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Drug-evoked synaptic plasticity causing addictive behavior - PubMed

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Drug-evoked synaptic plasticity causing addictive behavior

Christian Lüscher. J Neurosci. 2013.

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Figures

Figure 1.
Figure 1.

The mesocorticolimbic dopamine system as an initial target of addictive drugs. The VTA, at the origin of the mesocorticolimbic system, is composed of dopamine projection neurons that are under inhibitory control of GABA interneurons (somtimes described as an independent nucleus at the tail of the VTA, the rostromedial tegmentum). The main targets are the NAc and the mPFC. Addictive drugs cause an increase in mesocorticolimbic dopamine through three distinct cellular mechanisms: direct activation of dopamine neurons (e.g., nicotine); indirect disinhibition of dopamine neurons [opioids, gamma-hydroxybutyric acid (GHB), cannabinoids, and benzodiazepines]; as well as interference with dopamine reuptake (cocaine, ecstasy, and amphetamines). Note that the latter group also increases dopamine in the VTA itself, owing to the perturbation of the reuptake of dendritically released dopamine (modified from Lüscher and Malenka, 2011, with permission).

Figure 2.
Figure 2.

Drug-evoked synaptic plasticity in dopamine neurons of the ventral tegmental area. Addictive drugs or strong stimulation of dopamine neurons causes a synaptic plasticity on the excitatory afferents. This plasticity is expressed by the dual exchange of AMPA and NMDA receptors: GluA2-lacking AMPA receptors and GluN3A-containing NMDA receptors are inserted. As a consequence calcium enters the postsynaptic cell more readily when the membrane is hyperpolarized, which inverts the rules for activity-dependent synaptic plasticity. At baseline, LTP is induced when glutamate is released onto depolarized dopamine neurons (Hebbian LTP that is NMDAR dependent), while after cocaine exposure LTP can be observed when glutamate transmission coincides with a hyperpolarization (anti-Hebbian LTP that is AMPAR dependent). Normal transmission is restored by the activation of mGluR1. Together, addictive drugs evoked a permissive metaplasticity at excitatory afferents onto VTA dopamine neurons, which gate subsequent adaptations downstream (see text).

Figure 3.
Figure 3.

Experimental blueprint to establish causal relationship between drug-evoked synaptic plasticity and drug-adaptive behavior. In gray example experiments are from a proof-of-principle study (Pascoli et al., 2011). For further explanation see text.

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