A major problem in the treatment of addiction is relapse, which is often caused by the powerful and long-lasting memories of the drug experience.
Drugs of abuse can hijack or impair specific synaptic plasticity mechanisms in the mesolimbic dopamine system, which is central to reward processing in the brain.
Drugs of abuse or acute stress elicit long-term potentiation (LTP) at excitatory synapses on dopamine cells in the ventral tegmental area (VTA). Morphine prevents a novel form of LTP at inhibitory synapses on the same dopamine cells. Both changes are likely to increase dopamine cell firing.
Orexin, a neuropeptide implicated in arousal and feeding, enhances N-methyl-D-aspartate (NMDA) receptor-mediated synaptic responses in dopamine cells leading to LTP of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor-mediated responses. The actions of orexin in the VTA might be important for several of the behavioural adaptations caused by cocaine and, perhaps, other drugs of abuse.
At excitatory synapses on medium spiny neurons in the nucleus accumbens, cocaine causes a form of long-term depression (LTD) that is due to the removal of synaptic AMPA receptors. It also impairs endocannabinoid-mediated LTD. In contrast, during withdrawal from chronic cocaine administration, there appears to be an increase in excitatory synaptic transmission. Further work is necessary to determine whether other drugs of abuse have the same effects.
Other key brain areas in which drugs of abuse affect synaptic function and plasticity include the bed nucleus of the stria terminalis and the amygdala.
There may be important differences in the effects of drugs of abuse on synaptic function and plasticity depending on whether the drug is self-administered or not. It will be important in future work to use animal models that more closely mimic the behaviour of human substance abusers.
Addiction is caused, in part, by powerful and long-lasting memories of the drug experience. Relapse caused by exposure to cues associated with the drug experience is a major clinical problem that contributes to the persistence of addiction. Here we present the accumulated evidence that drugs of abuse can hijack synaptic plasticity mechanisms in key brain circuits, most importantly in the mesolimbic dopamine system, which is central to reward processing in the brain. Reversing or preventing these drug-induced synaptic modifications may prove beneficial in the treatment of one of society's most intractable health problems.
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The authors declare no competing financial interests.
- Long-term potentiation
(LTP). Activity-dependent strengthening of synaptic transmission that lasts at least one hour.
- Long-term depression
(LTD). Activity-dependent weakening of synaptic transmission that lasts at least one hour.
- Conditioned place preference
A behavioural task during which a subject learns to associate the drug experience with a specific physical environment. A subject will choose to spend more time in an environment in which it previously had a 'rewarding' experience and less time in an environment in which it had an aversive experience.
- Induction of synaptic plasticity
Refers to the cellular mechanisms required for the events initiating or triggering LTP or LTD.
- Excitatory postsynaptic currents
(EPSCs). Currents measured using electrophysiological recordings from a single neuron while electrically stimulating axons to release neurotransmitter. For the purposes of this Review, EPSCs are glutamate-mediated.
- Expression of synaptic plasticity
Refers to the cellular mechanisms responsible for maintaining a change in synaptic strength, for example, an increase in neurotransmitter release.
The observation that synaptic stimulation produces no further LTP (or LTD) presumably because the underlying cellular mechanisms have been maximally activated by some preceding stimulus. When LTP (or LTD) is absent, it is often difficult to determine whether it has been 'occluded' or blocked by inhibition or inactivation of one or more essential cellular mechanisms.
- Inhibitory postsynaptic currents
(IPSCs). Currents measured using electrophysiological recordings from a single neuron while electrically stimulating axons to release neurotransmitter. For the purposes of this Review, IPSCs are GABA-mediated.
- Yoked design
Experimental protocol in which a 'yoked' control animal receives a drug administered by the investigator in a non-contingent manner, in the same amount and temporal pattern as an animal that is self-administering the drug.
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Kauer, J., Malenka, R. Synaptic plasticity and addiction. Nat Rev Neurosci 8, 844–858 (2007). https://doi.org/10.1038/nrn2234
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