Past events

Abstract: Using a rat model of drug relapse and craving, we previously found time-dependent increases in cocaine seeking induced by exposure to drug cues after withdrawal from the drug, suggesting that cocaine craving incubates over time. In this lecture, I will first summarize our earlier behavioral and neurophysiological studies on incubation of cocaine craving. I will then discuss in more detail results from more recent studies implicating neuronal activity in the ventromedial prefrontal cortex and glutamate synaptic plasticity in the nucleus accumbens in the incubation of cocaine craving. I will also briefly address the relevance of our rat findings to the understanding of relapse to drug use in humans. Selected references related to incubation of cocaine craving Grimm JW, Hope B, Wise RA, Shaham Y (2001) Incubation of cocaine craving after withdrawal. Nature 412:141-142 Grimm JW, Lu L, Hayashi T, Su TP, Hope BT, Shaham Y (2003) Time dependent increases in brain-derived neurotrophic factor (BDNF) protein levels within the mesolimbic dopamine system following withdrawal from cocaine: implications for incubation of cocaine craving. The Journal of Neuroscience 23:742-747 Lu L, Dempsey J, Liu S, Bossert J, Shaham Y (2004) A single infusion of BDNF into the ventral tegmental area induces long-lasting potentiation of cocaine-seeking after withdrawal. The Journal of Neuroscience 24:1604-1611 Lu L, Grimm JW, Hope BT, Shaham Y (2004) Incubation of cocaine craving after withdrawal: a review of preclinical data. Neuropharmacology 47(S1): 214-227 (invited review for a special issue commemorating 30 years of NIDA research) Lu L, Hope BT, Dempsey J, Liu S, Bossert JM, Shaham Y (2005) Central amygdala ERK signaling pathway is critical to incubation of cocaine craving. Nature Neuroscience 8:212-219 Shaham Y, Hope BT (2005) The role of neuroadaptations in relapse to drug seeking. Nature Neuroscience 8:1437-1439 (special issue on Neurobiology of Addiction) Lu L, Uejima JL, Gray SM, Bossert JM, Shaham Y (2007) Systemic and central amygdala injections of the mGluR2/3 agonist LY379268 attenuate the expression of incubation of cocaine craving. Biological Psychiatry 61:591-598 Koya E, Uejima J, Wihbey K, Bossert JM, Hope BT, Shaham Y (2008) Role of ventral medial prefrontal cortex in incubation of cocaine craving. Neuropharmacology (in press, for a special issue commemorating 35 years of NIDA research)) Conrad KL, Tseng K, Uejima J, Reimers J, Heng L, Shaham Y, Marinelli M, Wolf ME (2008) Formation of accumbens GluR2-lacking AMPA receptors mediates incubation of cocaine craving. Nature (in press)

Although pain is a complex entity, understanding the mechanisms of pain will reveal clues for better control. Perception of nociceptive, inflammatory and neuropathic pain - although initiated by distinctive mechanisms - all depend to some degree on generation and transmission of noxious signals by specific sets of primary sensory afferent neurons, nociceptors. Local anesthetics, by blocking voltage-gated sodium channels, prevent the transmission of nociceptive information and therefore block pain. However, since all local anesthetics act non-selectively on all types of axons, they also cause a loss of innocuous sensation, motor paralysis and autonomic block. Thus, approaches that produce only a selective blockade of pain fibers are of great potential clinical importance. In my talk, I will present a novel method to selectively block pain sensation. Using capsaicin to activate the TRPV1 channel, the noxious thermo-sensitive transducer localized specifically to high-threshold nociceptors, we were able to introduce QX-314, a membrane impermeable and therefore clinically ineffective lidocaine derivative, into nociceptors, and thereby blocked their electrical activity. Neurons that did not express TRPV1 were not blocked by the combination of QX-314 and capsaicin. Injection of QX-314 and capsaicin in vivo together but not alone abolished the response to noxious mechanical and thermal stimuli, without any motor or tactile deficit. This approach could be used clinically to produce long lasting regional analgesia while preserving motor and autonomic function. In addition to applications for dental procedures, surgery and childbirth, this technique could also be used to diminish postoperative and cancer pain, as well as inflammatory and neuropathic pain. Moreover, using TRP channels as a “natural” drug delivery system will enable specific cationic drugs to be targeted only to those cells that express the TRP channel. This technique offers a new strategy for treating pain.

Fetal mesencephalic tissue has been used as a source of dopaminergic neurons for transplantation in clinical trials with Parkinson’s disease patients and in animal models of Parkinson’s disease. Due to the poor availability of human fetal tissue, and the ethical concerns associated with the use tissue from aborted fetuses, further development of the cell replacement therapy will critically depend on the access to alternative sources of cells for transplantation, based on the use of stem cells as a source of dopaminergic neurons. The recent discovery of Lmx1a and Msx1 as key determinant genes of mesencephalic dopaminergic neuron fate during development (Andersson et al. 2006) has opened new possibilities to drive undifferentiated stem cells towards fully functional mesencephalic dopaminergic neurons. Overexpression of these genes in stable embryonic stem (ES) cell lines is sufficient to generate neurons with almost 100% efficiency into a fully differentiated mesencephalic dopaminergic phenotype. The in vivo data obtained so far indicate that mesencephalic dopaminergic neurons can be generated in large numbers using this approach, and that they survive very well after transplantation to the striatum of 6-hydroxydopamine lesioned rats. In vivo, the Lmx1a- and Msx1-expressing cells develop into fully mature mesencephalic dopaminergic neurons, of both the A9 and A10 subtypes, and grow efficiently to form an extensive TH-positive axonal terminal network throughout the entire host striatum. Using this approach transplantable neurons with what appear to be a complete mesencephalic dopaminergic phenotype can be generated in large numbers from ES cell cultures.