Differential effects of dopamine D2 and D3 receptor antagonists in regard to dopamine release, in vivo receptor displacement and behaviour

Abstract

To establish possible functional differences between the dopamine D2 and D3 receptor we investigated the relation between the ability, for a set of nine mixed dopamine D2 and D3 receptor antagonists, to displace N, N-dipropyl-2-amino-5,6-dihydroxy tetralin (DP-5,6-ADTN) from striatal binding sites and the subsequent behavioural consequences in vivo. Dopamine D2 receptor preferring antagonists are powerful displacers of DP-5,6-ADTN from the striatum. Maximal displacement is followed by strong hypomotility. Displacement of the agonist by the D3 preferring antagonist U99194A is only partial and results in synergistic increases in locomotor activity. Superimposing haloperidol upon GBR12909 leads to a synergistic increase in striatal dialysate dopamine concentrations. This effect is absent when combining GBR12909 with the putative D3 antagonist U99194A. These data give support for the hypothesis that the dopamine D3 receptor is functionally relevant at the postsynaptic level. Here, in contrast to the D2 receptor, it is proposed to exert an inhibitory influence on psychomotor functions.

Dopamine D1 Receptors Synergize with D2, But Not D3 or D4, Receptors in the Striatum without the Involvement of Action Potentials

“…6). U-99194A pretreatment significantly increased amphetamineinduced rearing ( p Ͻ 0.05), similar to what has been reported earlier for this agent (Waters et al, 1993(Waters et al, , 1994.…”

“…L -745,870 has a 2000-fold selectivity for D 4 receptors relative to D 2 receptors in vitro and virtually no affinity for D 3 receptors (Kulagowski et al, 1996). All of these agents enter the brain on systemic administration (Waters et al, 1994;Bristow et al, 1997), and all of them lack intrinsic activity at their respective receptors.…”

“…On the test day each rat was placed into the observation chamber and injected intraperitoneally with one of the following selective antagonists: (1) L -741,626 (3.2 or 10 mg / kg), (2) U-99194A (16 mg / kg), (3) L -745,870 (1 or 10 mg / kg), or (4) vehicle. These doses were chosen on the basis of previously published data (with specific reference to in vivo receptor occupancy when available) and pilot experiments (Waters et al, 1993(Waters et al, , 1994Kulagowski et al, 1996;Bristow et al, 1997). Thirty minutes after antagonist pretreatment one-half of the rats in each antagonist treatment group received d-amphetamine sulfate (5 mg / kg, i.p.)…”

Repeated intravenous cocaine administration: Locomotor activity and dopamine D2/D3 receptors

“…Therefore, the majority of D3 receptors could be localized as striatal presynaptic autoreceptors. This hypothesis has recently been supported by studies which demonstrate D3 receptor stimulation inhibits dopamine synthesis (Meller et al, 1993) and release (Damsa et al, 1993;Mulder et al, 1987;Waters et al, 1994) in the striatum.…”

Selective Antagonism at Dopamine D3 Receptors Prevents Nicotine-Triggered Relapse to Nicotine-Seeking Behavior

“…For example, most compounds developed so far have a 10-to 30-fold selectivity for DA D 3 over D 2 receptors in vivo (Audinot et al, 1998;Sautel et al, 1995;Waters et al, 1994). In addition, the partial agonist BP 897 is also a potent and selective antagonist at both DA D 3 and D 2 receptors .…”