Neuron Effects of Addiction


From Acute Drug Effects to Persistent Synaptic Adaptations

Addictive drugs mediate their reinforcing properties by targeting the mesocorticolimbic dopamine (DA) system, which we define as including the ventral tegmental area (VTA) and its major targets, the nucleus accumbens (NAc) and prefrontal cortex (PFC).

Despite their chemical diversity and individual molecular targets, all addictive drugs have in common that they increase DA concentrations in projection areas of the VTA as well as the VTA itself…In brief:

nicotine can directly increase firing of DA neurons through α4β2-containing nicotinic receptors that are expressed on DA neuronsOpioids, cannabinoids, the club drug γ-hydroxybutyrate (GHB), benzodiazepines primarily target GABAergic interneurons in the VTA and decrease their activity, which leads to an indirect increase of DA neuron activity

The psychostimulants cocaine, amphetamines, and ecstasy target the DA transporter (DAT), which is normally responsible for the reuptake of DA. Since midbrain DA neurons also release DA from their dendrites DAT inhibition causes an increase of DA in the VTA as well as in the NAc and PFC. Important mechanistic differences exist between the individual members of this class. Cocaine directly inhibits the DAT, while amphetamines are transporter substrates that are taken up into the cell to enhance nonvesicular release of DA. Psychostimulants have in common that they decrease the firing rate of DA neurons through D2 receptor-mediated autoinhibition. The Gi/o-coupled D2 receptors hyperpolarize DA neurons by activating GIRK/Kir3 channels. Because the block of DA reuptake exceeds the consequences of reducing DA cell firing frequency, there is nevertheless a net increase of ambient DA.

Addiction is normally defined as the compulsive use of a drug despite the negative consequences. An addictive drug has the potential to induce the disease, but does so only in a fraction of consumers. …However, the acute actions of drugs of abuse dissipate as the drug leaves the brain and therefore, alone, cannot explain the development of addictive behaviors. To understand addiction, we must elucidate the specific traces the drug experience leaves in the brain and which of these are causally related to the development of addiction. Here, we will focus on some of the key synaptic adaptations that occur after single or repetitive exposures to an addictive drug. This focus is based on the assumption that, like virtually all forms of adaptive experience-dependent plasticity, the neural circuit adaptations that underlie drug-induced behavioral changes will involve drug-induced synaptic changes.

Indeed, converging evidence from many studies suggests that addictive drugs modify synaptic transmission in the mesocorticolimbic DA system by hijacking mechanisms normally used for adaptive forms of experience-dependent synaptic plasticity; hence the term “drug-evoked synaptic plasticity.” However, the term should not imply that drug exposure alone is necessarily sufficient to elicit synaptic plasticity. On the contrary, many forms of drug-evoked synaptic plasticity appear to depend on the context in which the drug has been experienced, presumably because the final synaptic adaptation will depend both on the molecular action of the drug and the pattern of neural activity in the brain at the time the drug is experienced. It is also important to note that a single drug experience is certainly not sufficient to induce addiction. However, the synaptic and neural circuit adaptations caused by a drug experience often persist and lay the foundation upon which further drug-induced adaptations occur.

Focusing on the mesocorticolimbic DA system makes sense not only because it is well established to be a major site of action of addictive drugs, but also because it has long been considered a structure that is essential for translating motivations into goal-directed actions.


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