Responses of limbic and extrapyramidal neurotensin systems to stimulants of abuse. Involvement of dopaminergic mechanisms.
In summary, we have observed that drugs of abuse, which can cause schizophrenia-like paranoia, alter striatal and accumbens NT systems in a similar, dramatic fashion. The NT responses to these drugs, in particular METH, are mediated by activation of DA D1 receptors. We have observed that NMDA-type glutamate receptors are essential for the D1-NT interaction. NMDA receptors are selective, since they do not contribute to the antagonistic effects of DA D2 receptors on NT activity. This observation suggests that NT responses to D1 and D2 regulation are mediated through separate and distinct mechanisms. Finally, we found that the presence of METH dramatically reduces striatal NT release, which most likely leads to NT accumulation in nerve terminals and the observed increase in NT tissue level. The blockade of NT release by a psychotogenic drug, such as METH, is consistent with the hypothesis that NT has antipsychotic activity and a decrease in its release may contribute to some forms of schizophrenia similar to that caused by intense use of the stimulants of abuse.
Hanson
G R
GR
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City 84112.
Singh
N
N
Merchant
K
K
Johnson
M
M
Bush
L
L
Gibb
J W
JW
D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D013287:Illicit Drugs / Q000494:pharmacology; D008032:Limbic System / Q000378:metabolism*; D008694:Methamphetamine / Q000494:pharmacology*; D009496:Neurotensin / Q000378:metabolism*; D010622:Phencyclidine / Q000494:pharmacology*; D011712:Pyramidal Tracts / Q000378:metabolism*; D051381:Rats; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism
D015259:Dopamine Agents; D013287:Illicit Drugs; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D016194:Receptors, N-Methyl-D-Aspartate; D009496:Neurotensin; D008694:Methamphetamine; D016291:Dizocilpine Maleate; D003042:Cocaine; D010622:Phencyclidine; D004298:Dopamine