The action of m-trifluoromethylphenylpiperazine (TFMPP) and m-chlorophenylpiperazine (m-CPP), inhibiting the exploratory activity (ambulation and peeping) of the rat was studied in the open field test. The effects of both these drugs were antagonized by mesulergine, metergoline and mianserin, and partly by methysergide. Spiperone showed an antagonistic action in one (mean) dose only. The effects of TFMPP and m-CPP were not antagonized by ipsapirone, gepirone, cyanopindolol, compound 21009, cyproheptadine, ritanserine, ICS 205930, idazoxan or atropine. The lesion produced by p-chloramphetamine attenuated the effects of TFMPP and abolished those of m-CPP. The obtained results permit an assumption that the TFMPP- and m-CPP-induced decrease in the exploratory activity is mediated probably by 5-HT1C receptors.

The effects of the atypical neuroleptic zotepine in comparison with clozapine, risperidone and haloperidol were examined in tests related to the central 5-HT2 activity. Zotepine, as well as clozapine and risperidone, were very potent inhibitors of the 5-HTP-induced head twitches (the behavior mediated by 5-HT2 receptors) in mice, with rank order of potency risperidone > zotepine > clozapine; haloperidol used in high doses only slightly reduced the effect of 5-HTP. Zotepine, clozapine, risperidone and haloperidol antagonized the stimulatory effects of mCPP on the hind limb flexor reflex in spinal rats. As the mCPP-induced stimulation is considered to be mediated by 5-HT2 receptors, the above results provide further evidence for the 5-HT2 antagonistic activity of the drugs studied. Te rank order of potency in that test was the same as in the 5-HTP-induced head twitches (risperidone > zotepine > clozapine). The effect of haloperidol was somewhat unspecific, since its active doses were very high. In the model of hind limb flexor reflex of spinal rats, the anti-alpha 2-adrenergic effect was also tested. Clonidine-induced stimulation of the hind limb flexor reflex (an alpha 2-adrenergic effect) was antagonized by zotepine, clozapine, risperidone and haloperidol. It may be concluded that zotepine, clozapine and risperidone show an alpha 2-adrenergic antagonistic activity (order of potency: zotepine = risperidone > clozapine). The effect of haloperidol may be considered unspecific, since it is observed at high (cataleptic) doses only. In conclusion, it appears that zotepine, as well as clozapine and risperidone, are strong 5-HT2 antagonists, while haloperidol is not.

The present study shows that low amounts of applied iron have a potent effect on the ventrolateral striatum. This is reflected by an influence on spontaneous night activity, cognitive behaviour during the water maze navigation task, exploratory activity and in response to postsynaptic apomorphine stimulation. Such functional disturbances could be observed up to months after a single application of either 0.3 microgram or 1.5 micrograms FeCl3. The low dose of iron stimulates while 1.5 micrograms inhibits the spontaneous dopaminedependent locomotor night and explorative activity. The low concentration of ionic iron injected intrastriatally also increases lipid peroxidation in striatal and hippocampal tissues. These results suggest that the functional integrity of the ventral striatum and the regulation of the iron metabolism are critical for the sensorimotor performance.

Influence of dopamine-agonists on the pharmacokinetics and pharmacodynamics of levodopaBackground: Despite the broad clinical use of levodopa and dopamine-agonists and their well established clinical efficacy in parkinsonian patients, little is known about the exact pharmacodynamics of both substances and their pharmaeodynamic interactions. However, exact knowledge of pharmacodynarrdcs is essentially for the optimization of therapeutic regimens and maximal clinical efficacy especially in fluctuating patients.Methods: An oral single dose challenge using 100 mg levodopa 25 mg benserazide was performed under standardized conditions in 10 parkinsonian patients with clear-cut wearing-off fluctuations. A continuous s.c. infusion of apomorphine in a clinical subthreshold dosage was coadmimstered to the levodopa challenge under double blind conditions vs. NaC1 in each patient. Levodopa serum-concentrations (LSC) and the actual motor disability (AMD) as the efficacy parameter were measured in 15 rain intervalls over 4 h. AMD was semiquantitatively measured by Columbia-University-Rating-Scale (CURS) sum-scoring, LSC was measured by HPLC. Calculation of main pharmacodynamic parameters (LPC-effect analysis) was performed individually using a semiparametric approach. Data were fitted by an Emax model.Results: Levodopa pharmacokinetics were not significantly influenced by the coadministration of apomorphine with exception of a slight increase of AUC. Pharmacodynamics were significantly altered by apomorphine. Starting from a similar level of basic disability Emax (19.9 _+ 7.7 vs. 19.7 -+ 7.7 pts.) was similar under both regimen but clear differences were seen in Teq (26-+ 8 vs. 19 + 10 min), MRTe (1.9 + 0.5 vs. 3.0 + 0.9 h) and EC50 (430 _+ 163 vs. 315 + 123 ng/ml). The slope factor N showed some decrease under apomorphine but remained still on a high level (17 vs. 7). Our data have shown that the "all or nothing" character of the motor response to levodopa ist preserved under coadministration of a dopamine-agonist and that the mnplitude of motor improvement remains unchanged whereas the duration of the on phase is clearly increased.