Replacement Medication for Cocaine Dependence

Grabowski, John; Roache, John D.; Schmitz, Joy M.; Rhoades, Howard M.; Creson, Daniel L.; Korszun, Ania

doi:10.1097/00004714-199712000-00008

Cited by 177 publications

(109 citation statements)

References 18 publications

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“…These observations are consistent with frequent human clinical self-reports of 'jitteriness' with cocaine use. 76,77 They accord with evidence for cocaine Molecular Psychiatry aversive features in some animal models. [78][79][80] They fit with the failure of mazindol, a widely used combined DAT/NET blocker, to exhibit any striking human clinical abuse liability and with its not-infrequent discontinuation due to jitteriness and sleep disturbances.…”

Section: Cocaine Reward and Aversion: Rich Patterns Of Multitransporsupporting

confidence: 57%

Cocaine, reward, movement and monoamine transporters

Uhl¹,

Hall²,

Sora³

2002

Mol Psychiatry

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Recent evidence enriches our understanding of the molecular sites of action of cocaine reward and locomotor stimulation. Dopamine transporter blockade by cocaine appears a sufficient explanation for cocaine-induced locomotion. Variation in DAT appears to cause differences in locomotion without drug stimulation. However, previously-held views that DAT blockade was the sole site for cocaine reward have been replaced by a richer picture of multitransporter involvement with the rewarding and aversive actions of cocaine. These new insights, derived from studies of knockout mice with simultaneous deletions and/or blockade of multiple transporters, provide a novel model for the rewarding action of this heavily-abused substance and implicate multiple monoamine systems in cocaine's hedonic activities. Cocaine is a prototypical psychomotor stimulant that increases locomotor activity and elevates mood with rewarding euphoria.1 It also produces fearful and jittery aversive effects in many who take it.2,3 Cocaine blocks monoamine uptake by neuronal plasma membrane transporters for dopamine (DAT), serotonin (SERT) and norepinephrine (NET), and can also block ligand-and voltage-gated channels with somewhat lower potencies. 4 Understanding the relationships between cocaine's molecular actions and its psychomotor stimulant and aversive properties has remained surprisingly incomplete. This review focuses on recent advances in our understanding of the complex relationships between cocaine's molecular actions and its locomotor stimulant, rewarding and aversive properties.The 'DAT-is-it' hypothesis drove thinking about cocaine reward for at least a decade, ideas widely linked to Kuhar, Spealman and their colleagues 4-8 who gathered evidence from structure-activity relationships of transporter-blocking compounds with differential potencies at DAT, SERT and NET. They examined relationships between potencies of these compounds in tests of reward and binding affinities at each of the monoamine transporters. They each identified the best correlations for the rewarding effects of cocaine with DAT blockade. These authors also cited prior work from lesion studies 9-12 and electrical brain stimulation studies [13][14][15][16][17] This 'DAT-is-it' hypothesis was a major motivation for work that resulted in cloning DAT cDNAs, genes and gene variants in our laboratory and others. [23][24][25][26][27][28][29][30] It drove characterization and study of DAT gene variants in humans 29,31-53 and animal models. 54,55 It led to the production and characterization of DAT-over-and under-expressing and DAT-knockout mice strains. [56][57][58][59] These studies revealed an exquisite DAT-dependence of cocaine's locomotor stimulation. By contrast, they also produced surprising results that refuted the strong 'DAT-is-it' hypothesis of cocaine reward. Cocaine-induced locomotion: DAT is itDAT variation in humans and mice links robustly with variation in both baseline locomotion and/or psychostimulant-induced locomotor activities. Three strains of DAT knockout ...

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Section: Cocaine Reward and Aversion: Rich Patterns Of Multitransporsupporting

confidence: 57%

Cocaine, reward, movement and monoamine transporters

Uhl¹,

Hall²,

Sora³

2002

Mol Psychiatry

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“…Viewed from this perspective, agonist substitution therapy can be described as "neurochemical normalization" therapy-the treatment medication "normalizes" dysregulated neurochemistry by substituting for the abused drug. This approach has been explored for the treatment of cocaine dependence (Alim et al, 1995;Grabowski et al, 1997Grabowski et al, , 2001Kampman et al, 2000;Walsh et al, 2000). Our results with PAL-287 extend the concept of agonist substitution by using a dual DA/5-HT releaser that exhibits the desired therapeutic effects of a replacement medication without the adverse side effects associated with prototypical psychomotor stimulants.…”

Section: Discussionmentioning

confidence: 66%

Development of a Rationally Designed, Low Abuse Potential, Biogenic Amine Releaser That Suppresses Cocaine Self-Administration

Rothman¹,

Blough²,

Woolverton³

et al. 2005

J Pharmacol Exp Ther

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Convergent lines of evidence support a dual deficit model of stimulant withdrawal, where reductions in synaptic dopamine (DA) and 5-hydroxytryptamine (serotonin) (5-HT) contribute to dysphoria, drug craving, and relapse. Thus, we predicted that a nonamphetamine compound with substrate activity at DA and 5-HT transporters (i.e., a dual DA/5-HT releaser) would be an effective medication for treating stimulant addictions. Ideally, this type of medication would alleviate withdrawal symptoms, suppress cocaine self-administration, and lack side effects commonly associated with central nervous system stimulants. In the present work, more than 350 compounds were screened in vitro for activity as substrate-type releasing agents at DA, 5-HT, and norepinephrine transporters. These efforts identified PAL-287 (1-napthyl-2-aminopropane) as a nonamphetamine compound with potent substrate activity at biogenic amine transporters. In vivo microdialysis in rats demonstrated that PAL-287 (1-3 mg/kg i.v.) increased extracellular DA and 5-HT in frontal cortex, but effects on 5-HT were somewhat greater. PAL-287 induced substantially less locomotor stimulation than (ϩ)-amphetamine, a drug that increases only extracellular DA. Administration of high-dose (ϩ)-methamphetamine or (Ϯ)-3,4-methylenedioxymethamphetamine to rats produced long-lasting depletion of cortical 5-HT, whereas PAL-287 (18 mg/kg i.p. ϫ 3) did not. PAL-287 displayed little or no reinforcing properties in rhesus monkeys trained to self-administer cocaine, yet PAL-287 produced a dose-dependent decrease in responding for cocaine when infused at a dose of 1.0 mg/kg/h. Collectively, the findings reported here demonstrate that nonamphetamine monoamine releasing agents such as PAL-287 might be promising candidate medications for the treatment of stimulant dependence.

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“…However, oral MP or AMP in cocaine-addicted subjects did not decrease cocaine consumption when compared with placebo treatment. 79,80 We believe this is explained by the fact that you need to block most if not all DAT to interfere with cocaine's effects 81 and the oral doses required to maintain this level of blockade would be very large (significantly larger than doses that have been tested) and very likely to have cardiotoxic effects. Also, oral MP and AMP would increase extracellular DA and in so doing would make events more salient.…”

Section: Treatment Implicationsmentioning

confidence: 99%

Dopamine in drug abuse and addiction: results from imaging studies and treatment implications

et al. 2004

Mol Psychiatry

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793

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The involvement of dopamine in drug reinforcement is well recognized but its role in drug addiction is much less clear. Imaging studies have shown that the reinforcing effects of drugs of abuse in humans are contingent upon large and fast increases in dopamine that mimic but exceed in the intensity and duration those induced by dopamine cell firing to environmental events. In addition, imaging studies have also documented a role of dopamine in motivation, which appears to be encoded both by fast as well as smooth DA increases. Since dopamine cells fire in response to salient stimuli, the supraphysiological activation by drugs is likely to be experienced as highly salient (driving attention, arousal conditioned learning and motivation) and may also reset the thresholds required for environmental events to activate dopamine cells. Indeed, imaging studies have shown that in drug-addicted subjects, dopamine function is markedly disrupted (decreases in dopamine release and in dopamine D2 receptors in striatum) and this is associated with reduced activity of the orbitofrontal cortex (neuroanatomical region involved with salience attribution and motivation and implicated in compulsive behaviors) and the cingulate gyrus (neuroanatomical region involved with inhibitory control and attention and implicated in impulsivity). However, when addicted subjects are exposed to drug-related stimuli, these hypoactive regions become hyperactive in proportion to the expressed desire for the drug. We postulate that decreased dopamine function in addicted subjects results in decreased sensitivity to nondrug-related stimuli (including natural reinforcers) and disrupts frontal inhibition, both of which contribute to compulsive drug intake and impaired inhibitory control. These findings suggest new strategies for pharmacological and behavioral treatments, which focus on enhancing DA function and restoring brain circuits disrupted by chronic drug use to help motivate the addicted subject in activities that provide alternative sources of reinforcement, counteract conditioned responses, enhance their ability to control their drive to take drugs and interfere with their compulsive administration.

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Replacement Medication for Cocaine Dependence

Cited by 177 publications

References 18 publications

Cocaine, reward, movement and monoamine transporters

Cocaine, reward, movement and monoamine transporters

Development of a Rationally Designed, Low Abuse Potential, Biogenic Amine Releaser That Suppresses Cocaine Self-Administration

Dopamine in drug abuse and addiction: results from imaging studies and treatment implications

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