleus accumbens as well as μ-receptors in the VTA. In addition, there is an important neurochemical evidence that acupuncture treatment directly affects the mesolimbic dopamine system. Acupuncture treatment at the specific acupoints Shenmen (HT7) significantly prevented a decrease of extracellular dopamine levels in the nucleus accumbens after withdrawal from chronic ethanol administration, with an accumbal dopamine concentration restored to approximately 90% of that of nave animal.[83] Given chronic ethanol-induced dopamine depletion in the mesolimbic system is linked to the dysphoria and anhedonia that often accompanies ethanol withdrawal,[84] acupuncture may play a role in relieving withdrawal syndrome and help to prevent compulsive drug-seeking behavior and relapse.

A hypothetical model of possible bidirectional effects of acupuncture on dopamine release in the nucleus accumbens. In positive reinforcement, acupuncture treatment activates GABAB receptors on the dopamine cell bodies, resulting in a decrease of dopamine release in the nucleus accumbens through the inhibition of dopaminergic neurons; additionally, acupuncture activates presynaptic κ-opioid receptors in the nucleus accumbens through dynorphin neurons, resulting in a decrease of dopamine release in the nucleus accumbens. In negative reinforcement, acupuncture treatment stimulates enkephalin neurons in the hypothalamus, such that methionine-enkephalin released in the VTA interacts with μ-opioid receptors to inhibit VTA GABAergic interneurons, inducing the disinhibition of dopaminergic neurons and thus, eventually increases the dopamine release in the nucleus accumbens.

Animal models for the acute reinforcing effects of abused drugs have included measures of preference for the environment paired with drug administration (conditioned place preference; CPP). Further support for a role of brain β-endorphin is the observation that low-frequency electroacupuncture reduced morphine-induced place preference in rats and this effect was reversed by pretreatment of opioid receptor antagonist naloxone at a small dose which is sufficient to block the opioid μ and δ, but not the κ, receptors.[85] The authors suggested that μ-opioid receptor might be involved in acupuncture's role in suppressing the negative reinforcing effect of morphine. In this study, since CPP paradigm was carried out 24 h after the last daily injection, the negative stimulus effects of acute morphine withdrawal may be responsible for the preference to the drug-pairing environment. Thus, it is possible that electroacupuncture reduces the negative stimulus effects by activation of dopamine release through β-endorphinergic and enkephalinergic neurons in the brain, especially in the arcuate nucleus. On the other hand, one behavioral study has indicated that high-frequency electroacupuncture suppressed the naloxone-induced morphine withdrawal syndrome and this effect was reversed by pretreatment with dynorphin A antibody or κ-receptor antagonist.[86]

The neuropharmacological data reviewed earlier, provide some evidence for the action of the endogenous opioid peptides in acupuncture analgesia. On the basis of these and other findings that low-frequency electroacupuncture facilitates the release of β-endorphin and enkephalin in the CNS, whereas high-frequency electroacupuncture produced an increase in dynorphin release,[87,88] it has been expected that low-frequency electroacupuncture can play a predominant role in attenuating withdrawal syndrome by activating the β-endorphinergic and enkephalinergic neurons. However, high-frequency electroacupuncture was more effective in suppressing morphine withdrawal syndrome compared to low-frequency electroacupuncture.[89] The exact neurochemical mechanisms mediating the suppressive effect of high-frequency electroacupuncture on withdrawal syndrome is unknown but these results suggest the possibility that electroacupuncture's role in suppressing the morphine withdrawal syndrome takes place by activating the κ-opioid receptor and dynorphin release. To summarize the research described earlier, low-frequency electroacupuncture appears to play a critical role in attenuating the motivational aspects of drug withdrawal, while high-frequency electroacupuncture may be most effective in reducing withdrawal symptoms.

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