Dopamine receptor agonists: Mechanisms underlying autoreceptor selectivity II. Theoretical considerations

Abstract

In a companion article, we extensively reviewed the pharmacological actions of the enantiomers of the dopamine analogue 3-(3-hydroxyphenyl)-N-n-propylpiperidine, 3-PPP. The profiles of action exhibited by transdihydrolisuride (TDHL) and the trans-fused 7-OH-1,2,3,4,4a,5,6,10-octahydrobenzo(f)quinoline (HW 165) were also described. These latter agents, along with (-)-3-PPP, exert a variety of effects at different DA receptors depending on the anatomical location of these receptor sites and the experimental conditions. In the first part of the present article, it is suggested that the intrinsic activity of these agents in different pharmacological models is dependent on the responsiveness of the relevant DA-receptors which, in turn, is related to the degree of previous agonist occupancy of these sites. In situations where these agents exhibit partial agonist activity, their pharmacological effect is also dependent on the relative concentrations of drug and endogenous DA competing for common receptor sites. A number of theoretical implications will be discussed relevant to the suggestion that DA receptors exist in various adaptational states which can influence drug action. In the second part of this review, we will consider the behavioural profile exhibited by (-)-3-PPP in relation to that observed with classical DA antagonists. In addition, the potential clinical application of (-)-3-PPP and similar-acting agents will be discussed.

Interactions of the Novel Antipsychotic Aripiprazole (OPC-14597) with Dopamine and Serotonin Receptor Subtypes

“…There is a traditional view that relates the higher sensitivity of presynaptic receptors to a large receptor reserve, activated by low concentrations of agonists or by agonists with weak partial efficacy (Clark et al 1985a(Clark et al , 1985b. The modest agonist actions of OPC-14597 observed in C-6 cells expressing D 2L receptors imply weak partial efficacy; thus, it might be expected to activate highly sensitive presynaptic receptors, yet to antagonize the actions of dopamine at less sensitive postsynaptic receptors.…”

Differential Effects of Cocaine on Dopamine Neuron Firing in Awake and Anesthetized Rats

“…Central effects of cocaine are attributed to its ability to inhibit reuptake of dopamine, serotonin, and norepinephrine (Reith et al, 1986(Reith et al, , 1997bRichelson and Pfenning, 1984;Ritz et al, 1990;Ross and Renyi, 1967). It is believed that blockade of the uptake, by increasing the synaptic concentrations of these neurotransmitters (Bradberry and Roth, 1989;Li et al, 1996;Reith et al, 1997a), leads to an increase in vigilance and sensory awareness, activation of defense mechanisms, cognitive distortion, euphoria, and a reduced need for sleep (Clark et al, 1985b;Freye and Levy, 2009). …”

“…Its consumption in modern society has become increasingly common, as shown by population statistics (Clark et al, 1985b;Freye and Levy, 2009). Consequences of chronic use include a massive addiction, an increased risk of psychiatric illnesses, and deleterious consequences on general health (eg, an increased risk of myocardial infarction) (Lange and Hillis, 2001).…”

Kappa-Opioid Agonist U69593 Potentiates Locomotor Sensitization to the D2/D3 Agonist Quinpirole: Pre- and Postsynaptic Mechanisms

“…It had been proposed that the depressive effects of dopamine agonists probably reflect stimulation of presynaptic dopamine receptors (Clark et al, 1985;Richtand et al, 2001;Starr and Starr, 1986). During the course of repeated administrations, the depressive effects of dopaminomimetic drugs diminish and the excitatory locomotor responses become stronger, occur sooner, and to lower doses of the drug (Segal et al, 1980;Szechtman et al, 1994b;Szumlinski et al, 1997).…”