No abstract

The benzodiazepines flunitrazepam, diazepam, and Ro 15-1788

No abstract

The D2 dopamine receptor is known to be functionally coupled to the inhibition of adenylate cyclase when expressed in a number of mammalian cell lines. However, functional coupling of the recently discovered D3 and D4 dopamine receptor subtypes has been more difficult to demonstrate. In this study, human D2, D3 and D4 receptors were stably expressed separately in human embryonic kidney cells (HEK 293). In these cells, activation of D2, D3 or D4 receptors resulted in the inhibition of forskolin-stimulated adenylate cyclase activity in a dose responsive manner. This activation was prevented by pre-incubation of the cells expressing these receptors with the dopaminergic antagonist haloperidol. Radioligand binding studies using [3H]spiperone confirmed that the atypical neuroleptic clozapine has higher affinity for the human D4 receptor than the D3 or D4 receptors, although only 6-fold higher than the D2 receptor in this study. In addition, ribonuclease protection studies demonstrated the presence of D4 dopamine receptor mRNA in human brain regions.

3 (+)-PD 128907 inhibited cell firing in both the ventral tegmental area and substantia nigra pars compacta with EC50 values of 33 nM (pEC5o= 7.48+0.10, n = 10) and 38 nM (pEC50= 7.42+0.15, n = 5), respectively. No effects of (+)-PD 128907 (100 nM) were observed on glutamate or GABA-mediated synaptic potentials elicited by focal bipolar stimulation. 4 L-741,626 antagonized these effects of (+ )-PD 128907 in a concentration-dependent and surmountable manner with an affinity, determined from Schild analysis, of 20 nM (pKB= 7.71 + 0.14)in the ventral tegmental area and 11 nM (pKB = 7.95 + 0.18) in the substantia nigra pars compacta.5 (+)-PD128907 also inhibited dopamine release in the caudate-putamen with an ECso of 66 nM (n = 5). The affinity of L-741,626 for these nerve terminal autoreceptors (pKB= 7.71 + 0.06; = 20 nM) was identical to that observed on midbrain dopamine neurones. 6 These data demonstrate that the D3 receptor ligand (+)-PD 128907 is a potent agonist on rat midbrain dopamine neurones. However, its lack of regional selectivity, and the high affinity of the selective D2 receptor antagonist L-741,626 for receptors activated by (+ )-PD 128907, was more consistent with an action on D2 autoreceptors rather than upon a D3 dopamine receptor subtype.