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1.
Br J Pharmacol ; 131(5): 990-6, 2000 Nov.
Article in English | MEDLINE | ID: mdl-11053221

ABSTRACT

The present study compared high affinity neurotensin (NT) binding in rat brain following acute or chronic treatment with the classical antipsychotic, haloperidol, and the newer antipsychotic drugs, clozapine and zotepine. Drugs were given orally, as an acute treatment (1 dose) or chronically (21 day dosing) and binding to the NT high affinity receptor was examined in three brain regions; striatum, nucleus accumbens/olfactory tubercle and frontal cortex. Acute dosing with either vehicle, haloperidol, clozapine or zotepine produced no significant changes in NT binding from controls (naïve rats). Chronic (21 day) dosing resulted in an increase in the K:(D:) and B(max) of high affinity receptors in the striatum following haloperidol, but not clozapine, zotepine or vehicles. In contrast, the newer antipsychotics, clozapine and zotepine but not haloperidol or vehicles, significantly altered NT binding in the nucleus accumbens/olfactory tubercle by decreasing the K:(D:) and B(max). Further differentiation between the two newer antipsychotic drugs occurred in the frontal cortex. Clozapine had no significant effect on NT binding, whereas zotepine significantly reduced the K:(D:) of the high affinity receptor with no alteration in B(max). The antipsychotic drugs tested did not interact directly with the NT high affinity receptor. Therefore, they must be acting indirectly via an alternative receptor mechanism to alter NT high affinity binding. In accordance with previously reported NT/dopamine receptor interactions, this would suggest cross-talk between these systems. Overall, these data demonstrate that chronic, but not acute, administration of antipsychotic drugs alters NT binding in the rat brain. In addition, anatomical differences in NT binding arise according to the antipsychotic drug under test. This may be predictive of drug side-effect profile, antipsychotic efficacy or atypicality.


Subject(s)
Antipsychotic Agents/pharmacology , Brain/metabolism , Neurotensin/metabolism , Animals , Male , Neurotensin/genetics , RNA, Messenger/analysis , Rats , Rats, Sprague-Dawley , Receptors, Dopamine/drug effects , Receptors, Dopamine/metabolism , Receptors, Neurotensin/metabolism
2.
J Neurosci Methods ; 100(1-2): 151-6, 2000 Jul 31.
Article in English | MEDLINE | ID: mdl-11040378

ABSTRACT

A highly selective and sensitive radioimmunoassay (RIA) for the detection of endogenous neurotensin (NT) has been developed. We have raised a C-terminally-directed antibody (CAb) that specifically binds 'biologically active' NT (NT and NT(8-13)) and that does not significantly cross-react with inactive NT metabolites or other bioactive peptides in the CNS. By reducing the volume of the assay to a low volume-RIA (30 microl), such that in vivo measurements can be made, we have increased the sensitivity (<0.3 fmol per tube), with inter- and intra-assay variations of 11.2 and 5.8%, respectively. Comparisons with similar methods of detecting NT have demonstrated that this RIA has a higher sensitivity than previously used RIA's and ELISA's. The data presented suggests that this sensitive RIA is a reliable method ideal for the detection of small quantities of biologically active NT.


Subject(s)
Brain Chemistry , Neurotensin/analysis , Radioimmunoassay/methods , Animals , Female , Neurotensin/immunology , Peptide Fragments/immunology , Protein Structure, Tertiary/physiology , Sheep
3.
Br J Pharmacol ; 117(4): 743-9, 1996 Feb.
Article in English | MEDLINE | ID: mdl-8646423

ABSTRACT

1. In vivo brain microdialysis has been employed to investigate the effects of ibogaine on nicotine-induced changes in dopamine overflow in the nucleus accumbens (NAc) of freely moving rats. The effects of the compound on locomotor responses to nicotine and behaviour in the elevated plus-maze were also examined. 2. No changes were observed in the dopamine overflow or the locomotor activity of the animals following the administration of ibogaine (40 mg kg-1, i.p.). However, ibogaine, administered 22 h earlier, significantly (P < 0.01) attenuated the increase in dopamine overflow but not the hyperlocomotion, evoked by nicotine. 3. In the elevated plus-maze test, significant reductions in the open:total runway entries in both saline-treated controls (P < 0.05) and nicotine-treated (P < 0.01) rats were obtained when the animals were tested 22 h after pretreatment with ibogaine (40 mg kg-1, i.p.). The total activity was significantly (P < 0.01) greater in the nicotine-treated rats but this response was not affected by ibogaine pretreatment. 4. Administration of ibogaine was associated with reductions in the tissue levels of 5-hydroxyindoleacetic acid (5-HIAA) in the NAc (P < 0.01) and striatum (P < 0.05) and an increase in the level of this metabolite in the medial prefrontal cortex (mPFC) (P < 0.01) while the levels of dopamine and 5-hydroxytryptamine (5-HT) in the mPFC were reduced (P < 0.05). The DOPAC/dopamine (P < 0.05) and 5-HIAA/5-HT (P < 0.01) ratios were significantly increased in the mPFC for at least 7 days after a single treatment with ibogaine. 5. Ibogaine attenuates the nicotine-induced increases in dopamine overflow in the NAc and may, therefore, inhibit the rewarding effects of this drug. However, the long lasting anxiogenesis induced by ibogaine warrant further investigation before its use could be recommended for smokers.


Subject(s)
Brain Chemistry/drug effects , Ibogaine/pharmacology , Motor Activity/drug effects , Nicotine/pharmacology , 3,4-Dihydroxyphenylacetic Acid/metabolism , Animals , Dopamine/metabolism , Hydroxyindoleacetic Acid/metabolism , Male , Rats , Rats, Sprague-Dawley , Serotonin/metabolism
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