Dopamine-sensitive Adenylate Cyclase Research Articles

Paul Greengard: Signals underlying moods, addictions, and brain disorders

Although certain neurotransmitters had been identified more than 40 years ago, scientists knew relatively little about how these chemicals actually functioned. The basis for much of what neuroscientists know today about brain signaling was shaped by National Academy of Sciences member Paul Greengard's 1972 PNAS Classic paper, “Dopamine-sensitive Adenylate cyclase in caudate nucleus of rat brain, and its similarity to the ‘dopamine receptor’” (1).

What dopamine does in the brain

In the early 1970s, receptors for neurotransmitters acting via second messengers had not been identified biochemically nor were there definitive links to such messengers. The discovery by John W. Kebabian and Paul Greengard of a dopamine-sensitive adenyl cyclase, accordingly, was a giant step forward. The investigators first characterized the enzyme in sympathetic ganglia wherein dopamine-producing cells link pre- and post-synaptic neurons. Then, in the corpus striatum, the brain area enriched in dopamine, they delineated the enzyme\x{2019}s properties and showed that it was inhibited by antipsychotic drugs, leading to a large body of research on dopamine as a mediator of antipsychotic drug action and putative roles for this transmitter in the pathophysiology of schizophrenia.

Effect of butaclamol on dopamine-sensitive adenylate cyclase in the rat striatum

Journal Article Effect of butaclamol on dopamine-sensitive adenylate cyclase in the rat striatum Get access Richard J Miller, Richard J Miller M.R.C. Neurochemical Pharmacology Unit, Department of Pharmacology, Medical School, Hills Road, Cambridge CB2 2QD, U.K. Search for other works by this author on: Oxford Academic Google Scholar Alan S Horn, Alan S Horn M.R.C. Neurochemical Pharmacology Unit, Department of Pharmacology, Medical School, Hills Road, Cambridge CB2 2QD, U.K. Search for other works by this author on: Oxford Academic Google Scholar Leslie L Iversen Leslie L Iversen M.R.C. Neurochemical Pharmacology Unit, Department of Pharmacology, Medical School, Hills Road, Cambridge CB2 2QD, U.K. Search for other works by this author on: Oxford Academic Google Scholar Journal of Pharmacy and Pharmacology, Volume 27, Issue 3, March 1975, Pages 212–213, https://doi.org/10.1111/j.2042-7158.1975.tb09444.x Published: 12 April 2011 Article history Received: 02 December 1974 Published: 12 April 2011

Limiting factors in the antagonism of neuroleptics on dopamine-sensitive adenylate cyclase.

Journal Article Limiting factors in the antagonism of neuroleptics on dopamine-sensitive adenylate cyclase Get access Pierre Laduron Pierre Laduron Department of Neurobiochemistry, Janssen Pharmaceutica, Research Laboratoria, B-2340 Beerse, Belgium Search for other works by this author on: Oxford Academic Google Scholar Journal of Pharmacy and Pharmacology, Volume 28, Issue 3, March 1976, Pages 250–251, https://doi.org/10.1111/j.2042-7158.1976.tb04141.x Published: 12 April 2011 Article history Received: 02 September 1975 Published: 12 April 2011

Dopamine receptors in rat striatum and nucleus accumbens; conformational studies using rigid analogues of dopamine.

A study was made of the actions of dopamine and of some 2-amino-1,2,3,4-tetrahydronaphthalenes on dopamine-sensitive adenylate cyclase in homogenates of rat striatum and nucleus accumbens. The compounds were also tested for their ability to stimulate motor activity following bilateral injection into the nucleus accumbens of conscious rats. The most active compounds on adenylate cyclase from both striatum and nucleus accumbens were dopamine and 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene(6,7-diOHATN). The 5,6-dihydroxy analogue (5,6-diOHATN) was 50 times less active than 6,7-diOHATN in striatal homogenates and 350 times less active in homogenates of nucleus accumbens. All dihydroxy compounds tested were active in causing stimulation of motor activity, the most active compounds being 6,7-and5,6diOHATN. Both dimethoxy derivatives tested were inactive on the adenylate cyclase and as locomotor stimulants.

Dopamine-sensitive adenylate cyclase in canine renal artery.

To characterize further a putative dopamine receptor in the renal artery, the effects of dopamine on canine renal artery adenylate cyclase activity were studied. Since the femoral artery is thought to be devoid of a similar dopamine receptor, the effects of dopamine on the adenylate cyclase activity of the canine femoral artery were also studied. In tissues from dogs with or without phenoxybenzamine pretreatment, renal artery adenylate cyclase was maximally stimulated by 4 muM dopamine, compared to 20 muM required for the femoral artery enzyme. The concentrations of isoprenaline required to maximally stimulate renal and femoral artery adenylate cyclase were 0-04 and 0-2 muM, respectively. In tissue from the phenoxybenzamine-pretreated dog, the sitmulatroy effect of dopamine on the renal artery enzyme was selectively blocked by 0-01 muM haloperidol, but not by 0-2 muM propranolol. In the femoral artery, however, the dopamine stimulation was blocked by both antagonists. Stimulation by isoprenaline of renal and femoral artery adenylate cyclase was blocked by propranolol. These data suggest the concept that dopamine interacts with a specific artery receptor apparently different from alpha-and beta-adrenoceptors.

Effect of chlorpromazine and some of its metabolites on the dopamine-sensitive adenylate cyclase of rat brain striatum.

Effect of chlorpromazine and some of its metabolites on the dopamine-sensitive adenylate cyclase of rat brain striatum.

Direct effect of a nomifensine derivative on dopamine receptors.

A study was made of the effects of nomifensine, 4'-hydroxynomifensine and 3',4'-dihydroxynomifensine on dopamine receptors in rat striatum and nucleus accumbens, using the dopamine-sensitive adenylate cyclase assay. Nomifensine and its 4'-hydroxy metabolite were both inactive as dopaminergic agonists. 3',4'-dihydroxynomifensine was, however, a potent agonist, being approximately 2 to 4 times less active than dopamine. The effects of dopamine and of 3',4'-dihydroxynomifensine were blocked by fluphenazine. It is concluded that the dopaminergic activity of 3',4'-dihydroxynomifensine is dependent upon the presence of the two hydroxyl groups.

The absence of sodium ions does not explain the failure of sulpiride to inhibit, in vitro, rat striatal dopamine-sensitive adenylate cyclase.

Journal Article The absence of sodium ions does not explain the failure of sulpiride to inhibit, in vitro, rat striatal dopamine-sensitive adenylate cyclase Get access N M J Rupniak, N M J Rupniak University Department of Neurology, Institute of Psychiatry & King's College Hospital Medical School, Denmark Hill, London SE5, UK Search for other works by this author on: Oxford Academic Google Scholar P Jenner, P Jenner University Department of Neurology, Institute of Psychiatry & King's College Hospital Medical School, Denmark Hill, London SE5, UK Search for other works by this author on: Oxford Academic Google Scholar C D Marsden C D Marsden University Department of Neurology, Institute of Psychiatry & King's College Hospital Medical School, Denmark Hill, London SE5, UK University Department of Neurology, Institute of Psychiatry & King's College Hospital Medical School, Denmark Hill, London SE5, U.K. Search for other works by this author on: Oxford Academic Google Scholar Journal of Pharmacy and Pharmacology, Volume 33, Issue 1, September 1981, Pages 602–603, https://doi.org/10.1111/j.2042-7158.1981.tb13877.x Published: 12 April 2011 Article history Received: 21 April 1981 Published: 12 April 2011

Stereospecific inhibition of dopamine-sensitive adenylate cyclase in carp retina by the enantiomers of (±)-1-cyclopropylmethyl-4-(3-trifluoro- methylthio-5H-dibenzo [a,d] cyclohepten-5-ylidene) piperidine (CTC)

Journal Article Stereospecific inhibition of dopamine-sensitive adenylate cyclase in carp retina by the enantiomers of (±)-1-cyclopropylmethyl-4-(3-trifluoro- methylthio-5H-dibenzo [a,d] cyclohepten-5-ylidene) piperidine (CTC) Get access K J Watling K J Watling MRC Neurochemical Pharmacology Unit, Medical Research Council Centre, Medical School, Hills Road, Cambridge, UK Correspondence: The Biological Laboratories, Harvard University, Cambridge, Massachusetts 02138, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar Journal of Pharmacy and Pharmacology, Volume 32, Issue 1, September 1980, Pages 778–779, https://doi.org/10.1111/j.2042-7158.1980.tb13065.x Published: 12 April 2011 Article history Received: 14 July 1980 Published: 12 April 2011

SDZ GLC 756, a novel octahydrobenzo[g]quinoline derivative exerts opposing effects on dopamine D1 and D2 receptors.

SDZ GLC-756, a novel octahydrobenzo[g]quinoline derivative, is equipotent in displacing [3H]SCH23390 from dopamine D1 receptors and [3H]205-501 from dopamine D2 receptor binding sites. It blocks dopamine sensitive adenylate cyclase with the same potency as SCH23390, indicating antagonist properties at dopamine D1 receptors. On the other hand, SDZ GLC 756 inhibits electrically evoked acetylcholine release from rat striatal slices with the same potency as the selective dopamine D2 receptor agonist bromocriptine. This effect is blocked by spiperone suggesting that it is mediated by dopamine D2 receptor activation. The opposing action of SDZ GLC 756 on dopamine D1 and D2 receptors is also evident in vivo. SDZ GLC 756, like SCH23390, blocks apomorphine-induced rearing in mice. On the other hand, it inhibits prolactin secretion and produces circling in unilateral 6-OHDA-lesioned rats, which is compatible with stimulant properties at dopamine D2 receptors. This drug might be a new tool to study linkage between dopamine D1 and D2 receptors.

Ontogenic development of adenylcyclase and phosphodiesterase in rat brain

The activities of adenylcyclase (AC) and phosphodiesterase (PDE) were determined in cerebral cortex of rats of 1 day to 18 months of postnatal age. The activity of dopamine-sensitive and serotonin-sensitive adenylcyclase was also determined in young and old rat brain. AC increased with age and attained a maximum at about 12 weeks of life which plateaued down at 5 months and remained unchanged in the later stages of life. Similarly PDE increased upto 15 weeks which later attained plateau. Dopamine-sensitive AC was not different between young and old rats. However, serotonin-sensitive AC was significantly more in old rats than in young rats. The increase in AC and PDE activity with aging is not only due to increase in protein content but might also be due to increase in cells rich in these enzymes.

Dopaminergic benzo[a]phenanthridines: resolution and pharmacological evaluation of the enantiomers of dihydrexidine, the full efficacy D1 dopamine receptor agonist.

Racemic trans-10,11-dihydroxy-5,6,6a,7,8,12b- hexahydrobenzo[a]phenanthridine (2, dihydrexidine) was shown previously to be the first bioavailable full efficacy agonist at the D1 dopamine receptor. In addition to its full D1 agonist properties, 2 also is a good ligand for D2-like dopamine receptors. The profound anti-Parkinsonian actions of this compound make determination of its enantioselectivity at both D1 and D2 receptors of particular importance. To accomplish this, the enantiomers were resolved by preparation of diastereomeric (R)-O-methylmandelic acid amides of racemic trans-10,11-dimethoxy-5,6,6a,7,8,12b- hexahydrobenzo[a]phenanthridine 4 that were then separated by centrifugal chromatography. An X-ray analysis of the (-)-N-(R)-O-methylmandel diastereoamide revealed the absolute configuration to be 6aS,12bR. Removal of the chiral auxiliary and O,O-deprotection afforded enantiomeric amines that were then tested for biological activity. In striatal membranes, the (6aR,12bS)-(+)-enantiomer 2 had about twice the affinity of the racemate and 25-fold greater affinity than the (-)-enantiomer at the D1 receptor labeled by [3H]SCH23390 (K0.5s of 5.6, 11.6, and 149 nM, respectively). Similarly, the (+)-enantiomer 2 had about twice the affinity of the racemate for human D1 receptors expressed in transfected Ltk- cells. Functionally, the (+)-enantiomer of 2 was a full agonist, with an EC50 of 51 nM in activating striatal dopamine-sensitive adenylate cyclase versus 2.15 microM for the (-)-enantiomer. With respect to D2-like receptors, (+)-2 had a K0.5 of 87.7 nM in competing with [3H]spiperone at D2 binding sites in rat striatal membranes versus about 1 microM for the (-)-enantiomer. Together, these data demonstrate that both the D1 and D2 activities of dihydrexidine reside principally in the (6aR,12bS)-(+)-enantiomer. The results are discussed in the context of structure-activity relationships and conceptual models of the D1 receptor.

Putative [formula omitted] opioid receptor complex in rat brain: Characteristic affinity profile for opioid peptides

Several lines of evidence suggest that μ- and δ-opioid receptors mediating inhibition of dopamine-sensitive adenylate cyclase (DA/AC) in rat neostriatum may interact non-competitively and may in fact constitute an opioid receptor complex. Using the highly selective antagonists CTOP (μ) and naltrindole (δ) we have shown that the interacting DA/AC-coupled γ- and δ-receptors may be distinguished pharmacologically from the (independent) γ- and δ-receptors mediating presynaptic inhibition of electrically-evoked release of, respectively, [ 3 H]NA from cortical slices and [ 14 C]ACh release from striatal slices

Repeated and chronic morphine administration causes differential long-lasting changes in dopaminergic neurotransmission in rat striatum without changing its δ- and κ-opioid receptor regulation

Repeated, once daily morphine treatment (14 days) as well as chronic morphine administration (6 days) caused a rebound reduction in the electrically evoked release of [ 3H]dopamine from superfused rat striatal slices 1 day after the last subcutaneous injection. Interestingly, whereas [ 3H]dopamine release remained significantly reduced for at least 3 weeks following morphine withdrawal in chronically treated (tolerant/dependent) rats, neurotransmitter release from dopaminergic nerve terminals gradually increased above control values following cessation of repeated morphine administration. Postsynaptically, dopamine D 1 receptor-stimulated adenylate cyclase appeared to be sensitized 1–3 days but was unchanged 3 weeks after chronic morphine treatment. In contrast, such an enhanced postsynaptic dopamine D 1 receptor efficacy did not occur 1–3 days following repeated morphine administration, but appeared to develop slowly resulting in a profound increase of dopamine-sensitive adenylate cyclase 3 weeks after the last injection. The inhibitory effect of dynorphin A-(1–13) on [ 3H]dopamine release, as well as that of [Met 5]enkephalin on dopamine D 1 receptor-stimulated adenylate cyclase appeared to be unchanged subsequent to repeated or chronic morphine treatment. These data indicate that, long after cessation of drug treatment, chronic morphine treatment causes a reduction whereas repeated morphine administration gradually induces an enhancement of opioid receptor-regulated dopaminergic neurotransmission due to local adaptive changes within the rat striatum. Such distinct long-lasting alterations of dopaminergic neurotransmission induced by different temporal patterns of morphine administration in projection areas of mesencephalic dopaminergic neurons may be related to the enduring effects of drug abuse such as behavioural sensitization and drug craving.

Opioid receptors and inhibition of dopamine-sensitive adenylate cyclase in slices of rat brain regions receiving a dense dopaminergic input

In slices of rat nucleus accumbens, olfactory tubercle, frontal cortex and mediobasal hypothalamus exposed to dopamine (DA), the activation of DA D 1 receptors stimulated cyclic AMP (cAMP) formation whereas, in nucleus accumbens slices only, activation of D 2 receptors appeared to inhibit D 1 receptor-stimulated adenylate cyclase at the same time. Activation of μ-opioid receptors by [D-Ala 2,MePhe 4,Gly-ol 5]enkephalin (DAMGO; 1 μM),but not of δ-opioid receptors by 1 μM [D-Pen 2,D-Pen 5]enkephalin (DPDPE), inhibited (by 35–40%) DA-stimulated cAMP production in slices of nucleus accumbens and olfactory tubercle. When adenylate cyclase was stimulated by selective D 1 receptor activation, i.e. by DA in the presence of (−)-sulpiride, DPDPE reduced cAMP formation (by about 45%) in nucleus accumbens slices but not in slices of the other brain dregions. The κ-agonist, U 50,488, did not affect DA- or D 1 receptor-stimulated adenylate cyclase activity in any of the brain regions. Preincubation of nucleus accumbens slices with the irreversible δ-ligand, fentanyl isothiocyanate (FIT; 1 μM), not only antagonized the inhibitory effect of DPDPE but also prevented the antagonism by naloxone of the inhibitory effect of DAMGO. Therefore in nucleus accumbens opioids may inhibit DA-sensitive adenylate cyclase through activation of a μ/δ-opioid receptor complex, whereas in olfactory tubercle μ-receptors appear to mediate the inhibition of adenylate cyclase activity. Opioids do not seem to affect DA-stimulated cAMP formation in frontal cortex and mediobasal hypothalamus.

Stimulation of diamondback moth ( Plutella xylostella) adenylate cyclase activity by a carbodiimide

1. DFCD or 3-(2,6-diisopropyl-4-phenoxyphenyl)-1- tert-butylcarbodiimide, a toxic metabolite of the thiourea acaricide/insecticide diafenthiuron, stimulated adenylate cyclase activity in preparations from heads of adult diamondback moths, Ptutella xylostella (L.). 2. Depending upon assay conditions, DFCD gave a biphasic response with K a, values of 0.025 and 1.25 μM for high and low affinity components, respectively, or a monophasic response with a K a of 0.4 μM. 3. Studies with potential agonists and antagonists suggested that octopamine-sensitive ( K a 7.5 μM) and dopamine-sensitive ( K a, 1.0 μM) adenylate cyclases were present. 4. At maximally effective concentrations, the activity of DFCD was nonadditive to that of octopamine or dopamine. 5. It appeared that DFCD was binding to octopamine- and dopamine-sensitive adenylate cyclases and that affinity of the carbodiimide was higher for the former than for the latter. 6. These actions on biogenic amine-sensitive adenylate cyclases likely are involved in the toxicity of diafenthiuron to diamondback moths.

In vivo partial inactivation of dopamine D1 receptors induces hypersensitivity of cortical dopamine-sensitive adenylate cyclase: permissive role of alpha 1-adrenergic receptors.

As shown by autoradiography, peripheral injections of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) induced a dose-dependent decrease of [3H]SCH 23390 and [3H]prazosin high-affinity binding sites in the rat prefrontal cortex. EEDQ showed similar efficacy in inactivating cortical and striatal dopamine (DA) D1 receptors, whereas prazosin-sensitive alpha 1-adrenergic receptors were more sensitive to the action of the alkylating agent, as for all doses of EEDQ tested (from 0.8 to 3 mg/kg, i.p.), the decrease in cortical [3H]SCH 23390 binding was less pronounced than that of [3H]prazosin. The effects of EEDQ on [3H]SCH 23390 binding and DA-sensitive adenylate cyclase activity were then simultaneously compared in individual rats. In the striatum, whatever the dose of EEDQ used, the decrease of DA-sensitive adenylate cyclase activity was always lower than that of D1 binding sites, suggesting the occurrence of a large proportion of spare D1 receptors. In the prefrontal cortex, a significant increase in DA-sensitive adenylate cyclase activity was observed in rats treated with a low dose of EEDQ (0.8 mg/kg), this effect being associated with a slight reduction in [3H]SCH 23390 binding sites (-20%). Parallel decreases in the enzyme activity and D1 binding sites were observed with higher doses. The EEDQ-induced supersensitivity of DA-sensitive adenylate cyclase did not occur in rats in which the decrease in [3H]prazosin binding sites was higher than 35%.(ABSTRACT TRUNCATED AT 250 WORDS)

A68930: A potent agonist specific for the dopamine D 1 receptor

A68930, [1R, 3S] 1-aminomethyl-5,6-dihydroxy-3-phenylisochroman HCl, is a potent, partial agonist in the dopamine-sensitive adenylate cyclase model of the D 1 dopamine receptor in fish retina. In the rat caudate-putamen model of the D 1 dopamine receptor, A68930 is a potent (EC50 2,1 nM) full agonist. In contrast, A68930 is a much weaker (EC50 = 3,920 nM) full agonist in a biochemical model of the D 2 dopamine receptor. A68930 also displays weak 2 agonist activity but the molecule is virtually inactive at the 1 and β-adrenoceptors. When tested in rats bearing a unilateral 6-OHDA lesion of the nigro-neostriatal neurons, A68930 elicits prolonged (> 20 hr) contralateral turning.

Dopamine receptor ‘supersensitivity’ occurring without receptor up-regulation

Unilateral 6-hydroxydopamine (6-OHDA)-induced lesions of the substantia nigra have been widely used to study various aspects of dopamine neurobiology, and to screen for antiparkinsonian drugs. This study examined the role of receptor alterations in pharmacological supersensitivity seen in response to lesioning of central dopamine pathways in rats by intracisternal (IC) administration of 6-OHDA (200 μg), as well as by bilateral (BIL) or unilateral (UNI) infusion of 6-OHDA into the substantia nigra (8 μg/side). Both IC and BIL lesions resulted in permanent decreases in dopamine concentration in the striatum, the major terminal projection from the substantia nigra. When challenged with apomorphine (0.3 mg/kg), IC-lesioned rats exhibited bursts of rapid locomotion interspersed by rearing, whereas BIL-lesioned rats displayed intense grooming or gnawing and nose poking of the cage floor; these behaviors were not seen in respective sham (i.e. vehicle)-lesioned rats injected with apomorphine. Scatchard analysis of saturation isotherms of both D 1 ([ 3H]SCH23390 binding sites) and D 2 ([ 3H]spiperone binding sites) dopamine receptors in the striatum revealed no difference in either the maximum number of binding sites (B max), or the dissociation constant (K d) of either receptor type when BIL and IC lesioned rats were compared to appropriate controls. Conversely, the UNI lesioned rats had, under identical conditions of analysis, the expected increase in the density of D 2 receptors on the lesioned side. There was no change in dopamine-sensitive adenylate cyclase activity in the striata of supersensitive IC-lesioned rats, but there was a shift to the left in the dose-response curve in striata from rats bilaterally-lesioned in the substantia nigra, similar to what occurs in UNI lesioned rats. Together, these data clearly demonstrate that although increases in receptor density and changes in cAMP systems are seen in the UNI model, neither mechanism is a requirement for functional supersensitivity in response to 6-OHDA lesions. These data suggest that other cellular events (e.g. alterations in receptor interactions) may play a role in the response to insult, and raise questions about the utility of the unilateral model as a screen for antiparkinsonian drugs.