The use and abuse of addictive substances are rife throughout the world. Tobacco and alcohol consumption are the fourth and fifth greatest contributors to the global burden of disease (World Health Organization). In western society, characterized here by the USA and UK, heroin and crack cocaine also make serious contributions to morbidity and mortality rates.
Introduction of Substance Abuse Disorders
By definition, the pharmacological actions of addictive drugs elicit enduring pathological changes in brain function. The pathological adaptations render the addict less responsive to interpersonal and social relationships and subject to an intrusive drive to seek and use drugs that successfully competes with engaging in biologically adaptive behaviors. Thus, there are two cardinal behavioral characteristics of addiction: (1) reduced responding to biological rewards such as social cooperation; and (2) inability to regulate the drive to seek drug reward. From a sociobiological perspective, addiction is caused by drug-induced changes in brain function that cause the drive to obtain and use drugs to supersede the drive to obtain biological rewards. Accordingly, a primary goal for treating addiction is to restore brain function and thereby allow addicts to regulate and suppress drug use.
Neurobiology of Addiction
Our understanding of the neurobiology of addiction is derived primarily from two research directions. The first major research effort is to understand the acute pharmacological actions of drugs of abuse that produce reward and reinforce the behavior. The second major direction is to understand the enduring neuroplasticity produced by addictive drugs that ultimately result in the cardinal features of addiction (e.g., augmented drive to obtain drugs and diminished drive for biological rewards).
The biological basis of the rewarding effects of addictive drugs and their ability to reinforce drug-seeking behavior has been distilled to activation of dopamine transmission in corticolimbic brain regions. The effect most widely agreed upon is that drugs promoting the release of dopamine into the nucleus accumbens will reinforce behaviors to obtain more drugs. Thus, while the initial molecular binding site for various classes of addictive drugs varies tremendously, all drugs have been found to increase dopamine release.
The progressive neuroplasticity facilitated by repeated drug-induced dopamine release resides to a great extent in excitatory synapses. The population of synapses most carefully studied in this regard is the glutamatergic synapses in the caudate and nucleus accumbens that arise from cortical and also cortical brain regions. Thus, enduring changes in glutamate release, the morphology of dendritic spines, and glutamate signaling have all been shown in animal models of relapse. Behavioral studies showed that corticofugal glutamatergic projections are necessary for drug-seeking in animal models and correspond to areas showing increased blood flow when the craving is induced in addicts, including the anterior cingulate, ventral orbital cortex, and amygdala.
Treatment of Substance Abuse Disorders
There is significant overlap in the circuitry and neurochemistry between different substance dependences. This includes increases in dopamine transmission in cortical and striatal regions produced by repeated drug use that facilitates pathological neuroplasticity underlying addiction, as well as changes in excitatory transmission in corticostriatal projections that mediate the intrusive and uncontrollable urges to take addictive drugs. Pharmacotherapy can modulate these systems, such as glutamatergic drugs in cocaine addiction (e.g., N-acetylcysteine and modafinil) and opioid antagonists in alcohol addiction. Besides pharmacotherapy, deep-brain stimulation (DBS) may play a role. In a preclinical model, DBS of the nucleus accumbens shell significantly attenuated the reinstatement of cocaine-seeking. Individuals who underwent DBS of the nucleus accumbens for a variety of neuropsychiatric conditions had higher rates of smoking cessation than the general population.
There is an ample and growing body of preclinical and neuroimaging evidence that informs us of the underlying neural circuitry of addiction and associated cognitive changes, both in terms of specific substances of abuse and in terms of global theories of addiction. With further research on psychiatric drug development, it seems likely that the near future will provide us with increasingly effective and biologically targeted pharmacotherapeutic treatments for drug addiction.
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