Drug abuse and dependence are major public health issues worldwide. Addiction is relatively unique among psychiatric/neurological disorders in that the deleterious actions are brought on by the willful intake of a substance even under conditions where the abuser is aware of the negative consequences. Thus addictive disorders are unique in being self-perpetuated by a conscious act. This perhaps increases the frustration with this disorder where the apparent “cure” is simply to stop taking the abused substance. For many years research and rehabilitative medicine focused on the initial negative consequences of cessation of intake, withdrawal. Increasingly however, addiction is understood as a long-lasting change in brain function outlasting withdrawal. Relapse driven by learned associations (cue, context) as well as by mental state transitions (stress, anxiety) can occur long after obvious negative consequences of cessation of drug intake have stopped. Thus, intense focus is being placed on neural mechanisms driving drug “craving” sensation and initiation of relapse to intake after extinction. Our lab takes a combination of brain slice electrophysiological and biochemical approaches coupled with behavioral analysis in mice to begin to determine the lasting changes produced by drugs of abuse that induce relapse behavior.
Lasting modifications of synaptic transmission in response to transient synaptic activity have long been hypothesized to play roles in animal behavior, particularly in learning and memory. Since the early 1970’s, it has been recognized that glutamatergic synapses in the hippocampal formation can undergo long-lasting enhancement of synaptic transmission. The most commonly studied form of persistent modification of synaptic transmission in the CNS is NMDAR-LTP at glutamatergic synapses within the hippocampus. The associative nature of NMDAR-mediated plasticity imparted by the required removal of tonic magnesium blockade of the NMDAR has made it particularly attractive for study as a substrate for some forms of associative learning. This has been particularly true of NMDAR-LTP in area CA1 of hippocampus.
A variety of data suggest that there exist multiple forms of synaptic plasticity in the mammalian brain. These include forms that differ in sign (lasting enhancement or depression of transmission), in induction mechanisms and in maintenance mechanisms. The induction of these distinct forms of plasticity depends upon synapse location, stimulus protocol, neuromodulation, and synaptic history. The clear delineation of the induction and maintenance mechanisms of these forms of plasticity has been hindered both by their frequent coexistence at synapses, as well as the difficulty in distinguishing modulators from mediators. Our lab is particularly interested in determining factors that govern modulation of synaptic plasticity, both in the hippocampus, as well as in drug reward circuitry.