Neurobiology of addiction

Almost all addictive drugs act on the brain reward system. However, unlike natural rewards, which when familiar cease to elicit dopamine release, addictive drugs continue to  cause dopamine release with  repeated exposure, resulting in  dysregulation of the reward and  affective basal  ganglia circuits, and  eventually long-term neuroplasticity that underpins craving and  compulsive drug-seeking behavior.Cocaine addiction can be induced and studied in animals. Cocaine produces tolerance through blocking the dopamine transporter (DAT) in the presynaptic terminals of mesolimbic neurons limiting dopamine reuptake so the concentration of transmitter in the synaptic cleft is raised. This causes down regulation of postsynaptic dopamine receptors. In addition dopamine binding to presynaptic receptors reduces dopamine synthesis and release. The overall effect is that higher amounts of transmitter and hence drug are required to achieve the similar level of dopamine transmission when drug use stops dopamine transmission in the mesolimbic system drops below normal. This loss in the effectiveness of the brain reward system is probably responsible for the lack of pleasure given by natural rewards seen with drug withdrawal.

Activation of D1 receptors that are positively coupled to cAMP switches on transcription of the creb gene. CREB (cAMP response element binding protein) is itself a transcription factor that influences the expression of genes with the cAMP response elements (cre) in their regulatory domains; that is, genes switched on by increases in cAMP. When the drug is withheld, the CREB changes reverse with a time course that matches the abstinence syndrome; hence creb overexpression contributes to this unpleasant phenomenon.

With   continued  drug   usage  eventually, and   paradoxically,  the   mesolimbic  system becomes more  sensitive to the  effects  of the  drug,  overwriting the  preexisting tolerance. This appears to be due to a gradual increase in the expression of a Fos family transcription factor, DFosB, in the nucleus accumbens. This molecule increases the expression of GluR2 AMPA receptors, cell signaling molecules, and brain-derived neurotrophic factor (BDNF), which can stimulate dendritic growth. DFosB expression may be the switch for transition from acute drug responses to chronic plastic changes in addiction.

In the early stages of drug use craving arises from the release of dopamine in the nucleus accumbens. As addiction takes hold and dopamine transmission in the mesolimbic system reduces, increased metabolic activity in the orbitofrontal cortex contributes to craving. This transition is due to glutamate-mediated plastic changes in ventral tegmental area, nucleus accumbens, and cortex akin to that which underpins learning in the hippo- campus and elsewhere, namely long-term potentiation (LTP) and long-term depression (LTD).

Recent history of drug experience alters the direction of plasticity at nAc excitatory synapses. Thus LTP occurs in the medium spiny neurons during a drug-free period after cocaine addiction has been established. This is accompanied by increased numbers of AMPA receptors and dendritic spines on MSN cells, making them more sensitive to excitatory inputs from the orbitofrontal and cingulate cortex, and amygdala, some of which encode drug-contextual learning. Remarkably, just a single dose of cocaine reverses this to bring about LTD, a reduced responsiveness to glutamate, most probably by NMDA receptor-controlled endocytosis of AMPA receptors. There is increasing evidence that inhibition of nucleus accumbens MSNs (GABAergic projection neurons), for example by LTD, promotes reward-seeking behavior, perhaps by disinhibiting downstream regions such as the ventral pallidum.

Vulnerability to relapse in long-term addicts lasts for years, implying that the neuroplasticity is extremely enduring or even irreversible by this stage.  Moreover, reinstatement of drug-seeking now depends on dopamine release not in the nucleus accumbens but in the amygdala and prefrontal cortex, probably due to plastic changes there.