Epileptiform Synchronization of the Anterior Cingulate Cortex of the Rat and its Modulation by Mu-Opioid Receptor

Over the past century, the cingulate cortex has been catching the interest of both basic science and clinical research in various fields of investigation due to its involvement in several physiological functions. This brain region can in fact modulate affection and behavior, motor responses and autonomic functions, and it has been implicated in the pathophysiology of psychiatric disorders and epilepsy. The relevance of considering seizures arising from the cingulate gyrus as a distinct neurological entity has been considered in light of the capability of this brain region to directly affect the functional balance of a more extensive system, involving frontal and temporal areas. The term “cingulate epilepsy” identifies a chronic neurological syndrome, which can be distinguished from other epileptic conditions by its peculiar clinical manifestations. The anterior cingulate cortex presents with a high density of opioid receptors, which account for the involvement of this cortical area in pain perception. Nonetheless, opioid receptors may be relevant to epilepsy as well, providing their contribution as modulators of cortical activity. However, whether opioid receptors exert a pro- or an anti-convulsant effect is still matter of debate. In light of the high expression of opioid receptors, the cingulate cortex represents a valuable anatomical substrate to address this question. Nonetheless, the data available from in vitro investigation performed so far are contradictory regarding the effect of opioid receptor activation on excitatory and inhibitory activities in this cortical area. Some inconsistencies are uncovered when comparing receptor-binding studies with electrophysiological investigations. Moreover, the currently available information about the role and involvement of the anterior cingulate cortex in epilepsy is mainly based upon clinical and imaging findings, while in vitro studies remain scarce, in light of the fact that the major interest regarding this cortical area points to its role in emotion and pain. Nonetheless, cingulate epilepsy accounts today for ~30% of brain surgery for refractory epilepsy in the United States. This leads to the need of finding new therapeutic approaches for the treatment of this neurological disorder. To this aim, understanding the basic mechanisms underlying epilepsy is of primary importance. This Thesis reports an in vitro electrophysiological study of the basic synaptic mechanisms underlying the generation of epileptiform discharges in the anterior cingulate cortex of the rat. Further experimental investigation is dedicated to clarify the role of muopioid receptor activation in epileptiform activity generated by this cortical area. Part I provides the reader with a general comprehensive overview of the structure and function of the anterior cingulate cortex, and summarizes the main clinical aspects of cingulate epilepsy. A separate chapter is dedicated to report the current knowledge about the role of opioid receptors in synaptic transmission in this cortical area. Part II provides an insight into the experimental approach by describing the model and the technique. Part III illustrates the electrophysiological findings of the current study and discusses the possible implications in epilepsy research. Most of the experiments presented in Part III were performed at the Montreal Neurological Institute, McGill University, in the laboratory of Dr. Massimo Avoli, and are published in Epilepsia (Panuccio et al., 2008, see Appendix II). In this section, Chapters 5 (Results) and 6 (Discussion) are excerpts from the published paper.