Serotonergic manipulations both potentiate and reduce brain stimulation reward in rats: involvement of serotonin-1A receptors.
A discrete-trial current-threshold self-stimulation procedure was used to assess the effects of increased and decreased serotonergic neurotransmission, and 5-HT(1A) receptor activation on brain stimulation reward. Systemic administration of the 5-HT(1A) receptor agonist 8-OH-DPAT had a biphasic effect on brain reward thresholds, without affecting the latency to respond, a measure of performance. The low dose of 8-OH-DPAT (0.03 mg/kg) lowered reward thresholds, whereas higher doses (0.1 and 0.3 mg/kg) elevated thresholds. The 5-HT(1A) receptor antagonist p-MPPI had no effect on brain stimulation behavior, but reversed both the 8-OH-DPAT-induced lowering and elevation of thresholds, indicating that both of these effects of 8-OH-DPAT are mediated through the 5-HT(1A) receptor. Injections of 8-OH-DPAT into the median raphé nucleus also lowered brain reward thresholds, without affecting measures of performance, whereas injections of 8-OH-DPAT into the dorsal raphé nucleus had no effect. A high dose of the selective serotonin reuptake inhibitor fluoxetine (10 mg/kg) elevated reward thresholds and responses latencies, whereas lower doses (2.5 and 5.0 mg/kg) increased response latencies without affecting thresholds. Furthermore, the coadministration of a 5-HT(1A) antagonist, p-MPPI, and a previously ineffective dose of fluoxetine, a drug combination that increases serotonin levels, significantly elevated thresholds. Thus, it is suggested here that the reward-potentiating effects of systemically administered low doses of 8-OH-DPAT may be the result of reduced serotonergic neurotransmission, mediated by activation of 5-HT(1A) somatodendritic autoreceptors in the median, but not the dorsal, raphé nucleus. In conclusion, the present data support the hypothesis that serotonin exerts an inhibitory influence on reward processes.
Department of Neuropharmacology, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037, USA.
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Harrison
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Markou
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology*; D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005473:Fluoxetine / Q000494:pharmacology; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D011903:Raphe Nuclei / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000502:physiology*; D044263:Receptors, Serotonin, 5-HT1; D012201:Reward; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
D000631:Aminopyridines; D010879:Piperazines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D005473:Fluoxetine; C087205:4-(2'-methoxyphenyl)-1-(2'-(N-(2''-pyridinyl)-4-iodobenzamido)ethyl)piperazine; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin