Samenvatting van dit proefschrift
Addiction to drugs of abuse such as cocaine and heroin is a disease characterized by loss of control over drug taking. Even when addicts quit for many months to years, they may encounter episodes of craving. In order to manage addiction a deeper understanding of this disease is necessary for the development of higher efficacy therapeutics. Animal models can play a vital role to this development, since the disease can be monitored from a drug-naive to the relapse state.
In order to understand addiction better, the factors that make individuals more vulnerable to addiction, before one comes in contact with the drug must be examined. It is currently thought that poor coping strategies to stressful situations may be linked to this. In addition, it is important to understand what factors maintain drug addiction in those individuals who have continued to use drugs. Until now, re-exposure to drug-related cues is known to trigger episodes of drug craving, which may lead to relapse into old habits.
The brain areas implicated in drug abuse include, but not limited to the target areas of the mesocorticolimbic system, which normally subserve naturally motivated behaviors such as eating and sex. These areas include, but are not limited to the medial prefrontal cortex (mPFC), orbital frontal cortex (oFC), nucleus accumbens core, shell (NAC, NAS), basolateral amygdala (BLA), and ventral tegmental area (VTA). Drugs of abuse are known to profoundly alter neural transmission, as a consequence molecular processes that are implicated in learning and memory, such as kinase phosphorylation and gene expression are affected. It is thought that through these processes, drug memories are powerfully consolidated and may underlie the persistence of phenomena such as craving. Therefore, aberrant functioning of these pathways may underlie addiction related behaviors. To that end, using an animal model, two key issues were examined in this thesis:
At the molecular level:
1) How does the brain of a potentially highly motivated cocaine abuser function in times of coping with stress?
2) How does the brain of a heroin abuser function during episodes of extreme drug desire?
In order to answer question 1), the high and low grooming (HG and LG) model was used. This model is very useful to study the relationship between coping with negative affect and motivation to use drugs. Rats engaged in self-grooming behavior when encountered with stressful situations like the elevated plus maze (EPM). HG rats compared to their LG counterparts, who are on the top and bottom quartile with respect to time spent self-grooming on the EPM, display more signs of stress and have an enhanced motivation to self-administer cocaine. HG and LG rats were selected and the molecular reactivity at the level of kinase (ERK, pkB, CamKIIa) reactivity and immediate early gene (IEG) (e.g. c-fos, arc, CRH) were examined immediately after EPM exposure. Although unique kinase phosphorylation and IEG expression patterns were found as a result of EPM exposure, no differences in molecular responsivity could be found between HG and LG rats. Other factors may be mediating the differences in responsivity to stress between the two groups.
For question 2), the cue-induced reinstatement model was employed to study brain functioning related to drug craving. Rats were trained to self-administer heroin and associate the rewarding effect of the drug with a complex compound cue for about 2 weeks. Following this phase was an extinction phase, lasting almost 3 weeks where responding for heroin did not result in a heroin delivery or cue presentation. One day after the last extinction session, rats were re-exposed to the heroin cue, which robustly elicited desire for heroin in the form of heroin seeking. As a result of cue exposure many genes were robustly induced in animals with a heroin history. In the mPFC, ania-3, mkp-1, c-fos, Nr4a3; and in the oFC and NAC ania-3 was induced. In order to see if this effect generalized to a seeking behavior for sucrose, a non-drug natural reward, the brains of animals who underwent the same behavioral testing procedures, but administered sucrose were examined, since these brain areas are known to be implicated in mediating motivation towards natural rewards. The IEG expression patterns did not generalize to sucrose seeking, indicating that different connectivity pathways in the brain may be involved in heroin vs. sucrose seeking behaviors.
The types of IEGs induced indicate various molecular neural adaptations that occur as a result of heroin, but not sucrose seeking: ania-3 (glutamate signaling), mkp-1 (ERK signaling), c-fos, Nr4a3 (transcription). Here, novel neural and molecular intervention targets that may have implications in interfering with heroin, but not sucrose seeking behaviors have been identified. The results here set the ground for further research in connecting these reactive areas and their corresponding molecular pathways to heroin, but not sucrose seeking, which has implications for anti-craving therapeutics development.