DESCRIPTION (provided by applicant): The abuse of the amphetamine-like psychostimulants is a medical and social problem throughout the world. The rewarding properties of these drugs are linked to their capacity to increase extracellular concentration of dopamine in the forebrain, notably in the nucleus accumbens. The dopaminergic neurons that innervate nucleus accumbens originate in the ventral tegmental area which has been shown to play a critical role in development of chronic drug effects. Despite the advances in our understanding of cellular and molecular actions of these drugs, effective pharmacological treatments for amphetamine and cocaine addiction remain elusive. More recently, a number of investigations have shown that in addition to dopaminergic role in psychostimulant effects, excitatory neurotransmission also plays a very critical role. Glutamate is the major excitatory neurotransmitter in the brain and both nucleus accumbens and ventral tegmental area receive a major glutamatergic innervation from prefrontal cortex. These studies suggest that drugs acting on excitatory neurotransmission may be effective therapeutic agents for treating psychostimulant abuse. The data presented in this proposal suggest that the recently discovered proteins that bind to glutamate receptors can alter glutamatergic transmission and may play an important role in long lasting neuroadaptations after repeated drug exposure. The Homer family of proteins is one of the glutamate receptor binding proteins that bind specifically to metabotropic glutamate receptors. The expression of these proteins in nucleus accumbens is altered after repeated cocaine exposure. Moreover, reducing the level of these proteins in NA during repeated exposure to cocaine prevents the development of behavioral sensitization. Based on these results and others in literature a series of experiments are proposed to study the functional role of these scaffolding proteins in excitatory transmission in nucleus accumbens and their role in drug induced synaptic plasticity.