Monoamine transporters and psychostimulant drugs

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Abstract

Most psychostimulants interact with monoamine transport proteins. This paper reviews work our laboratory has conducted to investigate the interaction of psychostimulants with monoamine transporters in order to advance our understanding of how these drugs affect the brain. We review two topics: (1) characterization of multiple binding sites for cocaine-like drugs and (2) an examination of the mechanisms of action of amphetamine-type anorectic agents. We conclude that the brain contains high abundance nonclassical binding sites for cocaine-like drugs that have micromolar affinity for cocaine and that none of the clinically available amphetamine-type appetite suppressants are equipotent substrates for dopamine transporter (DAT) and serotonin transporter (SERT) proteins. Future medications discovery efforts should focus on identifying new compounds which possess the equipotent substrate activity at DAT and SERT, but which lack the adverse effects of stimulants developed decades ago.

Introduction

The term “psychostimulant” generally refers to drugs that produce a spectrum of effects in humans that includes increased energy, cardiovascular stimulation, elevated mood, and a decreased need for sleep. At higher doses, or after longer periods of use, psychostimulants can produce a range of disordered thought processes, including severe psychotic episodes. In animals, psychostimulants increase locomotor activity and are readily self-administered due to their powerful reinforcing properties. Psychostimulants are often described as “amphetamine like”, since amphetamine is the prototypical stimulant agent. Table 1 lists a number drugs that are classified as psychostimulants. It is noteworthy that many of these drugs are useful medications with long histories of efficacy and safety, whereas others are highly addictive substances that are associated with considerable morbidity and mortality. In some cases, as with amphetamine itself, the same drug can be a therapeutic entity, or an abused substance, depending upon the context in which the drug is administered.

Most psychostimulants are known to interact with monoamine neurons in the central nervous system (CNS). Neurons that synthesize, store, and release monoamine transmitters [norepinephrine, dopamine, and serotonin (5-HT)] are widely distributed in the mammalian CNS. These neurons possess specialized plasma membrane proteins that function to transport previously released transmitter molecules from the extracellular space back into the cytoplasm Amara and Kuhar, 1993, Masson et al., 1999. Substantial evidence has shown that there are distinct transporter proteins expressed by norepinephrine neurons (i.e., norepinephrine transporters, NETs), dopamine neurons (i.e., dopamine transporters, DATs), and 5-hydroxytryptamine (5-HT) neurons (i.e., 5-HT transporters, SERTs). These proteins belong to a superfamily of Na+/Cl-dependent transporters that share genetic, structural, and functional homologies Blakely et al., 1994, Uhl and Johnson, 1994. Under normal circumstances, the transporter-mediated uptake of monoamine transmitters is the principal mechanism for inactivation of monoaminergic signaling in the brain. Accordingly, a variety of therapeutic and abused drugs interact with monoamine transporter sites (Amara and Sonders, 1998).

In general, drugs that target transporter proteins can be divided into two classes based on their precise mechanism of action: reuptake inhibitors and substrate-type releasers. Reuptake inhibitors bind to transporter proteins, but are not themselves transported. These drugs elevate extracellular transmitter concentrations by blocking transporter-mediated recapture of transmitter molecules from the synapse. Substrate-type releasers bind to transporter proteins, and these drugs are subsequently transported into the cytoplasm of nerve terminals. Releasers elevate extracellular transmitter concentrations by a two-pronged mechanism: (1) they promote efflux of transmitter by a process of transporter-mediated exchange and (2) they increase cytoplasmic levels of transmitter by disrupting storage of transmitters in vesicles Rudnick and Clark, 1993, Rudnick, 1997. This latter action increases the pool of neurotransmitter available for release by transporter-mediated exchange. Because substrate-type-releasing agents must be transported into nerve terminals to promote transmitter release, reuptake inhibitors can block the effects of releasers.

For more than a decade, we have carried out experiments in our laboratory to investigate the interaction of psychostimulants with monoamine transporters in order to advance our understanding of how these drugs affect the brain. It is hoped that the knowledge gained from these studies will aid in the development of pharmacotherapies for treating stimulant dependence and other psychiatric disorders. Aspects of this work have recently been reviewed Prisinzano et al., 2003, Rothman and Baumann, 2002a, Rothman and Baumann, 2002b. In the present paper, we will review two specific topics: (1) the characterization of multiple binding sites for cocaine-like drugs and (2) the examination of the mechanisms of action of amphetamine-type anorectic agents.

Section snippets

Multiple binding sites for cocaine-like drugs in the CNS

It is well accepted that cocaine is a monoamine reuptake blocker that binds with comparable affinity to NETs, DATs, and SERTs in nervous tissue. Interestingly, most antidepressant medications are also reuptake blockers that bind to one or multiple monoamine transporters. Although not a major focus of recent cocaine research, an unresolved question is why cocaine is not an effective antidepressant (Post, 1975). In fact, the seminal work of Post established that daily administration of cocaine

Evidence for site ‘X’

As mentioned previously, we first noted the occurrence of a second [125I]RTI-55 binding site in whole rat brain minus caudate membranes under DAT binding conditions (SERT binding blocked with 50 nM paroxetine) (Rothman et al., 1995). To test whether this novel site was related to the classic DAT site, radioligand binding studies were carried out in DAT knockout mice (Rothman et al., 2002b). We prepared membranes from whole brain minus caudate using tissue from wild-type mice, DAT knock out mice

Evidence for SERTsite2

A novel binding site associated with the SERT, known as SERTsite2 (Rothman et al., 1998b), was detected under SERT binding conditions (i.e., DAT binding blocked with 100 nM GBR12935) in membranes prepared from guinea pig, monkey, or human caudate, but not rat caudate. Fig. 2 illustrates the initial observation that led to the identification of SERTsite2. In contrast to the monotonic inhibition of [125I]RTI-55 binding under SERT conditions observed in rat brain membranes (Silverthorn et al.,

Summary: multiple binding sites for cocaine-like ligands

The work reviewed above establishes the existence of two nonclassical binding sites for the cocaine analog [125I]RTI-55. Both site ‘X’ and SERTsite2 are high-abundance binding sites that display Ki values for cocaine in the low-micromolar range, indicating these sites could be relevant to the pharmacological actions of cocaine. Unfortunately, there are significant impediments to the continued study of these two binding sites. For both site ‘X’ and SERTsite2, the lack of selective high-affinity

Mechanism of amphetamine-type anorectics

Cocaine and methamphetamine are generally acknowledged to be among the most addictive substances known Das, 1993, Gonzalez Castro et al., 2000, Musto, 1992. Long-term stimulant abuse is associated with considerable morbidity and mortality Anonymous, 1995, Das, 1993. The co-morbidity of drug abuse with psychiatric disorders, as well as the clinical presentation of primary stimulant dependence Kalechstein et al., 2000, Miller, 1994, Regier et al., 1990, indicates that efforts to develop new and

Conclusion

Psychostimulants are a fascinating group of centrally active compounds that continue to present many challenges to the researcher and clinician. On one hand, psychostimulants can be useful therapeutic agents, while on the other hand, many of these compounds can serve as powerful drugs of abuse. The discovery of novel cocaine binding sites offers the possibility of understanding more completely the pharmacological actions of this complex drug, as well as developing more effective treatments for

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