ABSTRACT
Daily injection of the dopamine D(2) receptor antagonist haloperidol is associated with the development of catalepsy sensitization in rats, which leads to a day to day increase of rigor and akinesia. The process of catalepsy sensitization incorporates different learning stages. Here we investigated the mechanisms underlying the consolidation of catalepsy sensitization. In particular, we asked whether NMDA- and non-NMDA (AMPA- and Kainate) receptors play a role in the consolidation of catalepsy sensitization. Accordingly, rats received post-training injections of the NMDA receptor antagonist MK-801 (single injection of either 0.1mg/kg or 0.25mg/kg; or a double injection of 0.1mg/kg immediately and 30 min after test cessation) or of the AMPA/Kainate receptor antagonist GYKI 52466 (single injection of 5mg/kg). Our results showed that the consolidation of catalepsy sensitization was decelerated by both glutamatergic AMPA/Kainate- and NMDA-receptor antagonists. With the higher MK-801 dosage, the deceleration was stronger, suggesting a dose dependent mechanism. We hence affirmed a role for the ionotropic glutamate receptors in the consolidation process of catalepsy sensitization.
Subject(s)
Catalepsy/chemically induced , Haloperidol/pharmacology , Receptors, AMPA/metabolism , Receptors, Kainic Acid/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Analysis of Variance , Animals , Benzodiazepines/pharmacology , Catalepsy/metabolism , Dizocilpine Maleate/pharmacology , Dopamine Antagonists/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Male , Rats , Rats, Sprague-Dawley , Receptors, AMPA/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitorsABSTRACT
A cultured mouse cell line with an integrated copy of a plasmid that contains a short dinucleotide repeat sequence (microsatellite) has been used to determine the frequencies and types of mutation induced by two frameshift mutagens. The presence of the microsatellite, which consists of 17 repeats of a poly(dC-dA).poly(dT-dG) sequence, disrupts the reading frame of a gene coding for neomycin resistance. Revertants were selected in G418, and mutations were analyzed by PCR. ICR-170 was found to increase the reversion frequency by ten- to 15-fold at its LD50, although most of the frameshifts that it induced were single-base insertions outside the microsatellite sequence. NA-AAF brought about a more modest increase in mutation frequency, but nearly all of the revertants in the NA-AAF-treated cultures had insertions or deletions of multiples of two base pairs within the DNA segment that included the microsatellite. This system can be modified to include different short tandem repeat sequences as targets for testing of compounds that are suspected of having frameshift-inducing activities.
