Heterogeneity of behavioural profile between three new putative selective D3 dopamine receptor antagonists using an ethologically based approach

The effects on behaviour of the putative selective D₃ dopamine receptor antagonists GR 103691, nafadotride and U 99194A were compared with those of the generic D₂-like antagonist haloperidol, using an ethologically based approach. Neither GR 103691 (0.008–1.0 mg/kg) nor nafadotride (0.025–1.6 mg/kg) influenced any element of behaviour. Conversely, U99194A (1.67–45 mg/kg) effected a dose-dependent stimulation of episodes of non-stereotyped sniffing, locomotion, chewing and eating, with some stimulation of rearing, and reduced baseline levels of grooming; thereafter, as sniffing and locomotion declined, stimulation of episodes of grooming emerged. Haloperidol (0.0008–0.1 mg/kg) failed to promote any element of behaviour and reduced baseline levels of grooming; responsivity to U99194A was antagonised by pretreatment with haloperidol. The lack of effect of GR 103691 (>100-fold D₃/D₂ selectivity) and nafadotride (10-fold D₃/D₂ preference), in contrast to the characteristic ‘‘ethogram’’ for U99194A (25-fold D₃/D₂ selectivity), indicated a fundamental difference in their mechanisms of action. This topography of responsivity to U99194A overlapped somewhat with the profiles of both D₂-like and D₁-like agonists, and its sensitivity to antagonism by haloperidol also indicated a dopaminergic basis thereto. However, differences among GR 103691, nafadotride and U99194A bore no relation to their relative selectivities for the D₃ receptor, and the basis thereof remains unclear. Theorising as to the behavioural role of the D₃ receptor may need to be tempered pending the identification of a range of chemically distinct D₃ antagonists of higher selectivity. Received: 14 August 1997/Final version: 10 October 1997     

Behavioural responses to the selective D1-dopamine receptor agonist R-SK&F 38393 and the selective D2-agonist RU 24213 in young compared with aged rats.

1. In aged male Sprague-Dawley rats (22 months) with a selective loss of D2- but not of D1-dopamine receptors, stereotyped behaviour induced by 0.5 mg kg-1 apomorphine was increased and prolonged in comparison with young (4 month) counterparts. This suggested a pharmacokinetic effect rather than a pharmacodynamic change. 2. The syndrome of non-stereotyped behavioural responses to the selective D1-agonist R-SK&F 38393, 1.25-20.0 mg kg-1, was unchanged in aged vs young animals, but the topography of individual behaviours constituting this overall syndrome was altered with aging. 3. Neither the overall syndrome of low intensity stereotyped behaviour nor the topography of individual behaviours induced by the selective D2-agonist RU 24213, 1.25-20.0 mg kg-1, were altered in aged vs young animals. 4. Loss of D2- but not D1-receptors with aging was therefore found to be associated with no change in responsivity to a D2-receptor agonist. The decreased intense grooming and increased vacuous chewing responses to the D1-agonist with aging parallel the previously demonstrated effects of selective D2-antagonists on these D1-stimulated behaviours. 5. It is suggested that age-related decline in D2-receptor activity may have greater functional consequences in relation to D1-:D2-interactions than in simply influencing responsivity to a D2-agonist. Such interactive effects should be taken into account when considering the pathophysiology and treatment of age-related extrapyramidal movement disorders.     

Agonist and antagonist properties of benzazepine and thienopyridine derivatives at the D1 dopamine receptor

Nine structurally related 1-phenyl-1H-3-benzazepine derivatives and two thienopyridines were tested for agonist and antagonist properties at the adenylate cyclase-coupled D1 dopamine receptor in homogenates of the striatum of the rat. The benzazepines SK&F 77434 and SK&F 82958, both of which contain a catechol ring, were agonists; the intrinsic activity of SK&F 77434 was similar to that of SK&F 38393, whereas SK&F 82958 was a full agonist. The remaining benzazepines inhibited the stimulation of adenylate cyclase by dopamine. Antagonist potency depended on the nature of the substituent at position 7 of the benzazepine molecule, 7-halogen compounds being the most potent. The Ki values, obtained from analysis of the antagonism of dopamine-stimulated adenylate cyclase, were significantly correlated with the Ki values for displacement of D1 ligands in binding experiments. Furthermore, antagonist activity of the resolved racemic benzazepine SK&F 83566 resided almost exclusively in the R-enantiomer. The thienopyridine derivatives SK&F 89641 and SK&F 89145 were partial agonists with greater efficacies than SK&F 38393.     

Loss of rat striatal dopamine receptors with ageing is selective for D-2 but not D-1 sites: association with increased non-specific binding of the D-1 ligand [3H]piflutixol

The effects of age on the binding of dopaminergic ligands to rat striatal membranes were studied. When compared with four month old animals, at 22 months there was a significant decrease in the density of specific binding sites for the D-2 ligand [3H]spiperone while their affinity was unaltered. However, the specific binding of [3H]piflutixol to D-1 sites was unaltered between these age groups. The non-specific binding of [3H]piflutixol was significantly increased in aged preparations. Age-related loss of striatal D-2 dopamine receptors does not extend to the D-1 type. Alterations in non-specific [3H]piflutixol binding may reflect other pathophysiological changes associated with senescence.     

Modification of the proteoglycans of rat incisor dentin – predentin during in vivo fluorosis

Proteoglycans (PGs) were isolated from the dentin–predentin of fluorotic and control rat incisor teeth using demineralization in EDTA, followed by extraction with 4 M guanidinium chloride in the presence of protease inhibitors. Differences in the behaviour of fluorotic and control PG were evident during purification by anion exchange chromatography on Q-Sepharose and MONO-Q interfaced with fast protein liquid chromatography. The PG from fluorotic teeth exhibited a more anionic profile, due to changes in glycosaminoglycan characteristics, since no apparent differences were evident between the respective core proteins, both of which were 45 kDa. The constituent glycosaminoglycan chains of fluorotic dentin were of lower molecular size and showed the additional presence of dermatan sulfate and heparan sulfate by comparison to non-fluorotic controls, where only chondroitin-4-sulfate was detected.     

The striatonigral GABA pathway: Functional and neurochemical characteristics in rats with unilateral striatal kainic acid lesions

Rats with unilateral striatal kainic acid (KA) lesions showed ipsilateral rotation to subcutaneous apomorphine, contralateral rotation to intranigral muscimol and reductions in striatal glutamic acid decarboxylase (GAD) activity and nigral γ-aminobutyric acid (GABA) concentration. Rotational responses to apomorphine were highly correlated with nigral GABA depletions, and were a sensitive index of the functional integrity of striatonigral GABA neurons. Rotational responses to muscimol were also correlated with nigral GABA depletions, consistent with supersensitivity of denervated nigral GABA receptors. Striatal GAD was not correlated with either behavioural measure or with nigral GABA, and was a poor index of striatonigral function. These results are discussed in terms of (i) the functional role and adaptive capacity of striatonigral GABA neurons in linking the striatum with its effector mechanisms, (ii) parallels between parameters in GABA-dependent and DA-dependent rotational models and (iii) the status of the striatal KA lesion as a model for Huntington's disease and other extrapyramidal movement disorders.