Anthony G. Molloy

Dopaminergic behaviour stereospecifically promoted by the D1 agonist R-SK & F 38393 and selectively blocked by the D1 antagonist SCH 23390

The selective D1 dopamine receptor agonist R-SK & F 38393 (20 mg/kg), but not its S-antipode, stereospecifically promoted episodes of prominent grooming behaviour. Typical stereotyped behaviour, such at that induced by apomorphine, was not seen. Grooming responses to 20 mg/kg R-SK & F 38393 were blocked by 0.1–0.5 mg/kg of the selective D1 antagonist SCH 23390 but not by 1.0–5.0 mg/kg of the selective D2 antagonist metoclopramide, while stereotyped behaviour induced by 0.5 mg/kg apomorphine was blocked by both antagonists. These results are consistent with certain individual dopaminergic behaviours such as grooming being mediated by D1 receptors. Other dopaminergic syndromes may involve complex functional interactions between D1 and D2 receptors.

Effects of the putative D-1 antagonist SCH 23390 on stereotyped behaviour induced by the D-2 agonist RU24213

The effects of the putative selective dopamine D-1 antagonist benzazepine SCH 23390 and of the selective dopamine D-2 antagonist Ro22-2586 on stereotypy induced by the selective D-2 agonist RU24213 were compared. RU24213 (0.5–15 mg/kg) dose-dependently induced stereotyped behaviour characterised by continuous downward sniffing and locomotion. These responses were antagonised, as expected, by 40–200 μg/kg Ro22-2586, but surprisingly blocked by 40–200 μg/kg SCH 23390. The selectivities of these compounds for dopamine receptor subtypes were verified in terms of their relative abilities to displace the in vitro binding of 3H-piflutixol to striatal D-1 receptors and of 3H-spiperone to D-2 receptors. As SCH 23390 fails to influence D-2 mediated prolactin secretion or emesis in vivo, there appears to be no significant formation of an active metabolite of SCH 23390 with D-2 antagonist activity. Because SCH 23390 has some affinity for 5-hydroxytryptamine receptors, any effect on the serotonergic behavioural syndrome induced by 10 mg/kg 5-methoxy-N,N-dimethyltryptamine was also studied. The serotonergic responses of hind limb abduction, reciprocal forepaw treading and Straub tail were unaltered after 40–200 μg/kg SCH 23390, indicating no significant 5-HT blockade or non-specific depressant action at these doses which might influence the expression of stereotypy. Thus, these data are consistent with blockade of tonic D-1 dopaminergic activity that may influence the expression of behaviours initiated byD-2 dopaminergic stimulation.

Sniffing, rearing and locomotor responses to the D-1 dopamine agonist R-SK&F 38393 and to apomorphine: Differential interactions with the selective D-1 and D-2 antagonists SCH 23390 and metoclopramide

The D-1 agonist R-SK&F 38393 induced non-stereotyped sniffing, rearing and locomotor responses that were blocked by the D-1 antagonist SCH 23390. The D-2 antagonist metoclopramide failed to block sniffing but blocked rearing and locomotion. Stereotyped sniffing and locomotion induced by apomorphine were each blocked by both antagonists. Either the criteria by which compounds are designated as D-1 or D-2 selective agents require revision, or else D-1 and D-2 mechanisms are able to reciprocally interact to influence the expression of behaviour initiated by stimulation of either receptor subtype.

Assessment of grooming and other behavioural responses to the D-1 dopamine receptor agonist SK & F 38393 and its R- and S-enantiomers in the intact adult rat

The behavioural effects of the D-1 dopamine receptor agonist SK & F 38393 were assessed in the intact adult rat using a conventional stereotypy rating scale and a rapid time sampling behavioural check list procedure. This combination technique allowed description of the nature of any behavioural response and quantification of the number of counts of individual behaviours. Using this combined procedure, SK & F 38393 clearly failed to induce typical stereotyped behaviour. However, in the well-habituated animal, SK & F 38393 dose-dependently increased the number of recordings of non-stereotyped sniffing, locomotion and grooming; some occasional rearing was also noted. An unusual pattern of intense grooming behaviour was a characteristic response to this drug. Using the resolved R-and S-enantiomers of SK & F 38393, promotion of sniffing, locomotion, rearing and grooming resided stereoselectively in the R-configuration. Under appropriate experimental conditions, specifically a requirement for prolonged habituation and the use of a rapid sampling behavioural check list to supplement the rating scale, it is possible to demonstrate that SK & F 38393 is behaviourally active in the whole animal.

Locomotor behaviors in response to new selective D-1 and D-2 dopamine receptor agonists, and the influence of selective antagonists

With the introduction of the selective D-1 dopamine receptor agonist and antagonist benzazepines, especially as enantiomeric pairs, there is now a range of D-1 compounds to complement the previously available selective D-2 agents. These have been used to investigate whether sub-types of dopamine receptors might be differentially involved in locomotor behavior. Stereotyped locomotion induced by the non-selective D-2 agonist apomorphine and by the selective D-2 agonist RU 24213 were blocked by the selective D-2 antagonists metoclopramide and Ro 22-2586 [-)-piquindone). Responses to either D-2 agonist were also blocked by the selective D-1 antagonists SCH 23390 and R-(but not S-) SK&F 83566. Non-stereotyped locomotion was induced by R- but not S-SK&F 38393, a stereoselective D-1 agonist, and was blocked by SCH 23390. Responses to the D-1 agonist were also antagonised by metoclopramide. Such results suggest concerted D-1:D-2 interplay in the regulation of at least some dopaminergic behaviors, such as locomotion.

The enantiomers of SK&F 83566, a new selective D-1 dopamine antagonist, stereospecifically block stereotyped behaviour induced by apomorphine and by the selective D-2 agonist RU 24213

The non-selective dopamine receptor agonist apomorphine and the selective D-2 receptor agonist RU24213 each induced a typical syndrome of stereotyped behaviour characterised by sniffing and locomotion. The syndrome and its associated behaviours induced by each agonist were dose-dependently antagonised by pretreatment with the R- but not with the S-enantiomer of the benzazepine SK&F 83566. R- but not S-SK&F 83566 stereoselectively blocks D-1 receptors with high affinity, while the enantiomers have a very weak affinity for D-2 receptors which shows negligible stereoselectivity. Therefore, enantioselective blockade of brain D-1 receptors appears able to influence the expression of behaviours initiated by D-2 receptor stimulation.

Pharmacological characterization in the rat of grooming and other behavioural responses to the D1 dopamine receptor agonist R-SK&F 38393

Grooming, sniffing, Iocomotor and rearing responses to the D1 dopamine receptor agonist SK&F 38393, as the racemic compound or its R-enantiomer, were characterized pharmacologically using typical neuroleptics, non-dopaminergic antagonists, selective D1 antagonists and selective D2 antagonists. The typical neuroleptics haloperidol and flupenthixol blocked all behaviours induced by SK&F 38393; this action of flupenthixol was stereoselective for its cis(Z)-isomer but not its trans(E)-isomer. Non-dopaminergic antagonists failed to reproduce the consistent effects of typical neuroleptics. The selective D1 antagonist SCH 23390 potently blocked all responses to SK&F 38393. A related selective D1 antagonist, SK&F 83566, also blocked these responses, and this action was stereoselective for its R-enantiomer but not its S-enantiomer. These data suggest that D1 receptor stimulation is the primary mechanism underlaying the induction of these behaviours by SK&F 38393. However, the expression of certain individual responses to SK&F 38393 were sensitive to attenuation by the selective D2 antagonists sulpiride or metoclopramide. These results extend the emerging view that the D1 receptor is behaviourally relevant and that there exist functional interactions between D1 and D2 receptor systems in the regulation of behaviour.

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.

Selective antagonism by clonidine of the stereotyped and non-stereotyped motor activity elicited by atropine.

The effects of clonidine, an indirectly-acting cholinergic antagonist, on 5 behaviors elicited by atropine (locomotion, rearing, sniffing, grooming and gnawing) were studied in rats. Clonidine did not alter the prevalence or magnitude of atropine-elicited locomotion and rearing. In contrast, clonidine suppressed the occurrence and degree of 3 stereotyped behaviors, namely, sniffing, grooming and gnawing. This selectivity of clonidine suggests differences in the neural pathways subserving the various stereotyped motor activities.

Benzazepine Derivatives: Nature of the Selective and Stereospecific Interactions of SK&F 38393 and SCH 23390 with Brain D-1 Receptors

Few studies have addressed the issue of any role for the D1 dopamine receptor in behaviour because of the lack of compounds known to act selectively at this site. Recently, two benzazepine derivatives, SK&F 38393 and SCH 23390, have become available and we have characterised them as showing unique selectivity and R-configuration stereospecificity at the D1 receptor (O’Boyle and Waddington, 1984). In behavioural studies, the agonist R-SK&F 38393 promoted non-stereotyped grooming behaviour which was blocked by the D1 antagonist SCH 23390 but not by the D2 antagonist metoclopramide, consistent with an underlying D1 receptor mechanism (Molloy and Waddington, 1984). However, SCH 23390 was also able to antagonise stereotypy induced by the selective D2 agonist RU 24213 (O’Boyle et al, 1984). This unexpected result has lead us to characterise further the mode of interaction of SCH 23390 with these sites.