Dr. Sammanda Ramamoorthy
Biographical Information

Project 3 - Monoamine Transport Modulation in Addiction.

Chronic self-administration of psychostimulats and other drugs of abuse are a major health problem world wide with profound social and financial cost. Cocaine produces its unconditioned reinforcing effects by binding to the dopamine (DA) transporter (DAT) and blocking the reuptake of DA into presynaptic terminal, thus potentiates DA neurotransmission. Cocaine also interacts with serotonin (5HT) transporter (SERT) and norepinephrine (NE) transporter (NET) to block reuptake and elevate synaptic 5HT and NE levels. Recent evidence indicates that SERT and NET also play an important role in modulating the tonicity of dopaminergic neurotransmission in cocaine sensitization. Thus, the monoamine transporters are the primary high affinity targets for cocaine in the brain and drug-induced changes in transporter kinetics and number will strongly influence the effects of subsequent drug administration. While changes in monoamine transporter mRNAs, and binding sites have been implicated in chronic cocaine administration, there are no studies investigating relevant alterations in transporter function, regulation and cell surface expression in presynaptic terminals that are associated with cocaine self-administration, extinction and reinstatement. Combining state-of-art biochemical approaches with the animal model of drug-primed relapse outlined in Core B, project # 3 will determine whether monoamine transporters are altered by cocaine self-administration, or whether a drug-prime differentially alters transporter function in subjects trained to self-administer cocaine. To accomplish this a number of dependent variables related to transporter function will be quantified, including 1) expression, transport activity, surface distribution, 2) phosphorylation state of transporters, transporter protein-protein association and 3) the degree to which the monoamine transporters are regulated by presynaptic auto- and hetero-receptors. Elucidating the monoamine transporter mechanisms that undergo adaptive changes in the animal model of relapse could identify novel molecular targets for pharmacological intervention in addiction.