The combination of nicotine with the D2 antagonist raclopride or the weak D4 antagonist L-745,870 generates a clozapine-like facilitation of NMDA receptor-mediated neurotransmission in pyramidal cells of the rat medial prefrontal cortex.
Clozapine and other atypical, but not typical, antipsychotic drugs (APDs), facilitate both dopaminergic and N-methyl-D-aspartate (NMDA) receptor-mediated glutamatergic transmission in the medial prefrontal cortex (mPFC), which is thought to improve cognition. Switching schizophrenic patients from typical APDs to clozapine may reduce their cigarette smoking. Here, we tested whether nicotine, which facilitates dopamine release, also facilitates NMDA receptor-mediated neurotransmission in the mPFC, when given alone or in combination with a D(2,3) antagonist, raclopride, or a D4 antagonist, 3-(4-[4-chlorophenyl]piperazin-1-yl)methyl-1H-pyrrolo[2,3b]pyridine (L-745,870), using intracellular recording in pyramidal cells of the rat mPFC. Neither nicotine nor raclopride or L-745,870 alone altered NMDA-induced currents in these cells. However, combining nicotine with raclopride or L-745,870 facilitated these currents. Similarly to clozapine the combination of nicotine with raclopride or L-745,870 also markedly potentiated evoked excitatory post-synaptic potentials in the mPFC. Our results support the idea that intense smoking in schizophrenia may represent a form of self-medication with nicotine.
Karolinska Institutet, Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Stockholm, Sweden.
Kent
K
Jardemark
Monica M
MM
Marcus
Asa
A
Konradsson
Torgny H
TH
Svensson
D000704:Analysis of Variance; D000818:Animals; D018492:Dopamine Antagonists / Q000494:pharmacology*; D004338:Drug Combinations; D004347:Drug Interactions; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D009538:Nicotine / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000166:cytology* / Q000187:drug effects; D017966:Pyramidal Cells / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D020891:Raclopride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects*
C099630:3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-1H-pyrrolo(2,3-b)pyridine; D018492:Dopamine Antagonists; D004338:Drug Combinations; D018690:Excitatory Amino Acid Agonists; D011725:Pyridines; D011758:Pyrroles; D016194:Receptors, N-Methyl-D-Aspartate; D020891:Raclopride; D016202:N-Methylaspartate; D009538:Nicotine