B R A I N S T O R M S Clinical Neuroscience Update Neurotransmission of Cognition, Part 1 Dopamine Is a Hitchhiker in Frontal Cortex: Norepinephrine Transporters Regulate Dopamine Stephen M. Stahl, M.D., Ph.D. © Copyright 2003 Physicians Postgraduate Press, Inc. Issue: Since the frontal cortex has a low density of dopamine transporters, dopamine has to be inactivated there by hitching a ride on the norepinephrine transporter of neighboring norepinephrine neurons. PROMISCUOUS TRANSPORTERS take pumps (e.g., fenfluramine and are plentiful on dopaminergic axon One“Ecstasy” personal [3,4-methylenedioxymeth- copy may be printed terminals, thus limiting the diffusion It is well known that the mono- amphetamine; MDMA] by the seroto- of dopamine away from dopamine amine neurotransmitters norepineph- nin transporter; norepinephrine and synapses.3–5 Furthermore, relatively rine, dopamine, and serotonin each dopamine both by the norepinephrine few noradrenergic nerve terminals have their own molecularly distinct transporter).1–4 are present in these same subcortical presynaptic transporters, sometimes This nonselectivity of the trans- brain areas, so the norepinephrine also called “reuptake pumps.”1,2 It is porter comes into play only when transporter has little or no regulatory also common knowledge that most something other than its own neuro- role for dopamine in these places. antidepressants block one or another transmitter shows up in the neigh- On the other hand, dopamine neu- of these transporters and that the pat- borhood. We used to think that rotransmission in the frontal cortex is tern of selectivity of antidepressants this promiscuous selectivity happened far different, because there are very results in their clinical effects (e.g., only when certain drugs capable of few dopamine transporters present serotonin selective vs. norepinephrine interacting with the transporters were in frontal cortex.3–5 This allows dopa- selective vs. dual serotonin and nor- administered or when pathologic cir- mine to diffuse away from the dopa- epinephrine actions).2 What is less cumstances were present, but we mine synapse after it is released, widely appreciated is the fact that the are now learning that it happens where it is free to affect any dopamine transporters themselves are promiscu- normally in frontal cortex to enhance receptor it can reach. The process of ous and not all that selective.3,4 Thus, the geographic scope of dopamine distant, nonsynaptic neurotransmis- numerous drugs and neurotransmit- neurotransmission there as well as sion is sometimes called “volume ters can be transported by these reup- dopamine’s ability to regulate cogni- neurotransmission.”2 This ability of tive functioning.1,3,4 dopamine to navigate over wide areas of frontal cortex may be linked to its BRAINSTORMS is a monthly section of The Journal of Clinical Psychiatry aimed at NEUROTRANSMISSION hypothesized key regulatory role in providing updates of novel concepts emerging DIFFERS FOR SUBCORTICAL cognitive functions, such as working from the neurosciences that have relevance to VERSUS CORTICAL DOPAMINE 2,5 the practicing psychiatrist. memory and attention. From the Neuroscience Education Institute Dopamine inactivation in frontal in Carlsbad, Calif., and the Department of Neurotransmission of dopamine in cortex thus does not depend on do- Psychiatry at the University of California San Diego. subcortical regions such as the basal pamine reuptake; rather, it depends Reprint requests to: Stephen M. Stahl, M.D., ganglia and limbic areas (e.g., nucleus on diffusion, metabolism by the Ph.D., Editor, BRAINSTORMS, Neuroscience Education Institute, 5857 Owens Street, Ste. 102, accumbens) is synaptic, because in enzyme COMT (catechol-O-methyl Carlsbad, CA 92009. these places, dopamine transporters transferase),5 and reaching noradren- 4 J Clin Psychiatry 64:1, January 2003 B R A I N S T O R M S Clinical Neuroscience Update Take-Home Points ◆ Neurotransmission of dopamine in subcortical regions is synaptic, because dopamine transporters © Copyrightare plentiful2003 on Physicians dopaminergic axon Postgraduate terminals there. Press, Inc. ergic nerve terminals that ◆ By contrast, neurotransmission of dopamine in epinephrine in frontal transport dopamine into frontal cortex is both synaptic and nonsynaptic, cortex demonstrate that the norepinephrine neu- because dopamine transporters are not plentiful the transporter for do- 1,3,4 pamine does not regulate rons. The norepineph- there. rine transporter, in fact, dopamine activity, but has even higher affinity ◆ Consequently, after being released from dopamine the transporter for nor- for dopamine than it does synapses in frontal cortex, dopamine diffuses away epinephrine does. Ex- for norepinephrine. This from the synapse to neighboring norepinephrine ploiting these actions with currently available arrangement makes it pos- neurons, which inactivate dopamine by transporting sible for dopamine to dif- drugs can lead to en- it into their presynaptic terminals. fuse over a much wider One personal copy may be printed hancing dopamine, nor- area than its own synapse, epinephrine, or both in and thus affect a much frontal cortex, which greater area of frontal cor- could have therapeutic tex than basal ganglia or nucleus by norepinephrine neurons will actions on cognition in a variety accumbens, for example. change how we use agents that of disorders including depression, act on neurotransmitter transporters. schizophrenia, and attention-deficit/ TWO FOR THE PRICE OF ONE We now know that transporter- hyperactivity disorder.4 ◆ selective reuptake inhibitors are not It is now clear that noradrenergic necessarily transmitter-selective re- neurons play a key regulatory role uptake inhibitors.3 How does this over dopaminergic function in frontal translate into practical psychopharma- REFERENCES cortex, and by extension, over do- cology? For example, if we want to pamine’s ability to regulate cognition. increase dopamine in frontal cortex 1. Gainetdinov RR, Sotnikova TD, Caron MG, Monoamine transporter pharmacology and Not only does dopamine hitch a ride therapeutically, we won’t give a se- mutant mice. Trends Pharmacol Sci on the norepinephrine reuptake pump, lective dopamine reuptake inhibitor 2002;23:367–373 it gets co-stored in synaptic vesicles because there are no dopamine trans- 2. Stahl SM. Essential Psychopharmacology. 2nd ed. New York, NY: Cambridge University with norepinephrine in noradrenergic porters there. We can give a dopa- Press; 2000 neurons. Because of this, both dopa- mine-releasing stimulant, but this 3. Moron JA, Brockington A, Wise RA, et al. mine and norepinephrine get released would also enhance dopamine release Dopamine uptake through the norepinephrine transporter in brain regions with low levels when frontal cortex noradrenergic in subcortical areas, which may not of the dopamine transporter: evidence from nerves fire: 2 neurotransmitters for be desired. Or, we can give something knock-out mouse lines. J Neurosci 2002;22: the price of 1 under physiologic con- that blocks the norepinephrine reup- 389–395 4. Bymaster FP, Katner JS, Nelson DL, et al. ditions in this region of the brain. take pump and increase both dopa- Atomoxetine increases extracellular levels of mine and norepinephrine in cortex, norepinephrine and dopamine in prefrontal TRANSPORTER-SELECTIVE but only norepinephrine in subcortical cortex of rat: a potential mechanism for effi- cacy in attention deficit/hyperactivity disorder. DRUGS ARE NOT NECESSARILY areas, which may be a more favorable Neuropsychopharmacology 2002;27:699–711 TRANSMITTER SELECTIVE portfolio of actions when treating 5. Egan MF, Godberg TE, Kolachana BS, et al. cognitive symptoms.4 Effects of COMT Val 108/158 Met genotype on frontal lobe function and risk for schizo- These new discoveries on the In summary, new insights into phrenia. Proc Natl Acad Sci U S A 2001;98: regulation of frontal cortex dopamine the regulation of dopamine and nor- 6917–6922 J Clin Psychiatry 64:1, January 2003 5.