The idea behind this thesis was to utilize recent tools and techniques, such as a new DA sensor, fiber photometry, opto/chemogenetics, and transgenic mouse lines in combination with a robust animal model of addiction to determine a precise and specific circuit underling the reinforcing properties of opioids, as well as to establish causality. Indeed, our approach enabled us to be cell- (through targeting of either dopaminergic or GABAergic neurons) and pathway- (by focusing on VTA-NAc) specific. The degree of specificity and precision that the latest technological advances have made possible have revealed cellular mechanisms, brain circuits, and neural regulatory mechanisms more complex than envisaged in previous decades 91,237,255,256. Factors which determine the occurrence or prevalence of a behavior take place at the circuit level. The interaction between structures, the balance between inhibition and excitation, and the strength of synaptic connections constitute dynamic modulatory mechanisms of an interconnected network. This is complicated even more by the fact that a behavioral output can drastically vary due to structural heterogeneity and the neuronal subpopulation and subsequent targets that are activated following a stimulus. Indeed, considering neural structures as homogeneous and isolated entities is an outdated mentality.
Moreover, given the knowledge that has been gathered over the past decade (thanks mostly to optogenetics), studies based solely on lesions or pharmacology in wild-type animals 183,186,188 to
dismiss a hypothesis supported by a strong body of evidence are no longer considered sufficient. This is exactly why we attempted to address the DA hypothesis using new technology and tools. While we were able to gather a significant amount of data to investigate the crucial role of the VTA in
imparting the reinforcing properties of psychostimulants, we still lack the ability to generalize these findings to other drugs of abuse. Moreover, while addiction has been studied for decades now, the concept of a circuit model for addiction is a somewhat recent idea 257. Acknowledging that plasticity of glutamatergic synaptic transmission evoked by the strong activation of mesolimbic dopamine is the neural substrate of addictive behaviors has been a first step toward establishing this circuit model. The next challenges will be to identify relevant circuits to establish causalities and design protocols to reverse the traces left by drug exposure.
Another problematic issue in the field is the systematic use of psychostimulants, especially cocaine
87,258,259. Cocaine is surely a convenient substance to work with, as it is easy to obtain and is a powerful tool because of its well-defined pharmacological targets (unlike alcohol for example).
However, nicotine and ethanol are currently more devastating drugs, in terms of the size of the population they effect and their cost to society 260. The US is currently struggling with an “opioid crisis” as, prescribed opioids are causing more deaths than illegally obtained heroin and cocaine combined 23,261. Opening the field of investigation to a broader range of drugs of abuse is important since it will highlight the existence of several forms of addiction. As discussed in this thesis, even though it has been shown that opioids lead to strong activation of mesolimbic DA, the causality between this observation and the reinforcing properties of this class of drugs is strongly debated
104,184,257. This is why we think our results will improve the current knowledge of the neural circuits which underlie addiction. We are very aware of the limitations of using a rodent model and we do not claim to capture addiction in its totality; instead, we argue the importance of this study in addressing the specific role of DA in the earliest stage of heroin exposure. We are also fully aware that further tests must be conducted to fully appreciate the data we collected. Such studies should address the significance of the specific subset of the VTA population identified here, as well as whether these VTA DA neurons have unique characteristics, whether a specific form of plasticity occurs at their synapses, and the relevance of other pathways which have been shown to be involved in mediating the reinforcing properties of opioids (i.e LDT-VTA and PPT-VTA). It would also be
interesting to investigate the implications of our findings on the progression of addiction as a disease.
Finally, another striking point when studying the literature on opioids and opioid addiction is the unique place they occupy in the field. Opioids are often considered so specific that they should be studied independently of the other drugs of abuse. As discussed in the introduction of this thesis, the
use, abuse, and misuse of opioids can be dated back to the earliest civilizations, giving this class of drugs status as both a medicine and a drug of abuse. Studying opioid circuitry is complex and tricky since opioids have been shown to target structures outside of the VTA with behavioral impact when activated 95,97,262. Moreover, the presence of an endogenous opioid system which is widely
distributed throughout the nervous system and is involved in nociception and stress-related responses, in addition to the reward-related mechanisms associated with drug use, further
complicates efforts to untangle and precisely identify the neural circuits which underlie one specific behavioral outcome 10. It is also important to note that, in humans, addiction to opioids is often accompanied by addiction to other drugs of abuse. Additionally, individuals addicted to opioids face marginalization and social isolation, making it very difficult to conduct clinical studies on human cohorts 261,263.
Nevertheless, our results are more than encouraging and fit well with a circuit model of addiction, with the activation of mesolimbic DA as the key neural substrate. Understanding and refining existing knowledge of the circuitry of neuropathologies is the first step toward designing efficient treatments.
Using a multifaceted approach permitted us to tackle an old question from a new angle with unprecedented specificity. This angle of analysis will surely benefit the field of addiction. Many neurological disorders remain poorly understood, and better comprehension of the relevant circuits and potential synaptic dysfunctions which occur in these conditions may provide new perspectives in fundamental research and clinical treatment. Work such as this sets the stage for a challenging but exciting future for both researchers and clinicians.