Remediation of addiction with a 1-2 punch of deep brain stimulation & dopamine receptor antagonists
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Pathological changes to synaptic transmission underlie part of the etiology of different neurological and psychiatric diseases including Parkinson’s disease and drug addiction. Deep brain stimulation (DBS) is an effective treatment for tremors associated with Parkinson’s disease.1 Recent optogenetic experiments have shown that both synaptic transmission and addiction-related behaviors are normalized by stimulation of medium spiny neurons (MSNs) through depotentiation of D1 receptor (D1R) expressing neurons in the nucleus accumbens (NAc).
These optogenetic experiments suggest an enticing therapeutic potential. However, optogenetic protocols are not approved for human use. On the other hand, DBS is a U.S. Food and Drug Administration (FDA)-approved treatment for Parkinson’s disease and evidence supports a possible use for DBS in treating addiction.2 However, the therapeutic benefits of DBS are highly transient and therapeutic duration needs to be increased. In a recent article published in Science, Creed, Pascoli and Lüscher demonstrate that a combination of DBS and pharmaceuticals leads to long-term improvement in synaptic transmission and addiction-related behavior.
The researchers used cocaine locomotor sensitization (a long-term enhancement of locomotor activity after repeated cocaine experience) and AMPA/NMDA receptor ratio (a measure of synaptic potentiation) to investigate addiction-related physiology. Five days of cocaine administration induced locomotor sensitization and increased AMPA/NMDA ratio in mice. Using a combination of optogenetics and pharmacology, Creed et al., were able to show in brain slices that a low stimulation frequency induced long-term depression of excitatory synapses onto D1R-expressing MSNs when used in conjunction with D1R antagonists, SCH23390 or SCH39166. When repeating this in vivo, they were able to show that the combination of low frequency optogenetic stimulation in the NAc shell and infusion of D1-antagonists abolished cocaine locomotor sensitization.
Finally, the researchers demonstrated that either 12-hz DBS or D1-antagonists alone had no impact on locomotor sensitization, but when both treatments were used together, they were able to significantly reduce locomotor sensitization in the animals without impairing the immediate response to cocaine. Importantly, cocaine sensitization in DBS and D1-anatagonist treated mice was still suppressed even if treatment occurred a week before a cocaine challenge, supporting the long-lasting impact of this treatment.
As DBS and D1-antagonist (SCH39166) are FDA-approved for human use, this study supports a potentially powerful role for already available therapies in the treatment of addiction. These experiments demonstrate a role for DBS in reversing the potentiation of excitatory neurotransmission onto D1R-expressing MSNs in the NAc shell, and suggest a methodology for translating optogenetically realized findings into potential DBS treatment protocols.
- Creed M, Pascoli VJ, Lüscher C (2015) Refining deep brain stimulation to emulate optogenetic treatment of synaptic pathology. Science 347(6222):659-664. doi: 10.1126/science.1260776
- 1. Miocinovic S, Somayajula S, Chitnis S, Vitek JL (2013) History, applications, and mechanisms of deep brain stimulation. JAMA Neurology 70(2):163-171. doi: 10.1001/2013.jamaneurol.45
- 2. Williams NR, Okun MS (2013) Deep brain stimulation (DBS) at the interface of neurology and psychiatry. The Journal of Clinical Investigation 123(11):4546–4556. doi: 10.1172/JCI68341