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We have examined the specific binding of the tritiated derivative of the potent histamine H3 receptor antagonist, [3,4-3H2]-cyclohex-yl-¿[4-(3H-imidazol-4-yl)-piperidin-l-yl] iminomethyl¿- amine ([3H]GR168320), to homogenates of rat cerebral cortex. Specific binding of [3H]GR168320 at 37 degrees C associated and dissociated rapidly. Binding was saturable (Bmax 412 +/- 89 fmol/mg protein) and of high affinity (Kd 0.12 +/- 0.11 nM). Saturation studies suggested the involvement of a single site. Histamine H3 receptor agonists and antagonists inhibited [3H]GR168320 binding with high affinity. Agonist and antagonist affinities correlated when compared with affinities obtained using the tritiated histamine H3 agonist radioligand N alpha-methylhistamine.

The aim of this study was to investigate the role of tachykinin NK1 and NK2 receptors, and calcitonin gene-related peptide (CGRP) receptors in neurogenic plasma protein extravasation, induced by electrical stimulation of the trigeminal ganglion, in dura mater of anaesthetised rats and guinea-pigs. This response was significantly (P < 0.05) blocked in both species by the selective peptide tachykinin NK1 receptor antagonist, GR82334 ([D-Pro9[spiro-gamma-lactam]Leu10,Trp11]physalaemin-(1-11)) (0.02-0.2 mg/kg i.v.) whilst the selective tachykinin NK2 receptor antagonist, (+/-)-SR 48968 ((S)-N-methyl-N-[4-(4-acetylamino-4-phenylpiperidino)-2-(3,4- dichlorophenyl) butyl] benzamide) (1 mg/kg i.v.) was without effect. The CGRP receptor antagonist, alpha-CGRP-(8-37) (0.1 mg/kg i.v.) significantly (P < 0.05) blocked this response in dura mater of guinea-pigs but not rats. These results suggest that substance P, acting via tachykinin NK1 rather than NK2 receptors, mediates neurogenic plasma protein extravasation in dura mater and that CGRP may have an involvement in this response in guinea-pigs.

The pharmacological activity of the histamine H3 receptor antagonist VUF 9153 (S-[3-(4(5)-imidazolyl)]propyl-N-(4-chlorobenzyl)isothiourea) has been investigated in vitro and in vivo. VUF 9153 displaced [3H]N alpha-methylhistamine binding to rat cortex/hippocampal membranes (pKi = 9.77 +/- 0.03) and antagonised the inhibitory responses to (R)-alpha-methylhistamine against electrical field stimulation in the isolated longitudinal smooth muscle preparation of guinea-pig ileum (pKB = 9.95 +/- 0.07). In these assays, VUF 9153 was 10-50-fold more potent than the prototype H3 receptor antagonist thioperamide. VUF 9153 showed no or very weak activity in in vitro functional assays for histamine H1 or H2 receptors. Systemic administration of VUF 9153 (s.c. or p.o.) dose-dependently inhibited the ex vivo binding of [3H]N alpha-methylhistamine to rat cortex/hippocampal membranes and dipsogenic responses induced by (R)-alpha-methylhistamine. Calculation of ED50 values, at the 1 h pretreatment time used, revealed that VUF 9153 administered s.c. or p.o., was approximately 2-fold weaker than thioperamide. These data indicate that, like thioperamide, VUF 9153 is a potent and selective antagonist for histamine H3 receptors in vitro, possesses the ability to penetrate the blood-brain barrier to access central H3 receptors and can inhibit H3 receptor-mediated functional responses in vivo.

Rats were given powdered diet containing L-DOPA (together with the peripheral decarboxylase inhibitor carbidopa) for a period of 6 months. The estimated daily intake was in the range 20-30 mg/kg. Initially, at 1 week and 1 month, L-DOPA-fed rats exhibited enhanced spontaneous locomotor activity, but this fell to within the control range by 3 and 6 months, although (+)-amphetamine-induced hyperactivity was greater at 6 months in L-DOPA-treated animals than in control rats. Six months after receiving L-DOPA in their diet rats showed enhanced stereotypy scores to a series of dopamine agonists administered acutely including (+)-amphetamine, nomifensine, L-DOPA, apomorphine and piribedil compared with the control animals. In another behaviour test L-DOPA administration reduced the cataleptic potency of both fluphenazine and haloperidol was increased. Biochemically 6 months treatment of rats with L-DOPA was associated with significantly increased plasma concentrations of L-DOPA, enhanced striatal levels of L-DOPA, dopamine and dopamine metabolites, enhanced specific binding (as indicated by increased Bmax values) of [3H] spiroperidol, [3H] ADTN and [3H] 5-HT to striatal membranes, and increased basal and dopamine-stimulated striatal adenylate cyclase activity. The results are discussed in the light of changes of sensitivity of cerebral dopamine receptors, an increase in receptor numbers, and the tolerance to L-DOPA which often develop in the treatment of Parkinson's disease.

L-Glutamate, N-methyl-D-aspartate, quisqualate and potassium chloride enhanced Ca2+ accumulation by rat cortical slices as determined using 45Ca2+ uptake and Ca2+ mobilisation in cortical synaptosomes as determined using quin-2 fluorescence. Quinolinate and kainate were ineffective. Responses to L-glutamate and N-methyl-D-aspartate were blocked by non-competitive (ketamine, phencyclidine, Mg2+) and competitive (2-amino-5-phosphonovalerate) antagonists. These data suggest that activation of excitatory amino acid receptors in the cortex results in enhanced Ca2+ mobilisation which can be blocked by selective antagonists. Such effects may be related to neurotoxic properties of the excitatory amino acids and the neuroprotection afforded by excitatory amino acid antagonists.

In rat striatal P2 membrane preparations examined under constant experimental conditions, activation of either D2-dopamine or opiate receptors inhibited basal adenylate cyclase with a similar maximal inhibition of approximately 30%. These inhibitions were not additive. D1 dopamine receptor-mediated activation of adenylate cyclase by SKF38393 was inhibited by morphine in an additive fashion, but the opiate had minimal effects on the net activation of adenylate cyclase by dopamine which activates both D1 and D2 receptors. From these results it would appear that opiate and D1 dopamine receptor-mediated activation of adenylate cyclase summate, but that opiate and D2 dopamine receptors regulate a common pool of adenylate cyclase in striatal membranes.