Clinical Textbook of Addictive Disorders 3rd ed - R. Frances, S. Miller, A. Mack (Guilford, 2005) WW

10 I. FOUNDATIONS OF ADDICTIONidea is that drug abuse alters a biological or physiological setting or baseline.One variant, by Koob and LeMoal (2001), is based on the idea that neurons ofthe mesolimbic reward pathways are naturally “set” to release enough DA inthe N-Ac to produce a normal level of pleasure. Koob and LeMoal suggest thatabused drugs cause addiction by initiating a vicious cycle of changing this setpoint, such that the release of DA is reduced when normally pleasurableactivities occur and these abused drugs are not present. Similarly, a change inset point occurs in the LC, but in the opposite direction, such that NA releaseis increased during withdrawal, as described earlier, thus accounting for boththe positive (drug liking) and negative (drug withdrawal) aspects of drug addiction.A specific way that the DA neurons can become dysfunctional relates toan alteration in their baseline (“resting”) levels of electrical activity and DArelease (Grace, 2000). In this second variant of the changed set point model,this resting level is the result of two factors that influence the amount of restingDA release in the N-Ac: cortical excitatory (glutamate) neurons that drive theVTA DA neurons to release DA, and autoreceptors (“brakes”) that shut downfurther release when DA concentrations become excessive. Activation of varioustypes of receptors by abused substances, such as mu opiate receptors by heroin,initially bypasses these brakes and leads to a large release of DA in the N-Ac. However, with repeated drug use, the brain responds to these successivelarge DA releases by increasing the number and strength of the brakes on theVTA DA neurons. Eventually, these enhanced “braking” autoreceptors inhibitthe neurons’ resting DA release. When this happens, the dependent addict willtake even more of the abused drug, such as heroin, to offset the reduction ofnormal resting DA release. When he or she stops the drug use, a state of DAdeprivation will result, manifesting in dysphoria (pain, agitation, and malaise)and other withdrawal symptoms, which can lead to a cycle of relapse to druguse.A third variation on the set point change emphasizes the sensitivity toenvironmental cues that leads to drug wanting or craving rather than just reinforcementand withdrawal (Breiter et al., 1997; Robinson & Berridge, 2000).During periods when the drug is not available to addicts, their brains canremember the drug, and desire or craving for the drug can be a major factorleading to drug use relapse. This craving may represent increased activity of thecortical excitatory (glutamate) neurotransmitters, which drive the restingactivity of the DA-containing VTA neurons, as mentioned, and also drive theLC NA neurons. As the glutamate activity increases, DA will be released fromthe VTA, leading to drug wanting or craving, and NA will be released from theLC, leading to increased withdrawal symptoms, particularly with opiates such asheroin. This theory suggests that these cortical excitatory brain pathways areoveractive in addiction, and reducing their activity would be therapeutic. Basicscientists and clinicians are currently researching compounds called “excitatory