Balance between Dopamine and Serotonin Release Modulates Behavioral Effects of Amphetamine-Type Drugs RICHARD B. ROTHMAN AND MICHAEL H. BAUMANN Clinical Psychopharmacology Section, IRP, NIDA, NIH, DHHS, Baltimore, Maryland 21224, USA
ABSTRACT: The abuse of illicit stimulants is a worldwide crisis, yet few medicines are available for treating stimulant addiction. We have advocated the idea of “agonist therapy” for cocaine dependence. This strategy involves administration of stimulant-like medications (e.g., monoamine releasers) to alleviate cocaine withdrawal symptoms and prevent relapse. A chief limitation of this strategy is that many candidate medicines possess high abuse liability due to activation of mesolimbic dopamine (DA) neurons in reward pathways. Evidence suggests that serotonin (5-HT) neurons can provide an inhibitory influence over mesolimbic DA neurons. Thus, it might be predicted that the balance between DA and 5-HT transmission is a critical variable when developing medications with reduced stimulant side effects. In this article, we review recent studies from our laboratory that examined neurochemical and behavioral effects of a series of monoamine releasers which displayed different potencies at DA and 5-HT transporters. The data show that increasing 5-HT release can attenuate stimulant effects mediated by DA release, such as motor stimulation and drug self-administration. Our findings support the work of others and indicate that elevated synaptic 5-HT can dampen certain behavioral effects of DA-releasing agents. Moreover, the relationship between DA and 5-HT releasing potency is an important determinant in developing new agonist medications with reduced stimulant properties. KEYWORDS: agonist therapy; dopamine (DA); serotonin (5-HT); releasing agent; stimulant dependence
INTRODUCTION The abuse of illicit stimulants, such as cocaine and methamphetamine, remains a major public health concern in the United States and elsewhere.1 In particular, the intravenous (i.v.) use of stimulant drugs negatively impacts public health through the spread of HIV-1, hepatitis B and C, and drug resistant Address for correspondence: Richard B. Rothman, M.D., Ph.D., CPS, IRP, NIDA, NIH, 5500 Nathan Shock Drive, Baltimore, MD 21224. Voice: 410-550-1487; fax: 410-550-2997. e-mail:
[email protected] C 2006 New York Academy of Sciences. Ann. N.Y. Acad. Sci. 1074: 245–260 (2006). doi: 10.1196/annals.1369.064
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tuberculosis.2 Despite the extent of the stimulant abuse crisis, development of medications to treat stimulant dependence has been largely unsuccessful.3 The use of stimulant-like medications to treat stimulant addictions is an approach described as “agonist therapy.” This strategy involves administration of medications that share neurobiological mechanisms of action with cocaine and methamphetamine, but are less potent and less addictive.4,5 From one perspective, agonist therapy might be viewed as “neurochemical normalization”— i.e., the treatment drug normalizes dysregulated neurochemistry by replacing the abused drug. Neurochemical normalization therapy has provided effective treatment options for nicotine dependence6 and opioid dependence.7,8 With regard to stimulant addiction, considerable evidence suggests that chronic cocaine exposure produces neurochemical deficits in dopamine (DA) and serotonin (5-HT) systems in the central nervous system (CNS).9 Accordingly, the ideal agonist therapy in this case would be expected to normalize DA and 5-HT dysfunction. Along with other researchers, we have advocated the use of amphetaminetype monoamine releasers as agonist therapies for cocaine dependence.10,11 Similar to cocaine, these compounds target monoamine transporters to elevate synaptic levels of norepinephrine (NE), DA, and 5-HT.9,12 Preclinical studies support the utility of amphetamines as agonist treatments.13,14 For example, Negus and Mello15 demonstrated that slow infusion of the DA releaser (+)-amphetamine decreases cocaine self-administration behavior in monkeys, with minimal effects on food-maintained behavior. Perhaps more importantly, Grabowski et al.16 and Shearer et al.17 showed that (+)-amphetamine is an effective treatment adjunct for reducing illicit cocaine use in cocaine-dependent human patients. Unfortunately, the use of amphetamine as a medication is limited by at least two problems. First, pure DA releasers possess significant abuse potential due to activation of mesolimbic DA neurons in reward pathways.18 Second, DA releasers will not correct 5-HT deficits that accompany long-term cocaine abuse. We have suggested the possibility of designing dual DA/5-HT releasers that can overcome both of the aforementioned limitations.19 The purpose of the present article is to review our published findings, and new unpublished data, addressing the hypothesis that 5-HT release can antagonize the stimulant and reinforcing effects mediated by DA release. To this end, we examined the neurochemical and behavioral effects produced by a series of monoaminereleasing agents that display varying degrees of potency for DA and 5-HT transporters.
MATERIALS AND METHODS Animals Male Sprague-Dawley rats weighing 280–320 g were housed at the animal facility of the National Institute on Drug Abuse (NIDA), Intramural Research
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Program (IRP). Food and water were freely available. For in vitro release experiments, rats were housed three per cage. For in vivo microdialysis and behavioral experiments, rats were single-housed post-surgery. Facilities are accredited by the American Association of the Accreditation of Laboratory Animal Care, and procedures were carried out in accordance with the Animal Care and Use Committee of the NIDA IRP. Male rhesus monkeys (Macaca mulatta) weighing 9–11 kg were individually housed in 1 m3 cubicles at the animal facility of the University of Mississippi Medical Center and were maintained in accordance with guidelines provided by the National Institutes of Health (NIH) Committee on Laboratory Animal Resources. Monkeys were provided with sufficient food to maintain stable body weight and water was freely available. Drugs FIGURE 1 depicts the various compounds discussed in this paper. (+)Amphetamine is a phenylethylamine analog, whereas PAL-287 is a naphthylethylamine analog. PAL-313, -314, -303, and -353 are ring-substituted amphetamines. In Vitro Release Assays In vitro assays measuring the release of [3 H]DA and [3 H]5-HT were carried out according to published methods.20 Synaptosomes were prepared from rat caudate (DA release) or whole brain minus caudate (5-HT release). Assays were performed in a Krebs-phosphate buffer (pH 7.4) containing 154.4 mM NaCl, 2.9 mM KCl, 1.1 mM CaCl 2 , 0.83 mM MgCl 2 , 5 mM glucose, 1 mg/ml ascorbic acid, 50 M pargyline, and 1 M reserpine. [3 H]5-HT release assays were performed in the presence of 100 nM nomifensine and 100 nM GBR12909 to prevent reuptake of tritium into NE and DA nerves. Synaptosomes were incubated to steady state with 5 nM [3 H]DA (30 min) or [3 H]5-HT (60 min). Preloaded synaptosomes were added to tubes containing test drugs and were incubated for 5 min. Assays were stopped by filtration and residual tritium in the tissue was counted. Non-displaceable tritium was measured in the presence of 10 M tyramine for [3 H]DA release and 100 M tyramine for [3 H]5-HT release. Data from three experiments were pooled and fit to the two-parameter logistic equation of best-fit estimates for EC 50 and E max using MLAB-PC. In Vivo Microdialysis in Rats In vivo microdialysis sampling was carried out as previously described.20 Indwelling jugular catheters and intracerebral guide cannulae were surgically
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FIGURE 1. Chemical structures of (+)-amphetamine, PAL-287, and PAL amphetamines.
implanted into rats anesthetized with 60 mg/kg i.p. pentobarbital. Guide cannulae were aimed at the prefrontal cortex according to coordinates ML-2.5 mm and AP+3.0 mm relative to bregma, DV-0.8 mm relative to dura. After a week of recovery, extension tubes attached to 1-mL syringes were connected to catheters, and microdialysis probes (3 mm × 0.5 mm exchange surface, CMA/12, CMA/Microdialysis; Solna, Sweden) were inserted into guide cannulae. Each rat was attached to a tether and placed into a 40 cm3 Plexiglas arena equipped with photobeams for automated assessment of motor activity (TruScan, Coulborn Instruments, Allentown, PA). Probes were perfused with Ringers’ solution overnight at 1 L/min. On the next morning, samples were collected at 20-min intervals and assayed for DA and 5-HT by microbore HPLC with electrochemical detection (HPLC-ECD). Three baseline samples were collected, averaged, and subsequent DA and 5-HT measures were expressed as a percent of mean baseline. Motor activity was monitored by beam-break analysis during dialysis sampling.
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Specifically, distance traveled in the horizontal plane (i.e., ambulation) and episodes of repetitive movements (i.e., stereotypic events) were quantified in 20-min bins and recorded using a computer. The neurochemical and locomotor data were evaluated using one-factor (drug treatment) repeated measures analysis of variance (rANOVA) followed by Duncan’s post hoc tests.
Behavioral Observations in Rats Rats were anesthetized with 60 mg/kg i.p. pentobarbital and indwelling jugular catheters were implanted. After a week of recovery, rats were brought into the testing room in their home cages. Extension tubes attached to 1-mL syringes were connected to catheters, and 0.5 mL of saline was flushed into the catheters. After 1 h of acclimation, rats received i.v. infusions of either PAL amphetamines or saline (1 mL/kg over 5 s). Drugs were dissolved in saline and administered at 1.0 and 3.0 mg/kg. DA-mediated behaviors including forward ambulation (all 4 feet move), rearing (forepaws off the floor), and stereotypy (vertical head-bobbing) were assessed every 10 min by an observer blind to the treatment. Behaviors were scored during 60-s intervals using a graded scale where 0: absent, 1: equivocal, 2: present, and 3: continuous or intense. Each rat was given a single behavioral score consisting of the summed scores for all behaviors over the first 30 min post-injection (i.e., three observation intervals). Behavioral data were analyzed by one-factor (drug treatment) ANOVA followed by Duncan’s tests.
Drug Self-Administration in Monkeys Details of the self-administration procedure have been previously published.21 Each monkey was fitted with a stainless-steel harness attached by a tether to the rear wall of the chamber. The front door of the chamber was transparent plastic while remaining walls were opaque. Two response levers were mounted on the inside of the door and four stimulus lights, two red and two white, were mounted above each lever. A peristaltic infusion pump delivered drug injections. A Macintosh computer with custom interface and software controlled all events in an experimental session. Monkeys were implanted with i.v. catheters and allowed to self-administer drugs by pressing the right lever on the chamber door (25 lever presses/ injection; FR25) for 2 h/day, beginning at noon, 7 days/week. At the start of a session, the white lights were illuminated above both levers and responding on the right lever resulted in the delivery of a drug injection for 10 s. During the injection, the white lights were extinguished and the red lights were illuminated. Pressing the left lever was counted but had no other programmed consequence. In baseline sessions, cocaine (0.01–0.03 mg/kg/injection) or saline was made
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available. Once stable cocaine- and saline-maintained responding was established, sessions with test drugs were introduced randomly among baseline sessions. A test session was identical to a baseline session, except that saline or one of various doses of cocaine (0.001–1.0 mg/kg/injection) or PAL compounds (0.001–1.0 mg/kg/injection) were made available for self-administration. After a test session, monkeys were returned to baseline conditions until cocaineand saline-maintained responding were again stable. Mean injection rates per session for each monkey were calculated from two test sessions as a function of dose. A dose of drug was considered reinforcing when the mean number of injections exceeded the levels seen with saline and the ranges did not overlap. For the PAL amphetamine drugs, group mean doseeffect functions for each drug were collapsed across monkeys with respect to the dose maintaining maximum injections; this was done to account for individual variations in the dose producing maximal responding. A statistical analysis was performed on group means normalized to dose using rANOVA followed by Newman–Keul’s tests.
RESULTS In Vitro Release Data TABLE 1 summarizes in vitro potencies of test drugs as releasers of [3 H]DA and [3 H]5-HT. The DA/5-HT ratio for each drug was calculated by dividing the EC 50 value for DA release by the corresponding value for 5-HT release. With this method, ratios greater than 1 indicate increasing 5-HT selectivity while ratios less than 1 indicate DA selectivity. All of the drugs are substrate-type releasers that cause efflux of preloaded tritiated transmitter via transportermediated mechanisms. The selectivity of drugs for DA and 5-HT transporters differs substantially. (+)-Amphetamine is often considered the prototypical monoamine releaser, and this compound has much higher potency for DA TABLE 1. Effects of test compounds on the release of [3 H]DA and [3 H]5-HT from rat brain synaptosomes. Data are mean ± SD for n = 3 experiments
Test drug (+)-Amphetaminea PAL-287 a PAL-313 b PAL-314 b PAL-303 b PAL-353 b a Data b Data
taken from Ref. 20. taken from Ref. 21.
[3 H]DA release EC 50 (nM)
[3 H]5-HT release EC 50 (nM)
DA/5-HT ratio
8.0 ± 0.4 12.6 ± 0.4 44.1 ± 2.6 33.3 ± 1.3 51.5 ± 1.7 24.2 ± 1.1
1756 ± 94 3.4 ± 0.2 53.4 ± 4.1 218 ± 22 939 ± 76 1937 ± 202
0.005 3.706 0.824 0.154 0.055 0.012
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release when compared to 5-HT release (DA/5-HT ratio = 0.005). The naphthalene derivative PAL-287 has 500-fold greater potency for 5-HT release when compared to amphetamine, while effects on DA are comparable (DA/5-HT ratio = 3.706). The substituted amphetamines, PAL-313, -314, -303, and -353, display roughly equivalent potency as DA releasers, but these compounds have varying potencies as 5-HT releasers, with PAL-313 exhibiting highest potency and PAL-353 exhibiting lowest potency. In Vivo Effects of PAL-287 In our initial investigations, we sought to identify and characterize nonamphetamine monoamine releasing agents.20 The first lead compound discovered from this search was PAL-287, and we compared the in vivo effects of PAL-287 to those of (+)-amphetamine. FIGURE 2 shows the effects of (+)amphetamine on extracellular DA and 5-HT in rat prefrontal cortex as determined by in vivo microdialysis. Consistent with in vitro data, (+)-amphetamine stimulates the release of endogenous DA, with little effect on endogenous 5-HT. In rats undergoing dialysis, (+)-amphetamine causes dose-related increases in ambulation and stereotypy as depicted in FIGURE 3. Amphetamine-induced hyperactivity increases in parallel with elevations in extracellular DA. After a 1 mg/kg i.v. dose of amphetamine, dialysate DA levels rise eightfold above baseline in conjunction with an ambulation distance of nearly 6000 cm. FIGURE 4 shows the effects of PAL-287 on extracellular DA and 5-HT in rat prefrontal cortex.20 In agreement with in vitro data, PAL-287 increases
FIGURE 2. Effects of (+)-amphetamine on extracellular DA and 5-HT in rat prefrontal cortex as determined by in vivo microdialysis. Rats received i.v. injection of 0.3 mg/kg (+)amphetamine at time zero, followed by 1 mg/kg 60 min later. Data are mean ± SEM for 7 rats/ group, expressed as % baseline. Baseline levels of DA and 5-HT were 0.38 ± 0.07 and 0.24 ± 0.06 pg/5 l. ∗ P < 0.05 compared to pre-injection control at a given time point, Duncan’s post hoc test. Taken from Reference 20.
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FIGURE 3. Effects of (+)-amphetamine on ambulation and stereotypy in rats undergoing microdialysis sampling. Rats received i.v. injections of 0.3 mg/kg (+)-amphetamine at time zero, followed by 1 mg/kg 60 min later. Data are mean ± SEM for 7 rats/ group, expressed as distance traveled in cm (ambulation) and number of repetitive movements (stereotypy). ∗ P < 0.05 compared to pre-injection control, Duncan’s post hoc test. Taken from Reference 20.
FIGURE 4. Effects of PAL-287 on extracellular DA and 5-HT in rat prefrontal cortex as determined by in vivo microdialysis. Rats received i.v. injection of 1 mg/kg PAL-287 at time zero, followed by 3 mg/kg 60 min later. Data are mean ± SEM for 7 rats/ group, expressed as % baseline. Baseline levels of DA and 5-HT were 0.43 ± 0.07 and 0.27 ± 0.06 pg/5 L. ∗ P < 0.05 compared to pre-injection control at a given time point, Duncan’s post hoc test. Taken from Reference 20.
dialysate DA levels to the same extent as (+)-amphetamine, while elevations in dialysate 5-HT exceed those of DA. Despite the large increase in extracellular DA produced by PAL-287, this drug produces very little ambulation as illustrated in FIGURE 5. Specifically, after a 3 mg/kg i.v. dose of PAL-287, dialysate DA levels are increased eight-fold above baseline but ambulation distance is only 1000 cm. One simple interpretation of these data is that marked release of
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FIGURE 5. Effects of PAL-287 on ambulation and stereotypy in rats undergoing microdialysis sampling. Rats received i.v. injections of 1 mg/kg PAL-287 at time zero, followed by 3 mg/kg 60 min later. Data are mean ± SEM for 7 rats/group, expressed as distance traveled in cm (ambulation) and number of repetitive movements (stereotypy). ∗ P < 0.05 compared to pre-injection control, Duncan’s post hoc test. Taken from Reference 20.
FIGURE 6. Self-administration of cocaine and PAL 287 by rhesus monkeys. Drugs were available under an FR25 schedule of reinforcement for 2 hours/day. Each point is the mean of two sessions of access to each dose of the drugs. Data are mean ± SEM for n = 4 monkeys. Symbols without bars have variability smaller than the points. ∗ P < 0.05 compared to saline-injected control, Newman–Keul’s post hoc test. Taken from Reference 20.
5-HT produced by PAL-287 attenuates stimulant effects normally produced by release of DA. Importantly, the findings in FIGURE 6 demonstrate that PAL-287 is not readily self-administered by rhesus monkeys, suggesting that serotonergic effects of PAL-287 blunt the reinforcing effects normally associated with release of DA.
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FIGURE 7. Effects of PAL amphetamines on DA-mediated behaviors in rats. Saline or drug injections were administered i.v. via indwelling catheters, and specific behaviors were assessed every 10 min for 30 min thereafter. Forward locomotion, rearing and stereotypic head bobbing were quantified using a graded scale where 0: absent, 1: equivocal, 2: present, 3: intense or continuous. Data are mean ± SEM for n = 7 rats/group expressed as the single summed scores for all behaviors measured. ∗ P < 0.05 compared to PAL-313 and PAL-314 at a given dose, Duncan’s post hoc test. p < 0.05 compared to 1.0 mg/kg dose, Duncan’s post hoc test.
In Vivo Effects of PAL Amphetamines Given our findings with (+)-amphetamine and PAL-287, we wished to further explore the notion that 5-HT release can modulate the behavioral effects of DA releasers.21 In this study, we examined the behavioral effects of a series of ring-substituted amphetamine analogs that release [3 H]DA with similar potency (∼25–50 nM), but differ in their potency for releasing [3 H]5-HT (see FIG. 1 for structures). As shown on TABLE 1, the 5-HT-releasing potencies for these drugs range from 53 nM for PAL-313 to 1937 nM for PAL-353. Upon i.v. administration, all PAL amphetamines cause increases in DA-mediated hyperactivity as illustrated in FIGURE 7. Specifically, the drugs elicit dose-related increases in ambulation, rearing, and stereotypy. Interestingly, the rank-order of potency for stimulating DA-mediated behaviors is inversely related to the potency for [3 H]5-HT release. PAL-313 and PAL-314, the most potent 5-HT releasers, produced significantly less motor activation when compared to the other two drugs. The data in FIGURE 8 show that all PAL amphetamines are readily selfadministered by rhesus monkeys, confirming that these agents function as positive reinforcers. However, the rank-order of efficacy, as measured by maximal number of injections, was inversely related to potency for [3 H]5-HT release.
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FIGURE 8. Self-administration of PAL amphetamines under an FR25 schedule of reinforcement. Drugs were available for self-administration for 2 h/day. Each data point represents the mean injections/session of each dose for four rhesus monkeys, and vertical error bars represent the SEM. values. The point above Sal or Coc represents self-administration of saline or the baseline dose of cocaine in test sessions, respectively. Data were normalized as to dose to adjust for individual differences in sensitivity. Max, dose that maintained maximum injections in each animal; Max−1, half-log dose lower than Max; Max+1, half-log dose higher than Max. ∗ P < 0.05 compared with PAL-314, PAL-303, or PAL-353, Duncan’s post hoc test. Taken from Reference 21.
The most potent 5-HT releaser, PAL-313, maintained significantly less injections than the other drugs. Thus, the monkey self-administration data indicate that 5-HT release can reduce the reinforcing efficacy attributable to concurrent DA release.
DISCUSSION The findings presented in this paper support the hypothesis that 5-HT release antagonizes the stimulant properties of DA-releasing drugs. The ability of 5-HT to diminish DA-mediated effects was demonstrated in several behavioral paradigms carried out in phylogenetically distinct mammalian species (i.e., rat and monkey), indicating a generalized phenomenon. Our data contribute to the growing body of knowledge that shows elevations in synaptic 5-HT can counteract stimulant and reinforcing effects mediated by elevations in synaptic DA.22–25 Self-administration studies provide ample evidence for the “antistimulant” actions of 5-HT. 5-HT precursor loading with dietary tryptophan attenuates amphetamine self-administration in rats.26 Similarly, pretreatment with 5-HT reuptake inhibitors reduces intravenous cocaine self-administration
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in rats27 and squirrel monkeys.28 Cocaine analogs with high 5-HT transporter affinity support less self-administration behavior than analogs with low 5-HT transporter affinity.29 The in vivo microdialysis data comparing PAL-287 with (+)-amphetamine offer direct evidence that 5-HT release dampens the effects mediated by DA release. PAL-287 (3 mg/kg, i.v.) and (+)-amphetamine (1 mg/kg, i.v.) increase extracellular DA to the same extent, yet the locomotor stimulant effects of PAL-287 are much less than those of (+)-amphetamine. We believe that weak locomotor and reinforcing effects afforded by PAL-287 are related to the marked increase in extracellular 5-HT produced by this drug, an effect which is not shared by (+)-amphetamine. The findings with PAL-287 are similar to those observed with PAL-313, the substituted amphetamine with greatest 5-HT-releasing potency. PAL-313 produced the least amount of motor activity in rats and supported the weakest self-administration behavior in monkeys. A pertinent correlate of our data is the anorectic agent chlorphentermine, which releases 5-HT to a greater extent than DA but does not increase locomotor activity and is weakly self-administered.30,31 It seems likely that 5-HT release counteracts the stimulant effects of amphetamine in humans, since fenfluramine administration decreases amphetamine-induced subjective effects in humans,32 and chlorphentermine is devoid of amphetamine-like subjective effects.33 Part of our initial rationale for the development of dual DA/5-HT releasers was based on the knowledge that selective 5-HT releasing agents, such as fenfluramine, lack stimulant properties and are not self-administered.34 Additionally, fenfluramine antagonizes locomotor and rewarding actions of DA releasers.19,30,35 Studies using co-administered phentermine and fenfluramine show that drug treatments producing simultaneous elevations in extracellular DA and 5-HT produce minimal motor activity,30 are not rewarding,36 and are not reinforcing.37 Unfortunately, interpreting the effects of fenfluramine is hampered by the complex pharmacology of the drug, and N-dealkylation produces a bioactive metabolite with potent agonist activity at 5-HT 2C receptors (for review, see Ref. 38). PAL-287 also displays activity at various 5-HT 2 receptor subtypes including 5-HT 2C sites.20 It is not clear to what extent direct agonist activities contribute to the ability of PAL-287 to attenuate DA-mediated behavioral effects, especially since transporter-mediated increases in synaptic 5-HT would be expected to “globally” activate all 5-HT receptors throughout the CNS. Nonetheless, 5-HT 2C receptors could be involved in the suppression of DA-mediated effects observed in our studies, as this receptor site has been shown to inhibit DA transmission under a variety of conditions.39–41 Obviously, it will be interesting to determine which 5-HT receptor subtypes are responsible for the anti-stimulant effects of PAL-287 and related agents.23 On the other hand, “selectively” non-selective drugs have proven to be superior treatments for mood disorders and schizophrenia,42 and the same may hold true for developing treatment agents for stimulant dependence.
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The ideal monoamine releaser for treating stimulant dependence should reduce drug-seeking behavior and correct neurochemical deficits produced by the abused drug. In this regard, cocaine abstinence in humans is accompanied by major depressive-like symptoms43,44 and increased suicide attempts,45,46 consistent with 5-HT dysfunction in the CNS. Neuroendocrine and behavioral studies in rats demonstrate that cocaine withdrawal produces serotonergic deficits.47–50 Importantly, the spectrum of endocrine and behavioral abnormalities in rats withdrawn from cocaine resembles that of humans diagnosed with major depression.51–54 Direct evidence for cocaine-induced 5-HT deficits in rats comes from electrophysiological55 and in vivo microdialysis experiments.56,57 Based on the findings mentioned above, we proposed a dual deficit model of stimulant withdrawal in which drug-induced DA and 5-HT dysfunction contributes to withdrawal symptoms, drug craving, and relapse.30,51,58,59 According to the model, decreased synaptic DA during stimulant withdrawal underlies anhedonia and psychomotor retardation, whereas decreased synaptic 5-HT gives rise to depressed mood, obsessive thoughts, and lack of impulse control. The dual deficit model predicts that pharmacotherapies capable of reversing abnormalities in DA and 5-HT function should be effective in treating stimulant dependence. The findings reviewed here support the feasibility of developing non-amphetamine releasers with low abuse potential, by designing dual DA and 5-HT releasing activity into a single molecule. We believe that drugs with a similar mode of action will provide neurochemical normalization therapy for the treatment of cocaine addiction, and such medications might also be useful for treating depression, obsessive compulsive disorder, attention deficit disorder, and obesity. .
ACKNOWLEDGMENT This research was generously supported in part by the Intramural Research Program of the NIH, NIDA. REFERENCES 1. BANKEN, J.A. 2004. Drug abuse trends among youth in the United States. Ann. N. Y. Acad. Sci. 1025: 465–471. 2. KRESINA, T.F. et al. 2004. Addressing the need for treatment paradigms for drugabusing patients with multiple morbidities. Clin. Infect. Dis. 38: S398–S401. 3. SHEARER, J. & L.R. GOWING. 2004. Pharmacotherapies for problematic psychostimulant use: a review of current research. Drug Alcohol Rev. 23: 203–211. 4. GRABOWSKI, J. et al. 2004. Agonist-like, replacement pharmacotherapy for stimulant abuse and dependence. Addict Behav. 29: 1439–1464. 5. GORELICK, D.A. 1998. The rate hypothesis and agonist substitution approaches to cocaine abuse treatment. Adv. Pharmacol. 42: 995–997.
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