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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA014328-03
Application #
6687845
Study Section
Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
Program Officer
Lin, Geraline
Project Start
2002-04-15
Project End
2008-02-28
Budget Start
2004-03-01
Budget End
2005-02-28
Support Year
3
Fiscal Year
2004
Total Cost
$217,500
Indirect Cost
Name
Marquette University
Department
Other Basic Sciences
Type
Schools of Allied Health Profes
DUNS #
046929621
City
Milwaukee
State
WI
Country
United States
Zip Code
53201
Ghasemzadeh, M Behnam; Vasudevan, Preethi; Giles, Chad et al. (2011) Glutamatergic plasticity in medial prefrontal cortex and ventral tegmental area following extended-access cocaine self-administration. Brain Res 1413:60-71
Ghasemzadeh, M Behnam; Vasudevan, Preethi; Mueller, Christopher et al. (2009) Neuroadaptations in the cellular and postsynaptic group 1 metabotropic glutamate receptor mGluR5 and Homer proteins following extinction of cocaine self-administration. Neurosci Lett 452:167-71
Ghasemzadeh, M Behnam; Windham, Lindsay K; Lake, Russell W et al. (2009) Cocaine activates Homer1 immediate early gene transcription in the mesocorticolimbic circuit: differential regulation by dopamine and glutamate signaling. Synapse 63:42-53
Ghasemzadeh, M B; Mueller, C; Vasudevan, P (2009) Behavioral sensitization to cocaine is associated with increased glutamate receptor trafficking to the postsynaptic density after extended withdrawal period. Neuroscience 159:414-26
Ghasemzadeh, M Behnam; Vasudevan, Preethi; Mueller, Christopher R et al. (2009) Region-specific alterations in glutamate receptor expression and subcellular distribution following extinction of cocaine self-administration. Brain Res 1267:89-102
Ghasemzadeh, M Behnam; Vasudevan, Preethi; Mueller, Christopher (2009) Locomotor sensitization to cocaine is associated with distinct pattern of glutamate receptor trafficking to the postsynaptic density in prefrontal cortex: early versus late withdrawal effects. Pharmacol Biochem Behav 92:383-92
Ghasemzadeh, M Behnam; Permenter, Lindsay K; Lake, Russel W et al. (2003) Nucleus accumbens Homer proteins regulate behavioral sensitization to cocaine. Ann N Y Acad Sci 1003:395-7