Blog Series Part 2: Effects of Substance Abuse

Effects of Substance Abuse

Imaging studies have revealed neurochemical and functional changes in the brains of drug-addicted subjects that provide new insights into the mechanisms underlying addiction (Volkow, 2003).  Most studies of drug addiction have concentrated on the brain dopamine system, since this is considered to be the neurotransmitter system through which most drugs exert their reinforcing effects (Koob, 1988). A reinforcer is defined as an event that increases the probability of a subsequent response, and drugs are considered to be much stronger reinforcers than natural reinforcers, like food or sex (Wightman, 2002). The brain’s dopamine system also regulates motivation and drive for everyday activities (Wise, 2002).

Neurochemical studies have shown that large and fast increases in dopamine are associated with the reinforcing effects of the drug and also has shown that after chronic drug abuse and during withdrawal, brain dopamine function is markedly decreased (Volkow, 2003). These decreases are associated with dysfunction of the prefrontal regions of the brain, including the orbitofrontal cortex (Volkow, 2003). The changes in brain dopamine function are likely to result in decreased sensitivity to natural reinforcers since dopamine also mediates the reinforcing effects of natural reinforcers and on the disruption of frontal cortical functions, such as inhibitory control (Hyman, 2001).

Functional imaging studies have also shown that during drug intoxication, or during craving, these frontal regions become activated as part of a complex pattern that includes the nucleus accumbens, the orbitofrontal cortex, the amygdala and hippocampus, and the prefrontal cortex and cingulated gyrus (Nestler, 2001). The nucleus accumbens is the brain circuitry involved in reward, the orbitofrontal cortex is the brain circuitry involved in motivation, the amygdala and hippocampus are involved with memory, and prefrontal cortex and cingulated gyrus are involved with cognitive control (Nestler, 2001).

Thus, in drug addiction, the value of the drug and drug-related stimuli is enhanced at the expense of other reinforcers (Volkow, 2003). During exposure to the drug or drug-related cues, the memory of the expected reward results in overactivation of the reward and motivation circuits while decreasing the activity in the cognitive control circuit (Hyman, 2001). When cues or stimuli occur that are associated with drug seeking, increased activation of projections from the prefrontal cortex occurs, which, in turn, increases the release of glutamate in the core of the nucleus accumbens (Thanos, 2001). This increase in glutamate causes an increase in drug seeking and intake (Thanos, 2001). Such cues or stimuli might include anything previously associated the drug use, a stressor, or even a single dose of the drug.

The release of dopamine in the prefrontal cortex and the amygdale is necessary for the amygdale to recognize cue-associations with drug use which are the motivationally relevant events, and for the prefrontal cortex to exert its effect on the nucleus accumbens which mediates behavior (Volkow, 2002). However, drug use does not allow the prefrontal cortex to restrict the compulsion to seek out stimuli that have cue associations with drug use (Volkow, 2002). This whole process may be the reason for the addiction or loss of control, with the addict continuing to use the drug even though there is no longer pleasure in using it (Volkow, 2002).

The changes that occur after chronic drug use are more permanent than changes that occur during acute drug use and may be a reason why relapse occurs in addicts (Simkin, 2006). Since adolescents may not be able to differentiate between motivationally relevant and irrelevant events, when addiction occurs, the prefrontal cortex may increase the tendency to seek out risky behaviors whether they are relevant or not (Simkin, 2006). Alternatively, addiction may turn the otherwise less sensitive amygdale found in adolescents into a more sensitive adult-like amygdala that seeks out only drug associated relevant events (Simkin, 2006).

Although patients may use substances to self-medicate their manic symptoms, it has been shown that the use of multiple substances may actually exacerbate the neurobiologic effects (Khantzian, 1997). In one study, patients (aged 18-65 years) presented with active marijuana and alcohol use in the manic phase, the marijuana did not decrease the level of the manic state (Salloum, 2005). It was determined that although the sensation of feeling calmer with marijuana may have been experienced by bipolar substance abusers who were manic and using alcohol, the mania symptoms were actually worse in those who presented with bipolar disorder and marijuana and alcohol use than in those  with bipolar disorder and alcohol use alone (Salloum, 2005).

Use of multiple substances may be a sign of a more progressive addiction, which would likely decrease the ability to inhibit compulsive behavior and the level of mania (Salloum, 2005). Furthermore, the type of treatment used may have greater effect on those who are actively using marijuana during their presentation with mania and alcohol (Salloum, 2005). Those who were treated with lithium and psychosocial therapy in this study, as opposed to those treated with one of those therapies alone, had the highest percentage of heavy drinking days (Salloum, 2005). The individuals who used alcohol and marijuana were younger than the other study participants; because alcohol and marijuana are the most frequent substances of abuse in adolescents with bipolar disorder, early onset of bipolar disorder and multiple substance abuse disorders may have a greater neurobiologic effect on the immature brain if the disorders go undetected and untreated (Geller, 1999).

If substance abuse occurs before the development of bipolar disorder, there may be a more rapid onset of mania because there is less ability to control or inhibit symptoms of mania or mood associated with sub-cortical structures because of the effect of addiction on the orbitofrontal cortex (Chang, 2004; Goldstein & Volkow, 2002). If the bipolar disorder occurs before the substance abuse , the effect on the orbitofrontal cortex may strengthen the compulsion to use drugs (Larson, 2005). In addition, the addiction process changes the way the orbitofrontal cortex normally performs by forming different connections; thus, the orbitofrontal cortex may not function as it normally would have before the addiction (Larson, 2005).

The reorganization of these connections may prevent the orbitofrontal cortex from ever fully developing (Simkin, 2006). If normal functioning or maturation of the orbitofrontal cortex does not occur in adolescence, this may lead to less control of symptoms of mania in adulthood (Simkin, 2006). This could explain why early onset of mania has a higher risk for a worse prognosis. Alternatively, if all adolescents must rely more on the less efficient dorsolateral prefrontal cortex for inhibitory control during adolescence, the adolescent with bipolar disorder, who has a less mature dorsolateral prefrontal cortex, may have more difficulty throughout this period of time (Simkin, 2006). Decreases in N-acetylaspartate levels in the dorsolateral prefrontal cortex which is used primarily during adolescence for inhibition, were found in euthymic bipolar patients and manic bipolar patients as compared to healthy adolescent subjects (Simkin, 2006). It is believed that earlier detection and treatment of bipolar disorder and substance abuse disorder, whether presented separately or together, would increase the likelihood that the orbitofrontal cortex would be able to fully mature (Simkin, 2006).

Conclusion

Early detection and treatment of bipolar disorder and substance abuse disorder seems extremely important to normal brain development in adolescents. If the developmental processes  discussed in this paper are accurate, not treating adolescents with bipolar disorder and substance abuse disorder may prevent normal development of the brain and decrease the ability of the adolescent to function at his or her fullest potential upon reaching adulthood as well as avoid permanent neurological damage (Winters, 2008). Similarly, not treating these disorders early may decrease the responsiveness of mature brain to medication interventions (Simkin, 2006). Since neurobiology is still in the early stages, more research is necessary to pinpoint and understand the underlying causes of bipolar disorder and substance abuse disorder in the developing brain (Volkow, 2002). More research is also needed in the area of finding treatments that would allow normal development of the brain to occur despite the onset of psychiatric disorders.