FIGURE 32–1 Major connections of the mesolimbic dopamine system in the brain. Schematic diagram of the brain illustrating that the dopamine projections (red) originate in the ventral tegmental area (VTA) and target the nucleus accumbens (NAc), prefrontal cortex (mPFC), basolateral amygdala (BLA), and ventral pallidum (VP). Neurons in the NAc fall into two classes, one expressing type 1 dopamine receptors (D1s) and the other expressing type 2 receptors (D2s). Both classes contain GABAergic projection neurons (green); the D1R neurons send their axons to both the VP and the VTA (where they target primarily the GABA interneurons), whereas the D2R neurons send their axons selectively to the VP. The NAc is also a site of convergence of excitatory projections from the mPFC, the ventral hippocampus (vHippo), and the BLA. The midbrain dopamine neurons receive a direct excitatory input (blue) from the lateral dorsal tegmentum (LDT), while the GABA neurons of the rostromedial tegmentum (RMTg) at the tail of the VTA are excited by neurons from the lateral habenula (LHb), typically when an aversive stimulus occurs. (Modified with permission from Lüscher C: Emergence of circuit model for addiction. Ann Rev Neurosci 2016;39:257.)
As a general rule, all addictive drugs activate the mesolimbic dopamine system. The behavioral significance of this increase of dopamine is still debated. An appealing hypothesis is that mesolimbic dopamine codes for the difference between expected and actual reward and thus constitutes a strong learning signal (see Box: The Dopamine Hypothesis of Addiction).
Since each addictive drug has a specific molecular target that engages distinct cellular mechanisms to activate the mesolimbic system, three classes can be distinguished: A first group binds to Gio protein-coupled receptors, a second group interacts with ionotropic receptors or ion channels, and a third group targets the dopamine transporter (Table 32–1 and Figure 32–2). G protein-coupled receptors (GPCRs) of the Gio family inhibit neurons through postsynaptic hyperpolarization and presynaptic regulation of transmitter release. These three classes of drugs loosely map onto three distinct cellular mechanisms to increase dopamine levels. The first is a direct stimulation of the dopamine neurons (eg, nicotine). The second mechanism is the interference with the reuptake of dopamine or the promotion of nonvesicular release (eg, amphetamines). This happens in the target regions as well as the VTA itself, because dopamine neurons also express somatodendritic transporters, which normally clear dopamine released by the dendrites. Although drugs of this class also affect transporters of other monoamines (norepinephrine, serotonin), action on the dopamine transporter remains central for addiction. This is consistent with the observations that antidepressants that block serotonin and norepinephrine uptake, but not dopamine uptake, do not cause addiction even after prolonged use. The third mechanism is indirect, whereby the drugs inhibit γ-aminobutyric acid (GABA) neurons that act as local inhibitory interneurons (eg, opioids).
DEPENDENCE: TOLERANCE & WITHDRAWAL
With chronic exposure to addictive drugs, the brain shows signs of adaptation. For example, if morphine is used at short intervals, the dose has to be progressively increased over the course of several days to maintain rewarding or analgesic effects. This phenomenon is called tolerance. It may become a serious problem because of increasing side effects—eg, respiratory depression—that do not show as much tolerance and may lead to fatalities associated with overdose.