|MadSci Network: Neuroscience|
Hi Mike! Reuptake inhibitors, such as fluoxetine (prozac) and other drugs of the SSRI (Selective Serotonin Reuptake Inhibitor) category, function by inhibiting synaptic reuptake transporters. These are transmembrane proteins found at synapses (primarily in the presynaptic cell), whose job it is to clear neurotransmitters from the synaptic cleft. Cloned transporters include the norepinephrine transporter (NET), the dopamine transporter (DAT), and the serotonin transporter (SERT). The molecular mechanisms of transporter function are a subject of vigorous research -- for the most current details, see the Blakely and Bauman review, cited below. SSRIs and other reuptake inhibitors bind to the appropriate transporter and impair its ability to clear neurotransmitter, thereby allowing more neurotransmitter into the synaptic cleft. In situations where neurotransmitter release and/or response is at nonoptimal levels, use of a SSRI can bring levels closer to a 'normal' baseline. Side effects of SSRIs and similar compounds can be attributed to nonspecific effects on other transporters or different synaptic proteins. Amphetamines are thought to function by essentially reversing the dopamine transporter (DAT) so that it spills dopamine into the synaptic cleft in an unregulated fashion. This is in contrast to the effects of another stimulant, cocaine, which exerts its effect by inhibiting (but not reversing) DAT -- and perhaps other targets, as studies of the DAT knockout mouse suggest. Curare works on a different synaptic mechanism: neurotransmitter response. It is a competitive (and reversible) antagonist of a receptor for the neurotransmitter acetylcholine. This receptor is found at the neuromuscular junction (where motor neurons meet skeletal muscle), where acetylcholine is the primary neurotransmitter. So, curare poisoning manifests itself as severe paralysis. Here is a great website on the pharmacology of acetylcholine (and the many drugs which interfere with cholinergic neurotransmission): http://www.dartmouth.edu/~rpsmith/Cholinergic_Transmission.html Additional sources are below. Hope this helps! Amanda Kahn email@example.com ++++++++++++++++++ Here are some abstracts which pertain to your question; more information may be found by doing a MEDLINE search or going to the journal's website. MEDLINE searches can be made for free using PubMed: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed +++++++++++++++++++ Blakely, RD; Bauman, AL. Biogenic amine transporters: regulation in flux. Current Opinion in Neurobiology, 2000 Jun, 10(3):328-36. (UI: 20311316) Abstract: Following vesicular release, the biogenic amine neurotransmitters dopamine, norepinephrine and serotonin are actively cleared from extracellular spaces by presynaptic transporters. These transporters interact with multiple psychoactive agents including cocaine, amphetamines and antidepressants. Recent findings indicate that amine reuptake is likely to be a tightly regulated component of synaptic plasticity rather than a constitutive determinant of transmitter clearance. Protein kinase C activation and transporter phosphorylation have been linked to regulatory protein trafficking, and both phosphorylation and trafficking may be influenced by transporter ligands. Recognition that transmitters, antagonists and second messengers can modify the intrinsic activity, surface expression or protein levels of amine transporters raises new questions about the fundamental nature of drug actions in vivo. The theory that dysregulation of transporters may contribute to disease states is supported by the recent discovery that a coding mutation in the human norepinephrine transporter contributes to orthostatic intolerance. ++++++++++++++++ Schloss, P; Williams, DC. The serotonin transporter: a primary target for antidepressant drugs. Journal of Psychopharmacology, 1998, 12(2):115-21. (UI: 98357395) Abstract: The serotoninergic system is known to modulate mood, emotion, sleep and appetite and thus is implicated in the control of numerous behavioural and physiological functions. Decreased serotoninergic neurotransmission has been proposed to play a key role in the aetiology of depression. The concentration of synaptic serotonin is controlled directly by its reuptake into the pre- synaptic terminal and, thus, drugs blocking serotonin transport have been successfully used for the treatment of depression. In addition to tricyclic antidepressants (TCAs; e.g. imipramine) which also block noradrenaline reuptake, highly specific serotonin reuptake inhibitors (SSRIs) such as fluoxetine and paroxetine have been developed, which are increasingly prescribed for depressed patients. The mode of action of these antidepressant drugs on their direct target, the serotonin transport protein, and possible regulatory mechanisms with respect to long-term alleviation of depression, although having been investigated both neurobiologically and clinically over the last years, are not yet understood. The cloning of the cDNA encoding the serotonin transporter has allowed a more precise characterization of this protein at the molecular level. This will show how antidepressants act at this target, thereby affecting the biochemical, pharmacological and electrophysiological properties of the serotoninergic system and give an introduction of how they might exert their therapeutic effect. This review gives an overview of the recent developments in this field, discusses mechanisms of antidepressant action on this target, and also possible interactions with other components of serotoninergic neurotransmission. +++++++++++ Jones, SR; Joseph, JD; Barak, LS; Caron, MG; Wightman, RM. Dopamine neuronal transport kinetics and effects of amphetamine. Journal of Neurochemistry, 1999 Dec, 73(6):2406-14. (UI: 20047425) Abstract: The dopamine (DA) transporter (DAT) regulates DA neurotransmission by recycling DA back into neurons. Drugs that interfere with DAT function, e.g., cocaine and amphetamine, can have profound behavioral effects. The kinetics of DA transport by DAT in isolated synaptosomal or single cell preparations have been previously studied. To investigate how DA transport is regulated in intact tissue and to examine how amphetamine affects the DAT, the kinetics of DA uptake by the DAT were examined in tissue slices of the mouse caudate-putamen with fast-scan cyclic voltammetry. The data demonstrate that inward DA transport is saturable and sodium-dependent. Elevated levels of cytoplasmic DA resulting from disruption of vesicular storage by incubation with 10 microM Ro 4-1284 did not generate DA efflux or decrease its uptake rate. However, incubation with 10 microM amphetamine reduced the net DA uptake rate and increased extracellular DA levels due to DA efflux through the DAT. In addition, a new, elevated steady-state level of extracellular DA was established after electrically stimulated DA release in the presence of amphetamine, norepinephrine, and exogenous DA. These results from intact tissue are consistent with a kinetic model of the DAT established in more purified preparations in which amphetamine and other transported substances make the inwardly facing DAT available for outward transport of intracellular DA. +++++++++++++++ Rocha, BA; Fumagalli, F; Gainetdinov, RR; Jones, SR; Ator, R; Giros, B; Miller, GW; Caron, MG. Cocaine self-administration in dopamine-transporter knockout mice [see comments] [published erratum appears in Nat Neurosci 1998 Aug;1(4):330] Nature Neuroscience, 1998 Jun, 1(2):132-7. (UI: 99211032) Abstract: The plasma membrane dopamine transporter (DAT) is responsible for clearing dopamine from the synapse. Cocaine blockade of DAT leads to increased extracellular dopamine, an effect widely considered to be the primary cause of the reinforcing and addictive properties of cocaine. In this study we tested whether these properties are limited to the dopaminergic system in mice lacking DAT. In the absence of DAT, these mice exhibit high levels of extracellular dopamine, but paradoxically still self- administer cocaine. Mapping of the sites of cocaine binding and neuronal activation suggests an involvement of serotonergic brain regions in this response. These results demonstrate that the interaction of cocaine with targets other than DAT, possibly the serotonin transporter, can initiate and sustain cocaine self-administration in these mice.
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