Dopamine-Di and D2 receptors

Momiyama, T, Nao5uiki, T and Saso, M (1993) A mechanism underl5dng dopamine Di and D2 receptor-mediated inhibition of dopaminergic neurons in the ventral tegmental area in vitro. Br. J. Pharmacol. 109 933-940. 

Fig. 7.4 Structures of compounds used in competitive MS binding assays for dopamine Di and D2 receptors.

Umemiya M, Berger AJ (1995) Presynaptic inhibition by serotonin of glycinergic inhibitory synaptic currents in the rat brain stem. J Neurophysiol 73 1192-1201 Usiello A, Baik JH, Rouge-Pont F, Picetti R, Dierich A, LeMeur M, Piazza PV, Borrelli E (2000) Distinct functions of the two isoforms of dopamine D2 receptors. Nature 408 199-203 Vanderschuren LJ, Wardeh G, De Vries TJ, Mulder AH, Schoffelmeer AN (1999) Opposing role of dopamine Di and D2 receptors in modulation of rat nucleus accumbens noradrenaline release. J Neurosci 19 4123-31... 

Vincent SL, Khan Y, Benes FM (1993) Cellular distribution of dopamine Di and D2 receptors in rat medial prefrontal cortex. J Neurosci 75 2551-2564. 

Bowden C, Theodorou AE, Cheetham SC, Lowther S, Katona CL, Crompton MR, Horton RW (1997) Dopamine Di and D2 receptor binding sites in brain samples from depressed suicides and controls. Brain Res 752 227-233. 

Joyce JN, Lexow N, Bird E, Winokur A (1988) Organization of dopamine Di and D2 receptors in human striatum receptor autoradiographic studies in Huntington s disease and schizophrenia. Synapse 2 546-557. 

Metoclopramide has inhibitory effects on dopamine Di and D2 receptors, which influences its prokinetic activity and CNS side effects. 

A comprehensive list of synthesized labeled receptor ligands is outside the scope of this chapter. Most attention has been focused on ligands for the dopamine-Di and D2 receptors. 

The answer is b. (Hardman, pp 282-283.) Central dopamine receptors are divided into Di and D2 receptors. Antipsychotic activity is better correlated to blockade of D2 receptors. Haloperidol, a potent antipsychotic, selectively antagonizes at D2 receptors. Phenothiazine derivatives, such as chlorpromazine, fluphenazine, and promethazine, are not selective for D2 receptors. Bromocriptine, a selective D2 agonist, is useful in the treatment of parkinsonism and hyperprolactinemia. It produces fewer adverse reactions than do nonselective dopamine receptor agonists. 

These receptors were first observed in the sympathetic nervous system in the nictitating membrane of the cat, dopamine reduced the release of noradrenaline via a receptor distinct from the 0,2-autoreceptor (Enero and Langer 1975). Most of the heteroreceptors are D2-like and inhibitory, but in rat nucleus accumbens and medial prefrontal cortex Di receptors enhance noradrenaline release (Table 1). The opposite effects mediated by Di and D2 receptors in rat nucleus accumbens have been explained by location of the inhibitory D2 receptors close to, and location of the fa-cilitatory Di receptors more distant from, dopaminergic varicosities (Vandschuren et al. 1999). 

Since cholecystokinin peptides show a neuroleptic-like profile in several screening tests for neuroleptics, cholecystokinin-dopamine interactions are of interest, especially the modulation of cholecystokinin release by dopamine receptors (Table 1). In the rat striatum both Di and D2 receptor activation was reported to increase, and both Di and D2 receptor blockade to depress, the release of the peptide. 

HT4 agonists enhance the release of acetylcholine in several peripheral tissues and several brain areas (Table 4). 5-HT4 antagonists counteract the effect but, in the studies published so far, caused no change when given alone. The co-location of facilitatory 5-HT4 and inhibitory 5-HTi receptors on hippocampal cholinergic terminals is reminiscent of the co-location of Di and D2 receptors on, for example, GABAergic terminals (Section 2.7). In contrast to the two dopamine receptors,... 

In addition to immediate short-term effects on channel properties, dopamine also plays a key modulatory role in the regulation of neuronal responses mediated by activation of excitatory amino acid receptors. The nature of the modulatory effects of dopamine depend on the excitatory amino acid receptor subtype and the specific dopamine receptor subtype activated. The modulation of NMD A and AMPA receptors by dopamine Dl and D2 receptors has been reviewed recently by Cepeda et al. (1998) and Di Chiara et al. (1994). 

Baldo BA, Sadeghian K, Basso AM, Kelley AE (2002) Effects of selective dopamine DI or D2 receptor blockade within nucleus accumbens subregions on ingestive behavior and associated motor activity. Behav Brain Res 73 7(1-2) 165-177. 

The postmortem investigations have failed to reveal any alterations on the binding or affinity of dopamine Di or D2 receptors in the striatum of depressed subjects (Bowden et al., 1997 Allard and Norlen, 2001). However, there is a documented increase in the dopamine receptors in antidepressant-treated suicide victims, but these subjects had also received neuroleptic treatment (Bowden et al., 1997). 

Apomorphine, a very potent non-selective dopamine agonist, which acts on both Di and D2 receptors, has been nsed with some snccess in Parkinson s disease, particn-larly in patients with severe long-term adverse effects of levodopa. Because of first-pass metabohsm it has to be used subcutaneously, sublingually, or intranasally. Its adverse effects resemble those of levodopa. 

Phenothiazines primariiy biock postsynaptic neurotransmission by binding to dopamine (Di and D2), muscarinic, histamine Hj, and serotonergic 5-HT2 receptors. Phenothiazines also possess peripheral a-adrenergic receptor blockade and quinidine-like cardiac effects. Phenothiazines may also lower the seizure threshold. 

Mansour, A. Meador, W.J. Bunzow, J.R. Civelli, O. Akil, H. Watson, S.J. (1990) Localization of dopamine D2 receptor mRNA and Di and D2 receptor binding in the rat brain and pituitary an in situ hybridization-receptor autoradiographic analysis. J. Neurosci. 10, 2587-2600. 

Waddington, JL (1989) Functional interactions between Di and D2 dopamine receptor systems their role in the regulation of psychomotor behaviour, putative mechanisms and clinical relevance. J. Psychopharm. 3 54-63. 

Detailed studies of the binding of H-labelled haloperidol to neuronal membranes showed that there was a much better correlation between the therapeutic potency of a neuroleptic and its ability to displace this ligand from the nerve membrane. This led to the discovery of two types of dopamine receptor that are both linked to adenylate cyclase but whereas the Di receptor is positively linked to the cyclase, the D2 receptor is negatively linked. It was also shown that the receptor is approximately 15 times more sensitive to the action of dopamine than the D2 receptor conversely, the receptor has a low affinity for the butyrophenone and atypical neuroleptics such as clozapine, whereas the D2 receptor appears to have a high affinity for most therapeutically active neuroleptics. 

Di-receptors (comprising subtypes Di and D5) and D2-receptors (comprising subtypes D2, D3, and D4). The aforementioned actions are mediated mainly by D2 receptors. When given by infusion, dopamine causes dilation of renal and splanchnic arteries. This effect is mediated by Di receptors and is utilized in the treatment of cardiovascular shock and hypertensive emergencies by infusion of dopamine and fenoldopam, respectively. At higher doses, Pi-adrenoceptors and, finally, a-receptors are activated, as evidenced by cardiac stimulation and vasoconstriction, respectively. 

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