1. Pharmacological characterization of behavioural responses to SK&F 83959 in relation to 'D1-like' dopamine receptors not linked to adenylyl cyclase
A M Deveney, J L Waddington Br J Pharmacol. 1995 Oct;116(3):2120-6. doi: 10.1111/j.1476-5381.1995.tb16420.x.
1. Behavioural responses to the new benzazepine derivative, SK&F 83959, a compound that both fails to stimulate adenylyl cyclase and inhibits the stimulation of adenylyl cyclase induced by dopamine, were characterized in detail. 2. In rat striatal membrane preparations, radioligand binding studies with [3H]-SCH 23390 and [3H]-spiperone indicated SK&F 83959 had a high affinity and >250 fold selectivity for D1 over D2 receptors. 3. Using a rapid time-sampling behavioural check list technique, SK&F 83959 (0.01-1.25 mg kg(-1)) induced grooming in the manner of all known D1 receptor agonists, together with some vacuous chewing, which declined at higher doses with the emergence of directed chewing and rearing as an adjunct to prominent sniffing; no stereotyped behavioural was evident. 4. Grooming to SK&F 83959 (0.05 mg kg(-1)) was blocked by the selective D1 receptor antagonists, SCH 23390 (0.01-1.0 mg kg(-1)) and BW 737C (0.04-5.0 mg kg(-1)) and was attenuated by the selective D2 receptor antagonist, YM 09151-2 (0.005-0.5 mg kg(-1)); vacuous chewing to SK&F 83959 was not influenced by either SCH 23390 or BW 737C and was enhanced by YM 09151-2. 5. The paradoxical induction of typical D1 receptor agonist-induced grooming by SK&F 83959, an agent satisfying criteria for a D1 receptor antagonist as classically defined, together with its blockade by typical D1 antagonists, strongly suggests mediation via a 'D1-like' site that appears to respond similarly to agents independent of whether they exert agonist or antagonist actions at the classical adenylyl cyclase-coupled D1 receptor. This direct functional evidence for a 'D1-like' site that is not linked to adenylyl cyclase readily complements neurochemical data suggesting the existence of a cyclase-independent 'D1-like' receptor that may be coupled to phosphoinositide hydrolysis.
2. The effects of clozapine on behavioural responses to the selective 'D1-like' dopamine receptor agonist, A 68930, and to the selective 'D2-like' agonist, RU 24213
S A Daly, J L Waddington Br J Pharmacol. 1994 Nov;113(3):839-44. doi: 10.1111/j.1476-5381.1994.tb17069.x.
1. The influence of the atypical antipsychotic clozapine on D1 dopamine receptor-mediated function was examined in terms of its effects on behavioural responses to the new isochroman selective D1 agonist, A 68930, and to the selective D2 agonist, RU 24213. 2. In rat striatal membrane preparations, radioligand binding studies with [3H]-SCH 23390 and [3H]-spiperone confirmed clozapine to show weak and non-selective affinity for both D1 and D2 receptors. 3. Using a rapid time-sampling behavioural check list technique, clozapine (4.0-36.0 mg kg-1) exerted only modest antagonism of RU 24213 (15.0 mg kg-1)-induced sniffing and locomotion, and weakly released some episodes of myoclonic jerking; such antagonism with release of jerking has been shown previously to occur only during concurrent stimulation of D2 receptors and attenuation of D1 function. 4. Over the same dose-range, clozapine completely blocked A 68930 (0.25 mg kg-1)-induced intense grooming but failed to influence the vacuous chewing response; this profile was similar to that demonstrated previously for selective D1 antagonists. 5. On the basis of complete blockade of typical D1 agonist-induced grooming and weak release of atypical jerking to D2 agonism in the face of modest reduction in typical D2-stimulated behaviours, clozapine appears to exert some preferential but not selective attenuation of D1 receptor-mediated function. Clozapine may attenuate activity through a classical D1 receptor at a level beyond the recognition site, for which it has little affinity, or by way of new, putative 'D1-like' site(s) that subserve distinct elements of dopaminergic behaviour.
3. Behavioural evidence for "D-1-like" dopamine receptor subtypes in rat brain using the new isochroman agonist A 68930 and isoquinoline antagonist BW 737C
S A Daly, J L Waddington Psychopharmacology (Berl). 1993;113(1):45-50. doi: 10.1007/BF02244332.
The full efficacy, high potency isochroman D-1 agonist A 68930 demonstrated greater than 220-fold selectivity for D-1 over D-2 receptors. A 68930 (0.06 and 0.25 mg/kg) readily induced intense grooming, together with vacuous chewing; these responses became less evident following higher doses (1.0 and 4.0 mg/kg) and sniffing became prominent. Intense grooming was blocked by three D-1 antagonists, the benzazepines SCH 23390 (0.01-1.0 mg/kg) and NNC-756 (0.01-1.0 mg/kg), and the isoquinoline BW 737C (0.2-5.0 mg/kg); however, vacuous chewing was not antagonised by SCH 23390 and NNC-756, but was blocked by BW 737C. Intense grooming was attenuated by the D-2 antagonist YM 09151 (0.005-0.5 mg/kg) while vacuous chewing was enhanced. These data suggest that intense grooming is mediated by a "D-1 like" receptor that recognises all known chemical classes of D-1-selective compounds, while vacuous chewing may be mediated by a pharmacologically distinct subtype of "D-1-like" receptor that recognises preferentially the isochromans and isoquinolines.
