PHAR 5091.001

Course Name: New views on monoaminergic neurotransmission: Are transporters important?

Course Director: Dr. Lynette Daws

Course Content: Monoamines (such as dopamine, norepinephrine and serotonin) are important neurotransmitters that mediate many physiological and psychological functions. Imbalances in the central extracellular concentration of these monoamines are thought to underlie disease states such as depression as well as addiction. Moreover, the acute adverse effects of drugs of abuse on cardiac function and regulation of core body temperature are also attributed to such imbalances. Understanding how monoaminergic neurotransmission is regulated has therefore been the subject of intense research for many years. By virtue of their role in actively removing monoamines from extracellular fluid, a focus of this research has been on monoaminergic transporters. This course will provide students with an understanding of monoamine transporter function and regulation as well as how these transporters serve to facilitate "hard-wired" versus "volume (or paracrine) transmission".

Readings:

Bunin M, Wightman RM. (1998) Quantitative evaluation of 5-hydroxytryptamine (serotonin) neuronal release and uptake: an investigation of extrasynaptic transmission. J Neurosci. 18(13):4854-4860.

Cass WA, Gerhardt GA. (1995) In vivo assessment of dopamine uptake in rat medial prefrontal cortex: comparison with dorsal striatum and nucleus accumbens. J Neurochem. 65(1):201-207.

Daws LC, Gould GG, Teicher SD, Gerhardt GA, Frazer A. (2000) 5-HT(1B) receptor-mediated regulation of serotonin clearance in rat hippocampus in vivo. J Neurochem. 75(5):2113-2122.

Galli A, Blakely RD, DeFelice LJ (1998) Patch-clamp and amperometric recordings from norepinephrine transporters: channel activity and voltage-dependent uptake. Proc Natl Acad Sci U S A. 95(22):13260-13265.

Giros B, Jaber M, Jones SR, Wightman RM, Caron MG. (1996) Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 379(6566):606-612.

Ingram SL, Prasad BM, Amara SG. (2002) Dopamine transporter-mediated conductances increase excitability of midbrain dopamine neurons. Nat Neurosci. 5(10):971-978.

Miner LH, Schroeter S, Blakely RD, Sesack SR. (2000) Ultrastructural localization of the serotonin transporter in superficial and deep layers of the rat prelimbic prefrontal cortex and its spatial relationship to dopamine terminals. J Comp Neurol. 427(2):220-234.

Ramamoorthy S, Blakely RD. (1999) Phosphorylation and sequestration of serotonin transporters differentially modulated by psychostimulants. Science. 285(5428):763-766.

Riddle EL, Rau KS, Topham MK, Hanson GR, Fleckenstein AE. (2003) Ceramide-induced alterations in dopamine transporter function. Eur J Pharmacol. 458(1-2):31-36.

Saunders C, Ferrer JV, Shi L, Chen J, Merrill G, Lamb ME, Leeb-Lundberg LM, Carvelli L, Javitch JA, Galli A. (2000) Amphetamine-induced loss of human dopamine transporter activity: an internalization-dependent and cocaine-sensitive mechanism. Proc Natl Acad Sci U S A. 97(12):6850-6855.

Zahniser NR, Doolen S. (2001) Chronic and acute regulation of Na+/Cl- -dependent neurotransmitter transporters: drugs, substrates, presynaptic receptors, and signaling systems. Pharmacol Ther. 92(1):21-55. Review.

Zhou FC, Lesch KP, Murphy DL. (2002) Serotonin uptake into dopamine neurons via dopamine transporters: a compensatory alternative. Brain Res. 942(1-2):109-119.

Zoli M, Jansson A, Sykova E, Agnati L, Fuxe K. (1999) Volume transmission in the CNS and its relevance for neuropsychopharmacology. Trends Pharmacol. 20:142-150.

Grading: Students will read each paper and discuss critically the content of each paper with the course director. During each discussion session the student will be expected to answer several questions related to the strengths and weaknesses of the paper, its important findings and their significance with respect to the role of monoamine transporters in regulating neurotransmission. It is expected that students will do some additional reading of the primary literature as needed to familiarize themselves with the paper under discussion. Once all papers have been discussed the student will write a short (maximum 10 page, double spaced), critical review of the given readings and related literature. This document should be formatted as a review article. Students will be graded based on the quality of discussions and the review article. Grading will be on a lettered scale.

Pre-requisites: Principles of Pharmacology

Credit Hours: 1 credit

When offered: Anytime