The impact of impulsivity on cocaine use and retention in treatment

Moeller, F. Gerard; Dougherty, Donald M.; Barratt, Ernest S.; Schmitz, Joy M.; Swann, Alan C.; Grabowski, John

doi:10.1016/s0740-5472(01)00202-1

Cited by 394 publications

(330 citation statements)

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“…; Figure 2). No main effect of treatment was observed for horizontal ambulations totaled for the entire 60 min test session [F (3,28) = 2.11, n.s. ; Figure 2, inset].…”

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confidence: 99%

“…17 Figure 3 displays the horizontal ambulations after treatment with vehicle or WAY163909 prior to administration of cocaine; data are presented as total horizontal ambulations in 15 min bins (Figure 3) or for the entire 60 min session (Figure 3, inset). A main effect of treatment [F (3,44) Figure 3). A main effect of treatment was observed for horizontal ambulations totaled for the entire 60 min test session [F (3,44) = 3.83, p < 0.05; Figure 3, inset]; a priori comparisons showed that 1 mg/kg, but not 0.1 or 0.3 mg/kg, of WAY163909 significantly suppressed cocaine-evoked horizontal ambulations (1 WAY-COC vs VEH-COC; p < 0.05; Figure 3, inset; dashed line indicates VEH-VEH levels).…”

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“…A main effect of treatment [F (3,44) Figure 3). A main effect of treatment was observed for horizontal ambulations totaled for the entire 60 min test session [F (3,44) = 3.83, p < 0.05; Figure 3, inset]; a priori comparisons showed that 1 mg/kg, but not 0.1 or 0.3 mg/kg, of WAY163909 significantly suppressed cocaine-evoked horizontal ambulations (1 WAY-COC vs VEH-COC; p < 0.05; Figure 3, inset; dashed line indicates VEH-VEH levels). Thus, we identified subthreshold doses of M100907 (0.03 mg/kg) 28 and WAY163909 (0.3 mg/kg; Figure 3) which do not alter cocaine-induced motor activity when tested alone ( Table 1).…”

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“…horizontal ambulations totaled for the entire 60 min test session [F (3,23) = 4.43; p < 0.05; Figure 4, inset]; a priori comparisons showed that while neither ligands tested alone at chosen doses altered horizontal ambulations, the combination of M100907 plus WAY163909 significantly decreased cocaine-evoked horizontal ambulations (M100-WAY-COC vs VEH-VEH-COC; p < 0.05; Figure 4, inset; dashed line indicates VEH-VEH-VEH levels). The effects of M100907 plus WAY163909 on cocaine-evoked vertical activity were similar to cocaineevoked horizontal ambulations (data not shown).…”

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confidence: 99%

“…Figure 5 displays the number of premature responses ( Figure 5A) and reinforcers earned ( Figure 5B) on the 1-CSRT task after treatment with vehicle, M100907 (0.01 mg/kg), WAY163909 (0.1 mg/kg), or the combination; data are presented as a percentage of the number of premature responses or reinforcers earned on the VEH-VEH session that preceded each dose/ combination evaluated. A main effect of treatment on premature responses was observed [F (3,51) = 5.18; p < 0.05; Figure 5A]; a priori comparisons showed that M100907 plus WAY163909 significantly decreased premature responses versus VEH-VEH (p < 0.05; Figure 5A; dashed line indicates VEH-VEH levels). Neither M100907 nor WAY163909 alone altered the number of premature responses (n.s.…”

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Synergism Between a Serotonin 5-HT_2A Receptor (5-HT_2AR) Antagonist and 5-HT_2CR Agonist Suggests New Pharmacotherapeutics for Cocaine Addiction

Cunningham¹,

Anastasio²,

Fox

et al. 2012

ACS Chem. Neurosci.

119

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Relapse to cocaine dependence, even after extended abstinence, involves a number of liability factors including impulsivity (predisposition toward rapid, unplanned reactions to stimuli without regard to negative consequences) and cue reactivity (sensitivity to cues associated with cocaine-taking which can promote cocaine-seeking). These factors have been mechanistically linked to serotonin (5-hydroxytryptamine, 5-HT) signaling through the 5-HT 2A receptor (5-HT 2A R) and 5-HT 2C R; either a selective 5-HT 2A R antagonist or a 5-HT 2C R agonist suppresses impulsivity and cocaine-seeking in preclinical models. We conducted proof-of-concept analyses to evaluate whether a combination of 5-HT 2A R antagonist plus 5-HT 2C R agonist would have synergistic effects over these liability factors for relapse as measured in a 1-choice serial reaction time task and cocaine self-administration/reinstatement assay. Combined administration of a dose of the selective 5-HT 2A R antagonist M100907 plus the 5-HT 2C R agonist WAY163909, each ineffective alone, synergistically suppressed cocaine-induced hyperactivity, inherent and cocaine-evoked impulsive action, as well as cue-and cocaine-primed reinstatement of cocaine-seeking behavior. The identification of synergism between a 5-HT 2A R antagonist plus a 5-HT 2C R agonist to attenuate these factors important in relapse indicates the promise of a bifunctional ligand as an anti-addiction pharmacotherapeutic, setting the stage to develop new ligands with improved efficacy, potency, selectivity, and in vivo profiles over the individual molecules. KEYWORDS: 1-Choice serial reaction time task, 5-HT 2A receptor, 5-HT 2C receptor, cocaine, cue reactivity, impulsivity, self-administration, serotonin D ependence on the psychostimulant cocaine is marked by problematic vulnerability to relapse even years into abstinence. 1,2 Two important liability factors that contribute to relapse are impulsivity (predisposition toward rapid, unplanned reactions to stimuli without regard to negative consequences) 3 and cue reactivity (sensitivity to cues associated with cocaine-taking that can promote cocaine-seeking). 4,5 Impulsivity and cue reactivity appear to be interrelated in human cocaine users, 6 and new pharmacotherapeutic strategies that effectively diminish both are likely to enhance abstinence in the highly vulnerable population of cocaine-dependent individuals.The underlying neurobiology of these liability factors includes a regulatory role for serotonin (5-HT; 5-hydroxytryptamine) neurotransmission. The actions of 5-HT in neurons are transduced by at least 14 subtypes of 5-HT receptors (5-HT X Rs) which are presently grouped into seven families (5-HT 1 R−5-HT 7 R) according to their structural and functional characteristics. 7−9 Selective blockade of the 5-HT 2A R 10−12 or activation of the 5-HT 2C R 10,13,14 consistently reduces impulsivity as measured by premature responses assessed in the 1-or 5-choice serial reaction time (1-or 5-CSRT) task, a preclinical Special Issue: Celebratin...

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“…; Figure 2). No main effect of treatment was observed for horizontal ambulations totaled for the entire 60 min test session [F (3,28) = 2.11, n.s. ; Figure 2, inset].…”

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