Interactions between serotonin and dopamine in the control of impulsive choice in rats: therapeutic implications for impulse control disorders.
Forebrain serotonergic lesions attenuate the ability of d-amphetamine to decrease impulsivity in a delay-discounting paradigm, potentially through interactions between the serotonin (5-HT) and dopamine (DA) systems. Nucleus accumbens (NAC) lesions increase impulsivity, but the extent to which accumbal DA is involved in regulating impulsive choice is unknown. In the current study, the effects of intra-accumbal infusions of 6-hydroxydopamine (6-OHDA) on impulsive choice were evaluated, in combination with d-amphetamine and serotonergic drugs, in order to investigate the importance of 5-HT : DA interactions in the control of impulsive behavior. Following training on a delay-discounting task, animals received intra-NAC 6-OHDA or sham surgery. Postoperatively, subjects received systemic injections of d-amphetamine (0, 0.3, 1.0, 1.5 mg/kg) and the 5-HT(1A) receptor agonist 8-OH-DPAT (0, 0.1, 0.3, 1.0 mg/kg). Intra-NAC 6-OHDA, which reduced local DA and NA levels by 70-75%, had no effect on delay-discounting, but transiently potentiated the d-amphetamine-induced decrease in impulsive choice. 8-OH-DPAT (1.0 mg/kg) increased impulsivity in sham-operated controls, an effect which was blocked by the 5-HT(1A) receptor antagonist WAY 100635. However, 8-OH-DPAT had no effect on impulsivity in 6-OHDA NAC lesioned rats. 8-OH-DPAT (0.3 mg/kg), which did not itself alter task performance, blocked the effect of d-amphetamine in sham-operated controls, while WAY 100635 augmented the effect of amphetamine in all subjects. In an additional experiment, intracerebroventricular administration of the selective serotonergic toxin 5,7-dihydroxytryptamine, which decreased forebrain 5-HT levels by 85-90%, did not block 8-OH-DPAT's ability to increase impulsive choice. These data suggest a significant role for 5-HT : DA interactions within the NAC in the control of impulsivity, and in the mechanism by which amphetamine decreases impulsive choice.
Winstanley
Catharine A
CA
Department of Experimental Psychology, University of Cambridge, Cambridge, UK. cath.winstanley@utsouthwestern.edu
Theobald
David E H
DE
Dalley
Jeffrey W
JW
Robbins
Trevor W
TW
D015116:5,7-Dihydroxytryptamine / Q000494:pharmacology; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D018663:Adrenergic Agents / Q000494:pharmacology; D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D007174:Disruptive, Impulse Control, and Conduct Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D008297:Male; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D009638:Norepinephrine / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D016627:Oxidopamine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists; D018490:Serotonin Agents / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
D018663:Adrenergic Agents; D010879:Piperazines; D011725:Pyridines; D058825:Serotonin 5-HT1 Receptor Agonists; D018490:Serotonin Agents; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D015116:5,7-Dihydroxytryptamine; D012701:Serotonin; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D016627:Oxidopamine; D000661:Amphetamine; D004298:Dopamine; D009638:Norepinephrine