PNAS CLASSIC PERSPECTIVE What dopamine does in the brain Solomon H. Snyder1 The Solomon H. Snyder Department of Neuroscience, Department of Pharmacology and Molecular Sciences, and Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205 Edited by Leslie Lars Iversen, University of Oxford, Oxford, United Kingdom and approved September 20, 2011 (received for review September 1, 2011) 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’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. n the early 1970s, a reasonable amount was known about the bio- I chemistry of neurotransmitters. A few chemical transmitters were ac- cepted—acetylcholine, norepinephrine, serotonin, and GABA. There were hints that certain common amino acids such as glutamate and glycine, besides their roles in general metabolism and protein syn- thesis, might also be neurotransmitters. However, this hint was still a controversial area. In 1970, Chang and Leeman (1) had isolated and sequenced Substance P in the brain as a peptide that stimulates sal- ivary secretion, but there was little else to argue for peptides as transmitters. The explosion of peptide transmitters that commenced with the isolation of enke- Fig. 1. Photographs of John W. Kebabian (Left) and Paul Greengard (Right) in the 1970s at about the phalins was several years in the offing (2). time of their pioneering work on dopamine-activating adenylate cyclase. Gases such as nitric oxide, carbon mon- oxide, and hydrogen sulfide as endogenous biologically active substances were not transmitter and drug receptors in the mid- Why did Kebabian and Greengard (5) even fantasized. 1970s came as a surprise (4). and Kebabian et al. (6) choose to explore The biosynthesis of acetylcholine, sero- For neurotransmitters that act by dopamine rather than a better character- tonin, norepinephrine, and GABA had opening ion channels, such as acetylcholine ized transmitter such as norepinephrine or been elucidated, and their degradative at the neuromuscular junction, transmitter serotonin? Dopamine is the metabolic pathways had been established. Their re- recognition was presumed to be trans- precursor of norepinephrine, differing lease by exocytosis was generally accepted. formed into an opening or closing of ion only in the absence of a hydroxyl at the Synaptic inactivation by an enzyme in the channels. For the biogenic amines, such as β-position, which is added by the enzyme case of acetylcholine and for amines and norepinephrine and serotonin, the picture dopamine β- hydroxylase (Fig. 2). Specu- amino acids, by reuptake into the nerve was murkier. Hence, the work of Kebabian lation that dopamine might be a biolog- endings that had released them seemed on and Greengard (5) and Kebabian et al. (6) ically active molecule in its own right came solid ground. However, molecular charac- (Fig. 1) implying that dopamine in the in the late 1950s when Carlsson et al. terization of the most important element of superior cervical ganglion and the brain’s (8) used the recently developed spec- fl synaptic transmission, transmitter receptors, caudate nucleus acts through a receptor trophoto uorometric techniques for mea- was still unattained, at least in the brain. coupled to a cAMP-forming enzyme—ad- suring biogenic amines to uncover ex- It was generally assumed that neuro- enylate cyclase—was a giant step forward. tremely high concentrations of dopamine transmitters bound to receptor proteins on How did Kebabian and Greengard (5) in the caudate nucleus of the brain, vastly postsynaptic membranes. Several inves- and Kebabian et al. (6) come to explore greater than norepinephrine levels in this tigators had identified the receptor protein adenylate cyclase as a target for the syn- region. Dopamine became clinically rele- for the actions of acetylcholine in the aptic effects of a neurotransmitter? The vant when Hornykiewicz (9) discovered electric organ of the electric eel through deep background for this work comes from its depletion in the caudate nucleus of the binding of radiolabeled α-bungarotoxin the pioneering efforts of Sutherland and (3). However, the receptor in these elec- Rall (7) that discovered cAMP as a second Author contributions: S.H.S. wrote the paper. tric organs comprises 20% of membrane messenger molecule for a number of hor- The author declares no conflict of interest. protein, about 1 million times as dense as mones. Sutherland and Rall (7) then This article is a PNAS Direct Submission. fi what would be expected in the brain. Thus, identi ed adenylate cyclase as a cAMP- See Classic Article “Dopamine-sensitive adenylate cyclase few investigators anticipated ever under- forming enzyme, which could be activated in caudate nucleus of rat brain, and its similarity to the standing neurotransmitter receptors in by hormones, each with its own distinctive ‘dopamine receptor’” on page 2145 in issue 8 of volume 69. the brain at a biochemical level, and the receptor coupled somehow to a unitary See Classic Profile on page 18872. identification by ligand binding of neuro- adenylate cyclase. 1E-mail: [email protected]. www.pnas.org/cgi/doi/10.1073/pnas.1114346108 PNAS | November 22, 2011 | vol. 108 | no. 47 | 18869–18871 Downloaded by guest on September 26, 2021 dopamine in the ganglion, and possibly elsewhere in the nervous system, may be Tyrosine mediated by stimulating the synthesis of adenosine-3′,5′-monophosphate” (5). The superior cervical ganglion is an ideal tissue for investigating synaptic transmission, with a single presynaptic and Tyrosine Hydroxylase a single postsynaptic neuron along with small interneurons linking the pre- and postsynaptic elements. Greengard then proceeded to the more challenging caudate nucleus, the area of highest dopamine DOPA density in the brain (8). He used similar strategies as in the ganglion. In homoge- nates of the caudate, dopamine stimulated adenylate cyclase with a potency about threefold greater than norepinephrine, DOPA Decarboxylase whereas at the known α- and β-receptors for norepinephrine, dopamine is much weaker. Moreover, the β-adrenergic receptor is most potently activated by isoproterenol, which failed to stimulate Dopamine adenylate cyclase in the caudate, even at high concentrations. Apomorphine, D1 Receptor D2 Receptor known to mimic dopamine pharmacologi- cally, was even more potent than dopa- (Stimulates Dopamine (Inhibits adenylate mine in stimulating the cyclase. adenylate cyclase) cyclase; blockade by In this study, Kebabian et al. (6) noted β-hydroxylase antipsychotic drugs that two antipsychotic drugs, chlorproma- underlies therapeutic zine and haloperidol, blocked dopamine’s efficacy) effects. These drugs, first introduced into psychiatry in 1952, had revolutionized the Norepinephrine treatment of schizophrenia, and therefore, understanding their mechanism of action was of great importance. The first insights into how they acted came from the studies of Carlsson and Lindqvist (12) just a Fig. 2. Biosynthesis and receptor actions of dopamine. few years after they identified dopamine as a putative neurotransmitter/neuro- patients with Parkinson’s disease, whereas The protein kinase was at least two steps modulator. Carlsson and Lindqvist (12) i.v. administration of L-dihydroxyphenyl- removed from the neurotransmitter. noted that the pharmacology of these alanine, the amino acid precursor of dopa- Hence, to link cAMP to neurotransmitters drugs resembled reserpine, an antipsy- mine, dramatically and rapidly alleviated would require monitoring cAMP levels, chotic drug that acts by depleting the brain Parkinsonian symptoms. which was a tedious procedure in small of dopamine, serotonin, and norepineph- The path of Kebabian and Greengard ganglia at that time. Because of his back- rine. Chlorpromazine and haloperidol (5) and Kebabian et al. (6) to character- ground as a neurophysiologist, Greengard failed to influence levels of dopamine or izing synaptic actions of dopamine began focused on the hyperpolarizing influences norepinephrine but increased metabolic in a peripheral system, the superior cervi- of presumed interneurons in the superior products of dopamine fairly selectively. cal ganglion, in which the presynaptic cervical ganglion. First, he showed that Carlsson and Lindqvist (12) speculated neuron uses acetylcholine as its trans- preganglionic stimulation increases cAMP that the antipsychotics were causing mitter, whereas the postsynaptic neuron levels several fold. At this point, he had no a functional dopamine depletion by employs norepinephrine. Besides rapid reason to favor dopamine over norepi- blocking receptors, leading to a feedback nephrine as the transmitter, because gan- excitatory transmission from presynaptic augmentation of dopamine turnover. The glionic levels of the two catecholamines are increased turnover of dopamine was con-