Can addictive behaviour be altered? The concept of drug-evoked synaptic plasticity
This summary is based on the article published in the Journal of Neuroscience: Drug-Evoked Synaptic Plasticity Causing Addictive Behavior (November 2013)
The core element of the addiction process: an initially neutral stimulus becomes attractive when associated with drug consumption, and even after prolonged periods of abstinence this cue may trigger craving and cause the subject to relapse.
Therefore, many researchers have argued that the secret to understanding addiction lies in the elucidation of the “memory trace” that links the cue to the compulsive drug use. The implicit underlying hypothesis is that addictive drugs generate an inappropriate learning signal that leads to the encoding of a unique trace, which, when reactivated, has a strong behavioral impact.
Drug-evoked synaptic plasticity
While the requirement for increased mesolimbic dopamine (DA) may explain the acute reinforcing effects of addictive drugs, it does not provide an explanation for craving and relapse. After all, these key features of addiction manifest long after the drugs have been cleared from the brain. Given the established modulatory role of DA on glutamatergic and GABAergic transmission, the synaptic trace of addictive drugs may actually be expressed at these synapses and not necessarily involve a change in DA modulation.
The experimental demonstration of such a trace was achieved over a decade ago using a clever ex vivo approach. Briefly, slices of the VTA were prepared 1 d following a single injection of cocaine and glutamatergic transmission at AMPA receptor (AMPAR) and NMDA receptor (NMDAR) was recorded in VTA DA neurons. Since the number of synapses stimulated in this preparation is beyond the control of the experimenter, the ratio of AMPAR- and NMDAR-mediated synaptic currents was calculated and found to be increased after the cocaine treatment.
Subsequent investigations revealed that this early drug trace can be observed with all addictive drugs tested to date, including ethanol, morphine, and nicotine, but also amphetamines and benzodiazepines.
Emerging ideas for rational addiction treatments
- A more comprehensive understanding of the precise nature of circuit remodeling caused by addictive drugs resulting from specific forms of drug-evoked synaptic plasticity may help us to design novel rational treatments for the human disease. Such treatments may be pharmacological in nature or use neuromodulatory approaches such as deep brain stimulation or transcranial magnetic stimulation (TMS).
- Perhaps a more selective intervention would be to target specific areas of the reward circuitry, such as the NAc, with deep brain stimulation.
- Ultimately, the understanding of drug-induced plasticity at specific synapses must be furthered to develop a therapy that reverses plasticity and associated drug-induced adaptive behavior.
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