Drug-evoked synaptic plasticity in addiction: from molecular changes to circuit remodeling

Abstract

Addictive drugs have in common that they target the mesocorticolimbic dopamine (DA) system. This system originates in the ventral tegmental area (VTA) and projects mainly to the nucleus accumbens (NAc) and prefrontal cortex (PFC). Here, we review the effects that such drugs leave on glutamatergic and GABAergic synaptic transmission in these three brain areas. We refer to these changes as drug-evoked synaptic plasticity, which outlasts the presence of the drug in the brain and contributes to the reorganization of neural circuits. While in most cases these early changes are not sufficient to induce the disease, with repetitive drug exposure, they may add up and contribute to addictive behavior.

Figure 1. The mesocorticolimbic dopamine system as target of addictive drugs

On a saggital slice, the vental tegmental area (VTA), the nucleus accumbens (NAc) and the prefrontal cortex (PFC) can be visualized. The projection neurons are mostly dopaminergic, and under inhibitory control of local GABA neurons (i.e. interneurons). Enlaged schematics to illustrate three cellular mechanims, by which addictive drugs increase mesolimbic DA levels. Nicotine can directly depolarize DA neurons, while opioids, GHB, benzodiazepines and cannabinoids act indirectly via pre- and postsynaptic inhibition of interneurons (i.e. disinhibition). Cocaine, amphetamines and ecstasy target the dopamine transporter (DAT) on axon terminals as well as on dendrites of DA neurons. While cocaine act as an inhibitor of the DAT, promote amphetamines and ecstasy non-vesicular release. In both cases DA levels in the VTA, NAc and PFC increase.

Figure 2. Drug-evoked synaptic plasticity in excitatory synapses onto VTA DA neurons

The schematics are drawn from a postembedding EM micrograph of a drug-naive mouse (courtesy Rafael Lujan, Albacete). Note that these asymetrical synapses are made directly onto the shaft of the dendrite (aspiny shaft synapse). In naïve animals NMDARs and AMPARs are present, the latter all containing GluA2. After one dose of cocaine, some GluA2 containing AMPARs are exchanged for GluA2 lacking ones through mechanisms involving endo- and exocytosis. After a week of a passive injection (months after self-administration) the baseline composition is restored through mGluR1 activation, mTOR signaling and de novo synthesis of GluA2 from prefabricated mRNA. Throughout the whole process the total number of receptors remains constant.

Figure 3. Drug-evoked synaptic plasticity in excitatory synapses onto medium spiny neurons in the NAc

The schematics are drawn from postembedding EM micrograph of a drug-naive mouse (courtesy Rafael Lujan, Albacete). Note that these neurons have prominent spines. In naive animals NMDARs and GluA2-containing AMPARs are present. After several dose of cocaine (or a challenge dose that terminates withdrawal), some AMPARs are endoytosed and the synapse depressed. After weeks of withdrawal, GluA-lacking AMPARs appear, which lead to a potentation of this synapse.

Figure 4. Emerging model of mesolimbic circuit known to be affected by drug-evoked synaptic plasticity

For simplicity several projections have been omitted to highlight the synapses that undergo drug-evoked adaptations. For further explanation see text. Dopamine neurons (red) GABA neurons (green) and glutamate neurons (blue).