Candidate Review:

Mechanisms for the Interaction of Dopamine andNorepinephrine in the Prefrontal Cortex: Implications for the Treatment of Cognitive Symptoms ofSchizophrenia

Peter Vollbrecht

Neuroscience Graduate Program, Vanderbilt University School of Medicine, U1205 Medical Center North, Nashville, TN 37232, USA.
Correspondencee-mail: peter.j.vollbrecht@vanderbilt.edu

Abstract | Full Text | PDF

Abstract | Reductions in prefrontalcortical dopamine (DA) levels have been associated with the cognitive symptomsof schizophrenia. When removal of the dopamine innervation to the prefrontalcortex (PFC) was tested in animal models, researchers reported a loss ofdendritic spines. Anatomical arrangements in the PFC suggest that dopamine mayplay a role in the regulation of dendritic architecture. Atypicalantipsychotics, but not typical antipsychotics, reverse the loss of dendriticspines seen upon DA denervation. Atypical antipsychotic drugs have also beenreported to reduce cognitive symptoms of schizophrenia. Taken together withtheir ability to reverse spine loss, these data suggest that spine loss may bea pathological correlate to cognitive deficits associated with the prefrontalcortex. The mechanism by which these drugs act to restore DA tone in the PFCremains unclear. Recent data has suggested that norepinephrine (NE) terminalsare capable of releasing the NE “precursor” DA. Atypical antipsychotic drugshave a wide target profile, including antagonism of NE autoreceptors. Thesedata suggest that interactions between the DA and NE systems may play a role intreatment for schizophrenia. Although DA and NE have been implicated indisorders involving the prefrontal cortex such as schizophrenia, affectivedisorders, and attention-deficit hyperactivity disorder (ADHD), the mechanismfor interactions between DA and NE has not been widely investigated.Understanding how these systems interact should have a major impact ontherapeutic possibilities for disorders arising from disruption of PFC function.

Dopamine (DA) and norepinephrine (NE)have consistently been shown to play a crucial role in cognitive processes. DAand NE share a common synthetic pathway, and have both been implicated inpsychiatric disorders such as attention-deficit hyperactivity disorder (ADHD)1,2, affective disorders3, and schizophrenia4-6. Both transmitter systems sendprojections to the prefrontal cortex (PFC), where they have been shown to beinvolved in processes such as attention, working memory, executive function,and behavioral inhibition1, 2, 4, 7-14. Disturbances in PFC function arelinked to the cognitive symptoms of schizophrenia, and are thought to be aresult of a hypodopaminergic state in the PFC15. First generation antipsychotics,such as haloperidol, primarily target the D2 dopamine receptor16. These drugs tend to improve thepositive symptoms of the disorder, such as hallucinations and delusions, yethave little effect on cognitive and negative symptoms17. Interestingly, second generationantipsychotics, such as clozapine, have a larger target profile and are moreeffective in treating the cognitive and negative symptoms of schizophrenia,such as deficits in working memory and a flattened affect18, 19. Among those receptors targeted bysecond-generation drugs are NE receptors, including α2C-receptors, increasing interest in the possibleinteractions of these parallel pathways. Despite commonalities in synthesis,localization, and drug interactions, interactions between DA and NE systemswithin the prefrontal cortex remain poorly understood. Here we will reviewevidence for the role of DA and NE in aspects of cognition, then delve intorecent studies that investigate possible interactions of these systems at thelevel of receptors, transporters, and possible co-release, and finally theimplications that DA/NE interactions have for our understanding ofneuropsychiatric disorders.

DOPAMINE AND NOREPINEPHRINE NEURONSPROJECT TO THE PFC

Early studies of both dopamine andnorepinephrine focused on the localization of these transmitters in the brain.Using fluorescent histochemistry, as well as electron microscopy, these studiesshowed that both DA and NE are present in the prefrontal cortex20-22.Prefrontal cortical DA projections originatefrom neurons in the ventral tegmental area (VTA)23, while NE projections originate fromthe locus coeruleous (LC)24. Dopamine has an abundance of axonterminals in deep layers of cortex in the rodent20 and primate25, primarily in layer V. This coincideswell with the distribution of dopamine receptors of which D1 is thedominant form in the PFC26. This selective area of activationimplies a selective function for the DA pathway in the PFC, which is furtherstrengthened by the presence of specific synaptic contacts being made onto theshafts and spines of layer V pyramidal cells25. Several studies suggest that NEterminals are more evenly distributed than DA terminals throughout theprefrontal cortex21, 27. The diffuse nature of NE terminalsacross both rodent and primate PFC lamina suggests a more general role of thistransmitter in the PFC. Norepinephrine terminals lack the synaptic contactsmade by DA terminals. However, functional specificity of NE may be determinedby NE receptors’ laminar distribution. Norepinephrine and DA distribution inthe PFC suggests these transmitters’ involvement in PFC function.

DOPAMINE AND NOREPINEPHRINE RECEPTORLOCALIZATION

Following these careful characterizationsof dopamine and norepinephrine distribution, investigation began to shift fromneurotransmitters to their receptors. Autoradiography was used in earlystudies, using tridiated ligands that showed specificity for the variousdopamine and norepinephrine receptors28-30.

Currently, five dopamine receptorshave been identified, which are classified as adenylate cyclase activating “D1-like”,or inhibiting “D2-like” receptors, with D1 and D5being grouped together and D2-4 grouped together31. Dopamine receptor identification inearly studies made no distinction between the various subtypes, and suggestedthat DA receptor localization in the PFC was focused in the deep layers V andVI29.  D2 receptors arelocalized to the PFC, yet the relative amount of this receptor is significantlylower than its counterpart26. Early studies indicated that D1was most abundant in superficial layers I, II, and III, with slightly lowerlevels in layers V and VI in primates, while showing specificity to deeperlayers in a rat model28, 30. D2 receptors show laminarlocalization primarily to layer V. Findings by Richfield et al. suggest auniform distribution of D1 receptors across all lamina in cats andmonkeys, but rats had increased D1 receptor binding in deep layers Vand VI26. An mRNA expression study of all fivereceptor subtypes in the PFC of primates found that expression for all fivesubtypes was highest in layer V32. This was in agreement with studiesof mRNA levels performed in the human PFC33, suggesting that layer V has aparticularly important role in catecholamine activity in the prefrontal cortex.

Norepinephrine acts on two classes ofreceptors, both α-and β-adrenergic receptors. These twoclasses are further broken into α1 and α2 as well as β12, and β3 subtypes.The α subtypes are each further dividedinto three subclasses, A, B and C31. The β-receptors activate adenylate cyclase34, while α2-receptors act to inhibit this enzyme35, 36. The α1-receptors are linked to PKC and the release of intracellular calciumthrough Gq coupling35, 37. The β receptors appear less abundant in the PFC than the α receptors and show an inverse laminardistribution28. The α1-receptors are more abundant than β-receptors, yet remain less prominent in the PFC than α2-receptors. Prazosin, a selective ligand for α1-receptors, exhibits strong binding in deep layers Vand VI. The most abundant NE receptor in the PFC is the α2-receptor. Clonidine binding (α2) shows a decreasing gradient from superficial to deeplayers28. Both α2A and α2C-receptors are found both presynapticallyand postsynaptically in the PFC38. Presynapticautoreceptors provide feedback inhibition to the NE terminal38, 39.

It is at the level of receptor bindingthat it first becomes apparent that interactions between DA and NE systems arelikely to occur. It has been shown that DA is capable of acting as an agonistat adrenergic receptors40, 41. Likewise, D1 and D2radioligands have been shown to be displaced by both DA and NE, implying NEbinding to DA receptors42. Cornil et al showed that DA hasaffinity for the α2c-adrenoceptor in rat brain43. It is widely recognized that NEtransporters have a higher affinity for DA than for NE, allowing possibleinteractions through transmitter reuptake. Finally, 2nd generationantipsychotics such as clozapine and olanzapine have affinities for both DA andNE receptors44-46. Due to the possibilities forinteractions between these systems, an investigation of the mechanisms of theseinteractions appears critical to our understanding of the effects of eitherpathway in PFC function.

DOPAMINE AND NOREPINEPHRINE IN THEPREFRONTAL CORTEX

The importance of interactions betweenNE and DA is underlined by the roles of these transmitters during PFC function.The prefrontal cortex is thought to control such executive cognitive functions asworking memory and attention. Given the innervation patterns of both dopamineand norepinephrine, it is not surprising that both have individually been shownto have links to these functions. Through the use of lesion studies within theprefrontal cortex, as well as studies of structures projecting to the PFC, transmitterloss-of-function has been explored.

Lesion of DA in the PFC can beperformed directly by injection of 6-hydroxydopamine (6-OHDA) into the PFC47, or indirectly by injection of 6-OHDAinto the VTA which supplies DA to the PFC48 along with a NET blocker such asdesipramine to spare NE terminals. Studies using both methods have suggestedthe importance of DA in working memory, and attention49. Interestingly, further research hasshown that excess DA in the PFC can have detrimental effects on cognitive tasksas well5.

Through injection of the NE terminalspecific toxin DBH-saporin, similar PFC specific lesions of NE can be performed50. Before the development of thistoxin, DNAB lesions using 6-OHDA were used1. Studies using both of these methodshave shown cognitive deficits similar to those seen in the DA system1, 14, 50. Once again, excess levels of NE canhave detrimental effects37, 51. These studies suggest that there isan optimal range for DA and NE within the PFC necessary for higher orderfunctioning. Given the involvement of the prefrontal cortex in cognitivefunctions such as working memory, and attention, as well as the role of DA andNE in these processes, understanding the interactions between thesetransmitters within the PFC could lead to major changes in the treatment ofneurological disorders, such as attention-deficit hyperactivity disorder (ADHD)and schizophrenia.

PREVIOUS HYPOTHESES

Past research often cites potentialDA/NE interactions as having an effect on their studies’ results3, 52, 53. Previous work in this area hasfocused on drugs that interact with both systems, rather than these systems’interactions with each other, and the body of literature working directly todetermine the mechanisms of these interactions is small. It has been welldocumented that changes in dopamine and norepinephrine in the prefrontal cortexare well-correlated, changing together in disorders such as schizophrenia53, and as a response to physiologicalchanges, such as stress51. (The link to stress may prove to beof further interest, as stress often induces schizophrenia symptoms. However,this link will not be discussed in this review). The correlation between DA andNE levels in the PFC is particularly evident in response to antipsychotic drugs54, 55. However, the mechanism of this DA/NEinteraction is still being debated. Hypotheses that have been put forthinclude: a direct effect of NE on DA release56, 57, an effect of NE on DA reuptake58, 59, and co-release of DA and NE from NEterminals60. Few researchers have activelyattempted to validate these hypotheses by studying the mechanisms by whichthese two transmitters are interacting.

STUDIES ADDRESSING THE DIRECT EFFECTOF NE ON DA RELEASE

Pozzi et al. used lesion studies,along with selective DA and NE reuptake inhibitors, to further the hypothesisthat increases in NE directly increase DA levels57. This study showed that increasingextracellular NE was correlated to increases in extracellular DA. Similarly,Gresch et al. suggested two possible explanations for their findings, 1) NEregulation of DA through receptors regulating DA release, or 2) transport of DAinto noradrenergic terminals56.

STUDIES ADDRESSING DA REUPTAKE THROUGHNE TERMINALS

The idea of NE affecting the uptake ofDA has been suggested given the relatively low abundance of DA transporter(DAT)61 in the PFC, and the broad coverageof  NE transporter (NET) in this area62. Moron et al. were able to show thatDAT knockout mice had normal rates of DA uptake in the frontal cortex, whileNET knockout mice exhibited greater than 50% loss of DA uptake59. This indicates that DA uptake in thePFC occurs largely through NET activity. If NE release increases, theprobability of DA being taken up by these transporters decreases, therebyincreasing the extracellular levels of DA in the region. In this indirect way,NE may increase extracellular DA. Studies using the α2-receptor antagonist mainserin, along with two NETinhibitors, reboxetine and desipramine, suggest that NET uptake of DA issignificantly higher in the PFC than in the parietal cortex or occipital cortex58 due to a lower NE/DA ratio than inthe latter two areas. It is important to note that mainserin was administeredvia i.p. injection, so effects were global and not PFC specific. Treatmentcaused an increase in DA levels in all three regions, and the authorsattributed this to the effect of the drug in the VTA causing DA neuron firing,rather than action in the PFC. NET’s high affinity for DA could cause morerapid clearance of DA than NE, and could cause the increases in DA whenextracellular NE is increased. Later research in which mainserin wasadministered locally suggests that α2-receptorshave a significant effect locally on DA release in the PFC63.

STUDIES ADDRESSING DOPAMINE ANDNOREPINEPHRINE CO-RELEASE

Ahn and Klinman reportedon the rate limiting steps of norepinephrine synthesis over 20 years ago64. They report that dopamine betamonooxygenase (dopamine beta hydroxylase, DBH), and not tyrosine hydroxylase,may be the rate-limiting step in NE synthesis. DBH is the final enzyme thatconverts DA into NE within the vesicles of NE terminals. If DBH is ratelimiting, at times the firing rate of NE neurons could be intensified, causingrelease of DA from these terminals along with NE. This interaction, coined the“co-release” hypothesis, proposes that DA and NE are released together from theNE terminal60. Microdialysis allowed investigationof the possible co-release of DA and NE in the PFC60. Looking at DA innervated regions(PFC) and non-, or minutely DA innervated regions (occipital cortex, primarymotor cortex) using dialysis, Devoto et al. showed that the extracellularlevels of DA were similar in both DA innervated and non-innervated regions.This implies another source of DA in these areas. Using selective α2-receptor antagonist infused through the probe,investigators saw increases in DA in all three areas, suggesting that DA wasbeing released through NE terminals, and furthermore that this release was, inpart, regulated by α2-receptors65. The α2-receptor agonist, clonidine, reduced extracellular DA levels along withNE levels, while the antagonist, idazoxan, increased DA and NE levels. A furtherstudy in 2003 by the same group performed a similar study looking at thedopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC)66. This study further verified that DAis likely being released from both DA and NE terminals in the PFC, but only byDA terminals in subcortical regions. Using clozapine, the first atypicalantipsychotic, Devoto et al. showed the effects of this drug on PFC DA and NElevels. In this study, treatment with clozapine elevated both NE and DA levelsin the PFC and occipital cortex, as did treatment with a α2 antagonist. Interestingly, treatment with clonidine,an α2-receptor agonist, reversed these effects, whiletreatment with a D2 agonist, which has been shown to decrease DArelease in the striatum, had no effect66. This evidence again suggests that DAis being released through the NE terminal, and that the atypical antipsychoticdrug clozapine is acting through a α2-receptormechanism to restore PFC DA levels. In later experiments, Devoto et al showedthat activation of the LC was sufficient to increase extracellular dopamine inthe PFC67. Considered with the resultsdiscussed above, it is likely that this increase is not solely due to the LCacting on the VTA but also through NE terminal firing in the PFC. Finally, Devotoet al. demonstrated that lesioning the VTA and removing DA innervation to thePFC has no affect on extracellular DA levels68. Tissue content of DA wassignificantly reduced, however extracellular levels remained unchanged. Thesedata provide very strong evidence suggesting that NE terminals do, in fact,release DA, providing an alternative explanation to the hypotheses that NE isaffecting DA levels through direct interaction with DA terminals or through DAreuptake.

Figure 1 | A possible mechanism for the effects of olanzapine and clozapine on DA tone. A) Proper DA and NE signaling. B) DA tone disturbance while NE signaling remains intact. C) The effects of a α2-receptor antagonist as it re-establishes DA tone through the NE terminal. DA (red circles) and receptors (red boxes), NE (green circles) and α2-receptors (green boxes), α2-receptor antagonist (blue triangle).

The release of DA from NE terminalsmay help to explain data derived in our own lab. We have shown that a loss ofDA innervation from the VTA causes a loss of dendritic spines on PFC layer Vpyramidal cells48. This loss of dendritic spines couldbe related to the loss of cortical volume seen in schizophrenia patients69, providing a possible pathologicalcorrelate to behavioral data suggesting impaired cognitive function in animalswith a loss of PFC DA signaling. Interestingly, the loss of spines in thesecells could be reversed through treatment with olanzapine, but not haloperidol.Given the ability of atypical, but not typical antipsychotic drugs to help inthe relief of cognitive symptoms of schizophrenia, this lends credibility tothe importance of dendritic spines in PFC function. Dendritic structure ismaintained through DA tone in the striatum70. If the same is true for the PFC, itcan be hypothesized that following DA depletion of the PFC, atypical drugtreatment acts to restore DA tone through an alternative DA source. Undernormal conditions, it appears that extracellular DA comes both from the DA andNE terminals, with DA terminals shouldering the majority of this load (Figure1a). However, in certain states such as schizophrenia, these DA levels arereduced, possibly through reduced transmission through the DA terminals (Figure1b). Through treatments capable of antagonizing the α2c-receptor, DA tone can be restored through release ofDA through the NE terminal (Figure 1c). Clozapine, the original atypicalantipsychotic, as well as olanzapine, has a high affinity for α2-receptors44 making these drugs candidates to actat the NE terminal.

CONCLUSIONS

Atypical antipsychotic drugs appear tohave effects on cognitive deficits not seen with typical antipsychotictreatments18. These drugs also have a restorativeeffect on DA denervated pyramidal cell morphology in the PFC48. Linking these two functions ofatypical antipsychotics could provide strong evidence that the ability ofatypical antipsychotic drugs to treat the cognitive deficits and negativesymptoms of schizophrenia is a result of their ability to affect non-DAreceptors, including the α2-receptor. Data from Devoto et al.have suggested that atypical antipsychotic drugs are capable of causing releaseof DA from NE terminals66. Our own work suggests that this maybe a factor in restoring dendritic spines in the PFC. Further research iscritical to linking the interactions of the DA and NE systems to the restorativeeffects of atypical antipsychotic treatment. In the future, understanding themechanism of interaction of DA and NE should lead to improved treatments ofdisorders of the prefrontal cortex, ranging from affective disorders toschizophrenia.

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FURTHER INFORMATION

ArielDeutch’s Lab