The Changed Set Point Model

The "changed set point" model of drug addiction has several variants based on the altered neurobiology of the DA neurons in the VTA and of the NA neurons of the LC during the early phases of withdrawal and abstinence. The basic idea 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 of the mesolimbic reward pathways are naturally "set" to release enough DA in the N-Ac to produce a normal level of pleasure. Koob and LeMoal suggest that abused drugs cause addiction by initiating a vicious cycle of changing this set point, such that the release of DA is reduced when normally pleasurable activities occur and these abused drugs are not present. Similarly, a change in set point occurs in the LC, but in the opposite direction, such that NA release is increased during withdrawal, as described earlier, thus accounting for both the positive (drug liking) and negative (drug withdrawal) aspects of drug addiction.

A specific way that the DA neurons can become dysfunctional relates to an alteration in their baseline ("resting") levels of electrical activity and DA release (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 resting DA release in the N-Ac: cortical excitatory (glutamate) neurons that drive the VTA DA neurons to release DA, and autoreceptors ("brakes") that shut down further release when DA concentrations become excessive. Activation of various types 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 successive large DA releases by increasing the number and strength of the brakes on the VTA DA neurons. Eventually, these enhanced "braking" autoreceptors inhibit the neurons' resting DA release. When this happens, the dependent addict will take even more of the abused drug, such as heroin, to offset the reduction of normal resting DA release. When he or she stops the drug use, a state of DA deprivation will result, manifesting in dysphoria (pain, agitation, and malaise) and other withdrawal symptoms, which can lead to a cycle of relapse to drug use.

A third variation on the set point change emphasizes the sensitivity to environmental cues that leads to drug wanting or craving rather than just reinforcement and withdrawal (Breiter et al., 1997; Robinson & Berridge, 2000). During periods when the drug is not available to addicts, their brains can remember the drug, and desire or craving for the drug can be a major factor leading to drug use relapse. This craving may represent increased activity of the cortical excitatory (glutamate) neurotransmitters, which drive the resting activity of the DA-containing VTA neurons, as mentioned, and also drive the LC NA neurons. As the glutamate activity increases, DA will be released from the VTA, leading to drug wanting or craving, and NA will be released from the LC, leading to increased withdrawal symptoms, particularly with opiates such as heroin. This theory suggests that these cortical excitatory brain pathways are overactive in addiction, and reducing their activity would be therapeutic. Basic scientists and clinicians are currently researching compounds called "excitatory amino acid antagonists" to see whether this potential treatment strategy really can work.

Thus, several mechanisms in the LC and VTA-N-Ac brain pathways may be operating during addiction and relapse. The excitatory cortical pathways may produce little response in the VTA during the resting state, leading to reductions in DA. However, when the addict is exposed to cues that produce craving, the glutamate pathways may get sufficiently active to raise DA and stimulate desire for a greater high. This same increase in glutamate activity will raise NA release from the LC to produce a dysphoric state predisposing to relapse and continued addiction.

The Cognitive Deficits Model

The cognitive deficits model of drug addiction proposes that individuals who develop addictive disorders have abnormalities in an area of the brain called the prefrontal cortex (PFC). The PFC is important for regulation of judgment, planning, and other executive functions. To help us overcome some of our impulses for immediate gratification in favor of more important or ultimately more rewarding long-term goals, the PFC sends inhibitory signals to the VTA DA neurons of the mesolimbic reward system.

The cognitive deficits model proposes that PFC signaling to the meso-limbic reward system is compromised in individuals with addictive disorders; as a result, they have reduced ability to use judgment to restrain their impulses and are predisposed to compulsive drug-taking behaviors. Consistent with this model, stimulant drugs such as methamphetamine appear to damage the specific brain circuit—the frontostriatal loop—that carries inhibitory signals from the PFC to the mesolimbic reward system. In addition, a recent study using magnetic resonance spectroscopy showed that chronic alcohol abusers have abnormally low levels of GABA, the neurochemical that the PFC uses to signal the reward system to release less DA (Behar et al., 1999). As well, the cognitive deficits model of drug addiction could explain the clinical observation that heroin addiction is more severe in individuals with antisocial personality disorder—a condition that is independently associated with PFC deficits (Raine, Lencz, Bihrle, LaCasse, & Colletti, 2000).

In contrast to stimulants and perhaps alcohol, heroin apparently damages the PFC but not the frontostriatal loop. Therefore, individuals who become heroin addicts may have some PFC damage that is independent of their opioid abuse, either inherited genetically or caused by some other factor or event in their lives. This preexisting PFC damage, which predisposes individuals to impulsivity and lack of control, may be important for most individuals who become addicted to drugs, and the additional PFC damage from chronic repeated drug abuse, particularly abuse of stimulants, increases the severity of these problems (Kosten, 1998).

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