Addiction is a pathological state that involves a transition from casual to compulsive patterns of drug use, characterized by an intensification of drug-seeking behavior and a vulnerability to relapse. My long-term goals are to understand the function of the neuronal circuits mediating addiction and how altered neuronal transmission within these circuits may contribute to the development and the persistence of this disorder. Several theoretical explanations have been proposed to explain addiction;one of the prominent theories is incentive sensitization developed by Robinson and Berridge (1993). This theory of addiction focuses on how drug cues trigger excessive incentive motivation for drugs, leading to compulsive drug seeking, drug taking, and relapse. To investigate this theory, researchers developed a behavioral model to measure the long-lasting increase to the psychomotor stimulatory and rewarding effects of drug of abuse following repeated drug exposure: this increased psychomotor stimulation is termed behavioral sensitization. This behavioral phenotype is a prominent model for the intensification of drug craving that occurs in human addicts with repeated drug exposure. Drug rewarding effects are known to be mostly mediated by the mesocorticolimbic system. Mainly, three brain structures have drawn attention in the study of drug addiction: prefrontal cortex (PFC), ventral tegmental area and the nucleus accumbens (NAc). Specifically, NAc, a regulator of motivated behaviors, is known to be a key site for cocaines actions both in humans and in experimental animals. For these reasons, studying the long-lasting neuronal adaptations occurring in the NAc, receiving information from the PFC, is a critical step in understanding important behavioral aspects and features characterizing drug addiction. Not surprisingly, repeated exposure to cocaine results in persistent adaptations in this key nucleus that are thought to underlie behavioral abnormalities in this animal model of addiction. Most of the advancement made on how neuronal excitability relates to behavioral sensitization has focused on adaptations in mesolimbic glutamatergic neurotransmission. However, knowledge is lacking about the ability of cocaine and other drugs of abuse to produce long-lasting changes in another fundamental determinant of neuronal excitability: intrinsic membrane properties. Indeed, plasticity in intrinsic excitability, characterized by a lasting change in the neurons capability to generate action potentials, is more and more recognized as an important means through which experience modifies neural circuits, and is thought to play an important role in models of multiple central nervous system disorders. To date, my work has established that a sensitizing treatment to cocaine triggers a long-lasting decrease in the neuronal excitability of the NAc that is manifested by a reduction of the number of action potentials that the neuron can generate. However, the mechanism by which cocaine leads to this neuronal adaptation still need to be discovered. Recent studies showed that Sigma-1 receptor (Sig-1R), a protein that reside in intracellular compartments can, upon stimulation, translocate to the surface of the cell where it can regulate a variety of ionic channelsthe main elements that are known to control intrinsic excitability and be affected by cocaine exposure. Because cocaine is known to induce the translocation of Sig-1R from intracellular compartment to the plasma membrane, we hypothesize that Sig-1R may be a link between cocaine exposure and changes in intrinsic excitability. To test this hypothesis I used an electrophysiological technique that allow to record neuronal excitability from brain slices preparation following in vivo cocaine associated or not with manipulation of Sig-1R function. I found that injection of Sig-1R antagonist can prevent both cocaine-induced changes in intrinsic excitability and the development of psychomotor sensitization. This indicates that Sig-1R may be a key element in the development of abnormalities in neuronal function that follow cocaine exposure. In my future research, I plan a systems-approach using complementary behavioral, neurochemical and cellular electrophysiology techniques to address important questions related to this phenomenon. Together, it will be possible to answer questions of behavioral relevance at multiple levels ranging from molecular to cellular to systems. This will provide insight into the cellular and molecular mechanisms of important phenomena that may hold some of the clues to drug addiction.
| Britt, Jonathan P; Bonci, Antonello (2013) Optogenetic interrogations of the neural circuits underlying addiction. Curr Opin Neurobiol 23:539-45 |
| Kourrich, Saïd; Hayashi, Teruo; Chuang, Jian-Ying et al. (2013) Dynamic interaction between sigma-1 receptor and Kv1.2 shapes neuronal and behavioral responses to cocaine. Cell 152:236-47 |
| Kourrich, Saïd; Su, Tsung-Ping; Fujimoto, Michiko et al. (2012) The sigma-1 receptor: roles in neuronal plasticity and disease. Trends Neurosci 35:762-71 |
