Dopaminergic basis for the facilitation of brain stimulation reward by the NMDA receptor antagonist, MK-801.
MK-801 (dizocilpine maleate), an antagonist of the NMDA receptor, was given alone or in combination with dopamine D1 and D2 receptor antagonists to rats self-stimulating in lateral hypothalamus to determine whether the dopamine neurons play a role in mediating the effects of MK-801. MK-801 given at a dose of 0.1 mg/kg i.p. to self-stimulators induced a prolonged facilitation of lever-pressing, but given to non-self-stimulators, the drug had no effects. Pretreatment of self-stimulators with the dopamine D1 receptor antagonist Schering 23390 (SCH 23390), 0.2 mg/kg given i.p. 15 min before MK-801, prevented the facilitation seen with MK-801, but did not suppress self-stimulation. SCH 23390 given alone suppressed self-stimulation. Pretreatment of self-stimulators with the dopamine D1/D2 receptor antagonist, haloperidol, 0.2 mg/kg given i.p. 15 min before MK-801, also prevented the facilitation of self-stimulation induced by MK-801 yet did not suppress self-stimulation. Haloperidol given alone suppressed self-stimulation. Pretreatment of self-stimulators with both SCH 23390 and haloperidol 15 min before MK-801 prevented the facilitation seen with MK-801 and suppressed self-stimulation. The combined treatment with SCH 23390 and haloperidol (without MK-801) suppressed self-stimulation, and the suppression lasted longer than the suppression seen when the two dopamine receptor antagonists were given as pretreatment, before MK-801. Pretreating self-stimulators with the combination of SCH 23390 and haloperidol 15 min before amphetamine (2 mg/kg) prevented the facilitatory response and suppressed responding for the brain reward. The suppression was of shorter duration than the suppression seen after the injection of SCH 23390 plus haloperidol. The treatment of self-stimulators with both MK-801 and amphetamine resulted in a greater and longer-lasting facilitation than the increase in responding produced by either drug alone. The similarity between the effects of MK-801 and those of amphetamine and between the effects of pretreatment with the dopamine receptor antagonists before MK-801 and before amphetamine suggests that dopaminergic activity played a significant role in the action underlying the effects of MK-801 on brain stimulation reward.
Olds
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Division of Biology, California Institute of Technology, Pasadena 91125, USA.
D000661:Amphetamine / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015259:Dopamine Agents / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006220:Haloperidol / Q000494:pharmacology*; D007031:Hypothalamus / Q000187:drug effects; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012653:Self Stimulation / Q000187:drug effects*
D001552:Benzazepines; D015259:Dopamine Agents; D018492:Dopamine Antagonists; D018691:Excitatory Amino Acid Antagonists; D016291:Dizocilpine Maleate; D000661:Amphetamine; D006220:Haloperidol