Antagonism of the effects of (+)‐PD 128907 on midbrain dopamine neurones in rat brain slices by a selective D₂ receptor antagonist L‐741,626

Abstract

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.

Habituation Deficits Induced by Metabotropic Glutamate Receptors 2/3 Receptor Blockade in Mice: Reversal by Antipsychotic Drugs

“…In contrast, D2 dopamine receptor-preferring antagonist L-741626 (D2/D3 selectivity ratio ϳ10-fold; Bowery et al, 1996) readily antagonizes effects of both LY-341495 (present study) and amphetamine (Millan et al, 2000). Furthermore, lithium chloride, a moodstabilizing agent, reverses a number of behavioral effects of amphetamine, including hyperlocomotion and acoustic star- jpet.aspetjournals.org tle prepulse inhibition deficits (Ong et al, 2005), and, in the present study, it was found to attenuate delayed hyperactivity in LY-341495-treated subjects.…”

Evidence for enhancement of gap junctional coupling between rat island of Calleja granule cells in vitro by the activation of dopamine D3 receptors

“…Given the receptor population reported to be present in the IC, these results strongly suggest that DA-mediated enhancement of coupling is initiated via the D× receptor. The functional consequences of postsynaptic or somatic D× receptor activation in situ have not previously been defined, there being a doubt about the specificity of available compounds used to analyse dopaminergic effects on D× receptors in the ventral tegmental area of the midbrain (Bowery et al 1996). Mitogenesis, c-Fos production, reduction of adenylyl cyclase activity and inhibition of calcium currents have all been variously described as a consequence of agonist activation in a number of cell lines forced to express the D× receptors (see .…”

Aberrant Dopamine D2-Like Receptor Function in a Rodent Model of Schizophrenia

“…All drugs demonstrated low nanomolar affinity for their respective receptors (Bowery et al, 1996;Merchant et al, 1996;Audinot et al, 1998) and were administered at 1 mg/kg (into lateral tail vein) before determining the number of spontaneously active DA neurons encountered while making six to nine vertical passes, separated by 200 m, in a predetermined pattern to sample equivalent regions of the VTA. Once a stable dopamine neuron was identified, baseline neuronal activity was recorded for 3 min.…”

“…The effect of selective ligands on the activity of the population of dopamine neurons in the VTA was determined by administering either a selective D2 [3-(4-(4-chlorophenyl-4-hydroxypiperidino)methyl)indole (L-741,626) (Bowery et al, 1996) (Audinot et al, 1998)], or D4 [sonepiprazole (Merchant et al, 1996)] antagonist or vehicle [either acidified (0.1% acetic acid) distilled water (D2) or acidified (0.1% acetic acid) 10% dimethyl sulfoxide in distilled water (D3 and D4)]. All drugs demonstrated low nanomolar affinity for their respective receptors (Bowery et al, 1996;Merchant et al, 1996;Audinot et al, 1998) and were administered at 1 mg/kg (into lateral tail vein) before determining the number of spontaneously active DA neurons encountered while making six to nine vertical passes, separated by 200 m, in a predetermined pattern to sample equivalent regions of the VTA.…”

“…To examine the relative contributions of the three distinct D2-like receptors to this response, we examined the effect of antagonists selective for the dopamine D2 (L-741,626;Bowery et al, 1996), D3 (GR 103691; Audinot et al, 1998), or D4 (sonepiprazole;Merchant et al, 1996) receptors. All three drugs were administered at equivalent doses and surprisingly produced qualitatively similar responses.…”