RU-24969 disrupts d-amphetamine self-administration and responding for conditioned reward via stimulation of 5-HT1B receptors.
Behavioural and neurochemical evidence indicates a facilitatory effect of 5-hydroxytryptamine (5-HT), acting via 5-HT1B receptors, on dopamine (DA) systems. To explore this interaction further, these experiments examined the effects of the 5-HT1A/1B agonist RU-24969 on behaviours known to involve the mesolimbic DA system. These behaviours were locomotor activity, intravenous self-administration of d-amphetamine, responding for a conditioned reward (CR), and the response potentiating effects of amphetamine on CR responding. Locomotor activity was enhanced by 1 and 3 mg/kg RU 24969, and both doses also reduced responding for d-amphetamine (60 microg/kg/infusion). Changing the unit dose produced a characteristic U-shaped dose-response curve. This dose-response relationship was not apparent following injection of RU-24969. Across all unit infusion doses of amphetamine, the level of responding was fairly constant. In the CR experiments, rats responded for a conditioned stimulus that was previously paired with water. RU-24969 completely disrupted responding for CR, and also abolished CR responding in rats injected with 3 microg d-amphetamine in the nucleus accumbens. RU-24969 also markedly suppressed responding for water. The suppressant actions of RU-24969 on amphetamine self-administration and CR responding involve stimulation of 5-HT1B receptors, since they were reversed by the 5-HT1B/1D antagonist GR 127935 (3 mg/kg), but not by the 5-HT1A antagonist WAY-100635 (1 mg/kg). None of the behavioural effects of RU-24969 are consistent with a selective action to enhance mesolimbic DA function. Rather, global activation of 5-HT1B receptors appear to exert a general disruptive effect on operant responding.
Fletcher
P J
PJ
Department of Psychology, University of Toronto, Centre for Addiction and Mental Health, Ontario, Canada. fletcher@psych.toronto.edu
Korth
K M
KM
D019969:Amphetamine-Related Disorders / Q000517:prevention & control*; D000818:Animals; D000697:Central Nervous System Stimulants / Q000008:administration & dosage; D003216:Conditioning, Operant / Q000187:drug effects*; D003913:Dextroamphetamine / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D008845:Microinjections; D009043:Motor Activity / Q000187:drug effects; D009714:Nucleus Accumbens; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin / Q000187:drug effects*; D012201:Reward; D012646:Self Administration; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D014867:Water
D000697:Central Nervous System Stimulants; D007211:Indoles; D010879:Piperazines; D011725:Pyridines; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D014867:Water; C025145:5-methoxy 3-(1,2,3,6-tetrahydro-4-pyridinyl)1H indole; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D003913:Dextroamphetamine