Dopamine-sensitive adenylate cyclase in caudate nucleus of rat brain, and its similarity to the “dopamine receptor”

Abstract

An adenylate cyclase that is activated specifically by low concentrations of dopamine has been demonstrated in homogenates of caudate nucleus of rat brain. A half-maximal increase in the activity of the enzyme occurred in the presence of 4 ,M dopamine. Concentrations of dopamine as low as 0.3 MAM stimulated the activity of the enzyme. The adenylate cyclase activity of the homogenates was also stimulated by low concentrations of apomorphine, a substance known to mimic the physiological and pharmacological effects of dopamine. The Recent work has implicated dopamine as a neurotransmitter in the basal ganglia of the mammalian brain (1-4). In addition, a variety of behavioral and pharmacological evidence supports the concept of a "dopamine receptor" within the basal ganglia (5-7). Moreover, evidence has accumulated that Parkinsonism can result either from depletion of the dopamine in the basal ganglia or from blockade of the "dopamine receptor" (1, 3). It would, therefore, seem of considerable importance to identify the biochemical receptor with which dopamine interacts in the basal ganglia.Recent studies on the role of adenosine 3':5'-cyclic monophosphate (cyclic AMP) in ganglia of the peripheral sympathetic nervous system have led to a partial clarification of the role and mechanism of action of dopamine within these peripheral ganglia. An adenylate cyclase was demonstrated in these ganglia that was specifically stimulated by very low concentrations of dopamine (8). The demonstration of this enzyme in these ganglia, together with other evidence presented elsewhere (9-12), led to the suggestion that cyclic AMP mediates dopaminergic transmission, and thereby modulates cholinergic transmission within these ganglia. More recently, a dopamine-sensitive adenylate cyclase has been reported by Brown and Makman (13) in mammalian retina, where dopaminergic amacrine cells occur. It seemed possible, particularly in view of the known balance and interaction of cholinergic and dopaminergic mechanisms in the extrapyramidal system, that a dopamine-sensitive adenylate cyclase might mediate dopaminergic transmission in the basal ganglia, with consequent modulation of cholinergic transmission. Therefore, we undertook a search for such an enzyme in the caudate nucleus. We report the results of these studies, which demonstrate the occurrence of this enzyme, and describe some of its pharmacological properties. The similarities between the pharmacological properties of this enzyme and those of the "dopamine receptor" suggest a close relationship between these two entities. METHODS Male Sprague-Dawley rats, weighing about 200 g, were killed by decapitation. The brain was rapidly excised in a cold room (40) and placed in cold Krebs-Ringer bicarbonate buffer that contained (in mmol/liter): NaCl, 122; KC1, 3; MgSO4, 1.2; CaCl2, 1.3; KH2PO4, 0.4; NaHCO3,25;10. This buffer had previously been equilibrated with a gas mixture of 95% 02-5% C02, and had a pH of 7.4 at 250. The brainstem and cerebellum were removed, and the brain was he...

Constitutive Activation of Gαs within Forebrain Neurons Causes Deficits in Sensorimotor Gating Because of PKA-Dependent Decreases in cAMP

“…Amphetamine, an indirect dopaminergic agonist, decreases PPI via dopamine D2 receptors (Ralph-Williams et al, 2002) that inhibit AC activity (Neves et al, 2002). Conversely, haloperidol, a typical antipsychotic that blocks D2 receptors (cf., Miyamoto et al, 2005) and increases cAMP signaling in forebrain structures (Berndt and Schwabe, 1973;Kaneko et al, 1992;Kaplan et al, 1999;Dwivedi et al, 2002; but see Kebabian et al, 1972;Carenzi et al, 1975), increases PPI (Ouagazzal et al, 2001). Thus, there appears to be a relationship between cAMP and PPI levels.…”

Memory enhancement induced by post-training intrabasolateral amygdala infusions of β-adrenergic or muscarinic agonists requires activation of dopamine receptors: Involvement of right, but not left, basolateral amygdala

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Behavioral Involvement of Central Dopamine and D2 Receptors in l-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-Lesioned Parkinsonian Cynomolgus Monkeys

“…In the present study, the non-selective dopamine agonist apomorphine was suggested to have sufficient dopamine D, agonistic activity to ameliorate the symptoms of parkinsonism in the primate model under blockade of its D2 agonist action, in contrast to SKF 38393 which deteriorated the parkinsonism (7), although apomorphine has been reported to exhibit a partial dopamine D1 agonistic activity in the adenylate cyclase assay of rat striatal homogenates, like SKF 38393 (19). These discrepancies may be due to following: The dopamine D1-receptor family, which is composed of DIA-and DIB-receptor subtypes, is coupled to the stimulation of adenylate cyclase, but the conventional assay for the adenylate cyclase can not detect differentially the intrinsic activity of some ligands on each subtype; and as a result, it is difficult at present to say whether apomorphine and SKF 38393 may act as a full or a partial agonist (possibly antagonist) to the DIAand DIB-receptor subtypes, although they may bind with a high affinity to both subtypes (2).…”