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Abstract

Cocaine addiction is a chronic mental illness affecting a small subgroup of cocaine users (approx. 18%). Little efforts have been taken so far to understand individual differences in the vulnerability to cocaine addiction; i.e. it is unclear why some users become addicted whereas the majority of them are able to maintain the control over drug-taking and -seeking. Most preclinical studies have not considered the possibility to study individual differences in addiction vulnerability and furthermore may explain the high failure rates of drugs that reach Phase III-IV of clinical trials. Hence, a translational animal model is fundamental to produce meaningful results to the clinic. In this thesis, a DSM-IV/5-based preclinical model of cocaine addiction was used to identify pre-existing vulnerability differences and the changes produced by pathological state of addiction. The so-called 0/3crit animal model consists of training rats for intravenous cocaine self-administration for at least 45 sessions. Thereafter, three main DSM-based addiction behavioral criteria were tested, (1) motivation to take the drug, (2) persistence to seek the drug, and (3) persistence of self-administration despite negative consequences (i.e., application of an electric foot-shock). For each of the three criteria, a score of either 1 or 0 was given to animals performing above or below 60th percentile of the population distribution, respectively. Animals positive for all criteria (3crit) were classified as addicted-like, whereas animals negative for all criteria (0crit) were classified as non-addicted-like/resilient rats. This thesis had three aims: (i) Neuroimaging studies in cocaine addicts revealed various structural and functional changes but findings are inconclusive and this may be due to pre-existing features in the function or structure in brains of vulnerable subjects and different drug intake patterns. Based on this, longitudinal studies, particularly in controlled animal models, are warranted. Here a longitudinal translational multimodal neuroimaging study was performed using the 0/3crit animal model of cocaine addiction to investigate pre-existing differences and changes in brains of cocaine addicted-like and non-addicted-like rats. (ii) Conditioned cocaine cues can trigger craving and relapse. Pavlovian conditioned stimuli can also impact ongoing instrumental behavior, even if the instrumental behavior is acquired independently of Pavlovian conditioning. This process is called Pavlovian-to-Instrumental transfer (PIT). A hypothesis in drug addiction posits that Pavlovian conditioned cues can bias instrumental behavior towards drug seeking and intake and that a more pronounced PIT response occurs in vulnerable subjects. The second aim was therefore to test this hypothesis and to ask whether 3crit rats show a more pronounced PIT response than 0crit rats. (iii) Pharmacological treatments in cocaine addiction are still lacking. In previous preclinical studies different glutamate receptor antagonists and GABAB agonists such as baclofen, have been tested but either failed in clinical studies or reported severe side effects in pharmacovigilance. Here, different pharmacological approaches were taken: First, the novel GABAB positive allosteric modulator CMPPE was tested in comparison to baclofen in order to produce lesser side effects. Second the NR3A subunit was selectively targeted as an alternative to NMDAR antagonists. Finally, melatonin was tested for normalizing altered circadian rhythmicity in cocaine addiction.

The longitudinal MRI results revealed structural changes in the brains of 3crit and 0crit rats. Grey matter (GM) volume was found to have increased in prelimbic (Prl) and cingulate (Cg) cortices, nucleus accumbens (NAc), caudate putamen (CPu), substantia nigra, and ventral and globus pallidum in the 3crit group, whereas 0crit rats showed no changes in GM volume, except for the CPu, compared to control. Diffusion tensor imaging (DTI) analysis revealed a higher fractional anisotropy in the zona incerta in the 0crit rats compared to 3crit rats. PET results showed higher activity of mPFC and right CPu in the 0crit group compared to controls. Arc expression was significantly reduced in the infralimbic (IFL) cortex in the 3crit group. Salience of conditioned-cues was found similar in 0crit and 3crit rats in the PIT paradigm. Positive allosteric modulator of GABAB receptors and melatonin abolished cue-elicited cocaine-seeking behavior.

In summary, cocaine addiction produced structural changes in brain regions central for motivation and drug rewarding effects in 3crit rats, whereas the addiction resilient rats showed increased volume in brain regions involved in habit behavior as well as an increased in microstructural integrity in a brain area that regulates adaptive behavior. Functional assessments indicated the relevance of the mPFC (Prl and IFL) activity for both controlled or compulsive drug-seeking and –taking. These results agree with clinical studies, where mPFC function negatively correlates with impulsive behavior in psychostimulant abusers as well as changes were found in brain regions, such as Prl, Cg, CPu, and NAc, that are known to play a role in drug addiction. Moreover, other factors, such as structural and functional changes, instead of Pavlovian or instrumental conditioning may lead to addiction behaviors because salience to conditioned stimuli and learning ability were similar between the groups. And finally, positive allosteric modulator of GABAB receptors and melatonin appears to be promising candidates for medication development in cocaine addiction. The 0/3crit model of cocaine addiction has excellent face validity and can be used to study the underpinning mechanisms that lead to compulsive drug use.