The psychotomimetic drugs D-amphetamine and phencyclidine release calcitonin gene-related peptide in the limbic forebrain of the rat.
Calcitonin gene-related peptide (CGRP) is the major product of the calcitonin gene in brain and exerts a number of actions in the central nervous system (CNS). In particular the finding that CGRP affects dopamine (DA) release and metabolism has raised the possibility that it may play a role in several neuropsychiatric disorders. Consequently, we have here studied the effects of two psychotomimetic drugs, namely, d-amphetamine (AMPH) and phencyclidine (PCP), on CGRP concentrations in brain microdialysates from freely moving rats. The animals were stereotaxically implanted with vertical concentric probes in the medial prefrontal cortex (mPFC), the ventral striatum (vSTR), or the hippocampus; and the experiments were performed 48 hr after surgery. The dialysis probes were perfused with a modified Ringer's solution at the rate of 5 microliters/min. AMPH 1.5 mg/kg, PCP 2.5 mg/kg, or NaCl 0.9% were injected s.c.; and the perfusates were collected at 60 min intervals before and after the injections and used for CGRP-like immunoreactivity (-LI) determination by radioimmunoassay (RIA). In separate experiment, KCl (100 mM), veratridine (50 microM), or tetrodotoxin (2 microM), were added to the perfusate and infused in the vSTR. Baseline levels of CGRP-LI were detected in dialysates from all three regions. Both AMPH and PCP caused a significant and sustained increase (maximum about 300%) in CGRP-LI concentrations, in particular from the mPFC and vSTR, while saline had no effect. KCl and veratridine also increased CGRP-LI in dialysates during the first posttreatment period, while tetrodotoxin induced a significant but delayed decrease in CGRP-LI levels. Finally, cervical dislocation also elevated CGRP-LI in dialysates from the mPFC and the vSTR. Our findings demonstrate that 1) CGRP-LI can be measured in vivo in microdialysates from mPFC, vSTR, and hippocampus; 2) the release in vSTR is action potential-dependent; and 3) systemic administration of AMPH or PCP results in a long-lasting release of CGRP-LI in the mPFC and vSTR, thus demonstrating a novel action of these drugs in the brain. Since other studies have shown that major antipsychotic drugs appear to reduce CGRP release in brain, our study provides, in principle, support for a role of CGRP in psychotic disorders.
Mathé
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AA
Department of Clinical Neuroscience, St. Göran's Hospital, Karolinska Institutet, Stockholm, Sweden.
Hertel
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P
Nomikos
G G
GG
Gruber
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S
Mathé
J M
JM
Svensson
T H
TH
D000704:Analysis of Variance; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects; D003913:Dextroamphetamine / Q000494:pharmacology*; D006213:Hallucinogens / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects; D008032:Limbic System / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D010622:Phencyclidine / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects; D016548:Prosencephalon / Q000187:drug effects* / Q000378:metabolism; D011863:Radioimmunoassay; D051381:Rats; D017208:Rats, Wistar
D006213:Hallucinogens; D010622:Phencyclidine; D015740:Calcitonin Gene-Related Peptide; D003913:Dextroamphetamine