The Neurobiology of Opioid Dependence: Implications for Treatment

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 NAc to produce a normal level of pleasure. Koob and LeMoal suggest that opioids 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 opioids 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 above. Under this model, both the positive (drug liking) and negative (drug withdrawal) aspects of drug addiction are accounted for.

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 NAc: 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 opioid receptors by heroin and heroin-like drugs initially bypasses these brakes and leads to a large release of DA in the NAc. However, with repeated heroin 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 heroin to offset the reduction of normal resting DA release. When he or she stops the heroin use, a state of DA deprivation will result, manifesting in dysphoria (pain, agitation, 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 and 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 opioid withdrawal symptoms. This theory suggests that these cortical excitatory brain pathways are overactive in heroin addiction and that reducing their activity would be therapeutic. Scientists are currently researching a medication called lamotrigene and related compounds called excitatory amino acid antagonists to see whether this potential treatment strategy really can work.

Thus, several mechanisms in the LC and VTA-NAc 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 addicted individual 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.