J Korean Med Assoc.  2013 Sep;56(9):762-770. 10.5124/jkma.2013.56.9.762.

Neurobiology, pharmacokinetics and pharmacodynamics of drug abuse

• Kim SY
• Lee JS
• Han DW

• KMID: 2015672
• DOI: http://doi.org/10.5124/jkma.2013.56.9.762

Abstract

All drugs of abuse, like neural rewarding behaviors such as sex and eating, increase extra-cellular dopamine (DA) levels in the nucleus accumbens (NA), which is a part of the common reward mesolimbic pathway from the ventral tegmental area (VTA) to the NA. As addiction progresses from initial use to obsessive compulsive use, the neurobiology shifts from a DA-based behavioral system to a predominantly glutamate-based one, still relying on DA. A DA release in the prefrontal cortex (PFC) and amygdala in the relapse stimulates glutamate transmission between the PFC and amygdala and glutamate release in the pathway from the PFC to the NA core, constituting a "final common pathway" for drug-seeking behavior. Dysfunction of critical PFC structures results in drug craving and impaired decision making. Inhalation and smoking are the routes of administration that allow the most rapid delivery of drugs to the brain, while intravenous injection maximizes the bioavailability of a drug. The pharmacokinetic properties of a drug that dispose the user to increased self-administration include rapid absorption, rapid entry into the central nervous system, high bioavailability, short half-life, small volume of distribution, and high free drug clearance. The pharmacokinetic properties associated with drug dependence are a long half-life, low free drug clearance, and presence of the drug at high enough concentrations and for a sufficient time to permit tolerance to develop. Pharmacokinetics and pharmacodynamics play an important role in predicting the dependence and abuse potential of drugs.

Keyword

Substance-related disorders; Dopamine; Neurobiology; Pharmacokinetics; Pharmacology

MeSH Terms

Absorption
Amygdala
Biological Availability
Brain
Central Nervous System
Decision Making
Dopamine
Drug-Seeking Behavior
Eating
Glutamic Acid
Half-Life
Inhalation
Injections, Intravenous
Neurobiology
Nucleus Accumbens
Prefrontal Cortex
Recurrence
Reward
Smoke
Smoking
Street Drugs
Substance-Related Disorders
Ventral Tegmental Area
Dopamine
Glutamic Acid
Smoke
Street Drugs

Figure

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  Figure 1 Models of the circuitry regulating the transition from psychostimulant reward to relapse. (A) Dopamine (DA) projections and how chronic psychostimulant use produces a transition from reliance on accumbens DA for drug reinforcement to reliance on the prefrontal and amygdale DA to trigger relapse, to DA in the caudate in regulating habit responding. (B) The circuitry in which DA projections are embedded that initiates relapse to drug-taking. DA input to the amygdala and prefrontal cortex is critical, as is the glutamatergic output from these regions to the NA. From Ross S, et al. Clin Neuropharmacol 2009;32:269-276, with permission from LWW [9].

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  Figure 2 Addiction circuitry. (A) Schematic and oversimplified sagittal view of a brain depicting four circuits that are postulated to have key interdependent and overlapping roles in addiction: 1) reward prediction and the core substrates of pleasure (red) located in the nucleus accumbens (NA) and ventral pallidum (VP); 2) memory and learning, and the main substrate of conditioning (purple), located in the amygdala (Amyg) and hippocampus (HIP); 3) motivation, drive and salience evaluation (green) located in the orbitofrontal cortex (OFC); and 4) cognitive control (blue), in charge of restraining cravings, located in the prefrontal cortex (PFC) and anterior cingulate gyrus (ACG). (B) Hypothetical model of addiction as the result of impaired information processing within the reward network. Compared with the non-addicted state (left), the salience value of a drug (red) and its associated cues (purple) is enhanced in the addicted state (right), whereas the strength of inhibitory control is weakened (blue), setting up the stage for an unrestrained motivation (green) resulting in compulsive drug taking without regard to potentially catastrophic consequences. From Baler RD, et al. Trends Mol Med 2006;12:559-566, with permission from Elsevier [2].

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