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Does a Presynaptic Dopamine Surplus Cause Psychosis?

12 April 2012. A meta-analysis of dopamine imaging studies in schizophrenia reports elevated presynaptic dopamine function. By contrast, no change in dopamine transporter activity and a small, antipsychotic-dependent increase in dopamine 2/3 (D2/3) receptor availability were found. The study, published online April 2 in the Archives of General Psychiatry, suggests that future antipsychotic drugs might target the presynaptic regulation of dopamine synthesis and release, rather than block D2 receptors, as most current drugs do.

The dopamine hypothesis is schizophrenia’s most venerable (see SRF Hypothesis), and was initially based on the observation that antipsychotic drugs are dopamine antagonists. The hypothesis posits that hyperactive dopamine signaling in subcortical brain regions is responsible for the positive symptoms of the illness, and has been bolstered by findings of increased striatal D2/3 receptor density and dopamine in postmortem tissue (Mackay et al., 1982), and elevations in cerebrospinal fluid (CSF) dopamine levels (Widerlöv et al., 1988). Positron emission tomography (PET) and single-photon emission computerized tomography (SPECT) studies have enabled the in-vivo measurement of dopamine function in the illness, and the large number of these studies affords the opportunity for meta-analysis.

Probing dopamine function
Led by Oliver Howes of King’s College London, U.K., researchers in the current study combed databases for PET and SPECT dopaminergic imaging studies published between 1960 and 2011. The researchers limited their meta-analysis to studies of striatal dopamine function, since this region can be reliably imaged and is where dopamine dysfunction in schizophrenia has been linked to illness onset, symptom severity, and treatment response (Laruelle et al., 1999). Howes and colleagues analyzed different aspects of dopaminergic function in schizophrenia using three separate meta-analyses measuring: 1) presynaptic function (including dopamine synthesis capacity, dopamine release, and synaptic dopamine levels); 2) dopamine transporter availability; and 3) D2/3 receptor availability.

A total of 17 studies examining 231 patients and 251 control subjects were included in the meta-analysis of presynaptic dopamine function, which found a significant elevation with a large effect size in schizophrenia subjects. Importantly, this effect does not seem to be mediated by antipsychotics, as a similar result was obtained after exclusion of medicated subjects. This elevation is likely due to a functional change in dopamine synthesis and release, rather than a change in axon terminal or neuron number, since there is no evidence that dopamine terminal density and neuron number are altered in schizophrenia (Taylor et al., 2000; Bogerts et al., 1983).

By contrast, no significant difference was observed between the 152 schizophrenia subjects and 132 controls used in a second meta-analysis of dopamine transporter availability. This finding persisted when antipsychotic-treated subjects were excluded. Unlike the analysis of presynaptic dopaminergic functioning, moderate to large heterogeneity between studies was observed, likely due to differences in the radiotracers utilized across studies.

The largest sample size (337 patients and 324 controls) was available to examine D2/3 receptor availability, and a significant elevation was observed. However, the effect size was much smaller than for presynaptic dopamine function, and appeared to be due to antipsychotic treatment, as no difference was seen between control antipsychotic-free schizophrenia subjects. Moreover, moderate to large heterogeneity between studies was present, and in over half of the iterations of a leave-one-out analysis, there was no difference between patients and controls, indicating that the difference was not robust.

Overall, the results of this in-vivo meta-analysis support the dopamine hypothesis of schizophrenia, and point to a specific abnormality in presynaptic dopamine function. Interestingly, this effect appears to be specific to schizophrenia, as alterations are not observed in non-psychotic affective and anxiety disorders (Howes et al., 2007). Howes and colleagues also examined subregions of the striatum, finding that presynaptic function was elevated in the putamen but not the caudate. Neither dopamine transporter nor D2/3 receptor availability was altered in either subregion alone. More work will be needed to address whether the presynaptic alterations are also present in other brain regions besides the striatum.

Implications for treatment
Since all current antipsychotics block D2 receptors, the results of the present study suggest that these treatments are acting downstream of the major dopamine abnormality, and thus that new drugs should target presynaptic dopamine synthesis and release. Interestingly, reserpine and α-methylparatyrosine, drugs that reduce presynaptic dopamine levels, can ameliorate psychotic symptoms (Hollister et al., 1955; Abi-Dargham et al., 2000), suggesting that this mechanism may be useful in schizophrenia.

However, as noted by the authors, several challenges with this treatment strategy remain. For example, given that part of the synthetic pathway for dopamine overlaps with that of norepinephrine, altering dopamine synthesis may create adverse side effects from abnormal norepinephrine signaling. Moreover, regional specificity of the drug target may be necessary to avoid worsening the negative and cognitive symptoms that are thought to result, in part, from alterations in frontal dopamine function through D1 receptors (see SRF related news story).—Allison A. Curley.

Reference:
Howes OD, Kambeitz J, Kim E, Stahl D, Slifstein M, Abi-Dargham A, Kapur S. The Nature of Dopamine Dysfunction in Schizophrenia and What This Means for Treatment: Meta-analysis of Imaging Studies. Arch Gen Psychiatry. 2012 Apr 2. Abstract

Comments on News and Primary Papers


Primary Papers: The nature of dopamine dysfunction in schizophrenia and what this means for treatment.

Comment by:  Bryan Roth
Submitted 18 April 2012
Posted 18 April 2012

The dopamine hypothesis of schizophrenia, in various guises, has captivated the attention of, literally, a large army of psychiatric researchers for nearly 50 years (see, e.g., Carlsson and Lindqvist, 1963). Indeed, a PubMed search of the terms "schizophrenia" and "dopamine" elicits nearly 7,000 articles. Further, every approved antipsychotic drug modulates D2-dopamine receptors and—with the exception of aripiprazole, which is a functionally selective D2 agonist—is a D2 antagonist. Finally, despite nearly three decades of research and billions of dollars spent by the pharmaceutical industry, no drug that does not interact with D2 dopamine receptors has proven to be any more effective than haloperidol for non-treatment-resistant schizophrenia.

Despite this focused research on dopamine, dopamine receptors, and schizophrenia, no clear consensus has emerged regarding whether schizophrenia is associated with excessive dopaminergic neurotransmission. As succinctly stated many years ago:

“The dopamine hypothesis of schizophrenia is by definition supported by no direct evidence. No one has found anything conclusively abnormal about dopamine (DA) in body fluids or brains of schizophrenics….” (Snyder, 1976) (italics mine)

Now, Howes and colleagues provide a nice meta-analytic study and attempt to address this issue conclusively as well as make suggestions for treatment. Briefly, they find that individuals with schizophrenia have a significant enhancement of what they interpret to be presynaptic dopaminergic function. A much smaller increase in D2-dopamine receptors was also reported. Not being a statistician, I cannot comment on the validity of the approach or the conclusions, though I will provide a perspective on what this might mean for drug discovery with the assumption that their results are correct.

What does it mean for drug discovery if there is excessive presynaptic dopamine activity in schizophrenia?
In the paper the authors discuss the potential of presynaptic D2 agonists, selective inhibitors of dopamine synthesis, and the use of dopamine-depleting drugs like reserpine. All of these approaches have been attempted with varying degrees of success, though since all catecholamines share the same biosynthetic pathway it will be essentially impossible to selectively inhibit dopamine synthesis without altering the synthesis of norepinephrine and epinephrine. As well, neither selective targeting of presynaptic D2 receptors nor selective depletion of dopamine is likely to be a pharmacologically viable option.

An alternative approach might be to target receptors that regulate dopamine release presynaptically. Thus, drugs that inhibit the release of dopamine might be salutary for schizophrenia. A quick literature search reveals, however, that several failed drug classes had as their raison d’être inhibition of presynaptic dopamine release, including:

Although I list only these three classes of compounds (each of which is directed at a different molecular target implicated in regulating presynaptic dopamine release) there are likely many others in the public and private domains.

What I believe this means is that it is possible to create drugs which inhibit presynaptic dopamine release, but that the jury is still out as to whether these will offer any substantial advantage over drugs which target postsynaptic D2 signaling.

References:

Carlsson A, Lindqvist M. Effect of chloropromazine or haloperidol on formation of 3methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol Toxicol (Copenh) . 1963 Jan 1 ; 20():140-4. Abstract

Gewirtz GR, Gorman JM, Volavka J, Macaluso J, Gribkoff G, Taylor DP, Borison R. BMY 14802, a sigma receptor ligand for the treatment of schizophrenia. Neuropsychopharmacology. 1994 Feb;10(1):37-40. Abstract

Kikuchi T, Tottori K, Uwahodo Y, Hirose T, Miwa T, Oshiro Y, Morita S. 7-(4-[4-(2,3-Dichlorophenyl)-1-piperazinyl]butyloxy)-3,4-dihydro-2(1H)-quinolinone (OPC-14597), a new putative antipsychotic drug with both presynaptic dopamine autoreceptor agonistic activity and postsynaptic D2 receptor antagonistic activity. J Pharmacol Exp Ther. 1995 Jul;274(1):329-36. Abstract

Snyder SH. The dopamine hypothesis of schizophrenia: Focus on the dopamine receptor. Am J Psychiatry. 1976 February; 133(2):197-202. Abstract

Spooren W, Riemer C, Meltzer H. Opinion: NK3 receptor antagonists: the next generation of antipsychotics? Nat Rev Drug Discov . 2005 Dec ; 4(12):967-75. Abstract

View all comments by Bryan Roth

Primary Papers: The nature of dopamine dysfunction in schizophrenia and what this means for treatment.

Comment by:  Christoph Kellendonk
Submitted 18 April 2012
Posted 18 April 2012

The meta-analysis by Howes et al. once more confirms that there are abnormalities in the dopamine system in the striatum of patients with schizophrenia.

What is new is recent evidence about the location of the dopaminergic hyperfunction. Several high-resolution imaging studies performed in the last few years suggest it to be located in the head of the caudate rather than the ventral striatum. The head of the caudate receives projections from the dorsolateral prefrontal cortex, an area important for the cognitive symptoms of schizophrenia. These new findings contradict the widely accepted hypothesis that the dopaminergic hyperfunction in the striatum is mainly in the ventral or “limbic” striatum.

Another interesting new finding is that the abnormalities in the striatal dopamine system are already present in prodromal subjects. They therefore may occur early in the disease process and could be of primary origin. Obviously, to really understand the etiology of the disorder we would have to image the dopamine system at even earlier developmental stages—something that, due to practical and ethical reasons, is not currently possible.

View all comments by Christoph Kellendonk

Comments on Related News


Related News: Cognition and Dopamine—D1 Receptors a Damper on Working Memory?

Comment by:  Michael J. Frank
Submitted 19 February 2009
Posted 19 February 2009

McNab and colleagues provide groundbreaking evidence showing that cognitive training with working memory tasks over a five-week period impacts D1 dopamine receptor availability in prefrontal cortex. Links between prefrontal D1 receptor function and working memory are often thought to be one-directional, i.e., that better D1 function supports better working memory, but here the authors show that working memory practice reciprocally affects D1 receptors.

An influential body of empirical and theoretical research suggests that an optimal level of prefrontal D1 receptor stimulation is required for working memory function (e.g., Seemans and Yang, 2004). Because acute pharmacological targeting of prefrontal D1 receptors reliably alters working memory, causal directionality from D1 to working memory remains evident. Nevertheless, these findings cast several other studies in a new light. Namely, when a population exhibits impaired (or enhanced) working memory and PET studies indicate differences in dopaminergic function, it is no longer clear which variable is the main driving factor. For example, those who engage in cognitively demanding tasks on a day-to-day basis may show better working memory and dopaminergic correlates may be reactive rather than causal. Finally, the possibility cannot be completely discounted that the observed changes in D1 receptor binding may reflect a learned increase in prefrontal dopamine release; this would explain the general tendency for D1 receptor availability to decrease with cognitive training, due to competition with endogenous dopamine.

The McNab study also finds that only cortical D1 receptors, and not subcortical D2 receptors, were altered by cognitive training. The significance of this null effect of D2 receptors is not yet clear. First, all tasks used in the training study involved recalling the ordering of a sequence of stimuli and repeating them back when probed. While clearly taxing working memory, these tasks did not require subjects to attend to some stimuli while ignoring other distracting stimuli, and did not require working memory manipulation. Both manipulation and updating are characteristics of many working memory tasks, particularly those that depend on and/or activate the basal ganglia. Indeed, previous work by the same group (McNab and Klingberg, 2008) showed that basal ganglia activity is predictive of the ability to filter out irrelevant information from working memory. Similarly, Dahlin et al. (2008) reported that training on tasks involving working memory updating leads to generalized enhanced performance in other working memory tasks, and that this transfer of learned knowledge is predicted by striatal activity. These results are consistent with computational models suggesting that the basal ganglia act as a gate to determine when and when not to update prefrontal working memory representations and are highly plastic as a function of reinforcement. Thus, future research is needed to test whether training on filtering, updating, or manipulation tasks leads to changes in striatal D2 receptor function.

References:

McNab, F. and Klingberg, T. (2008). Prefrontal cortex and basal ganglia control access to working memory. Nature Neuroscience, 11, 103-107. Abstract

Dahlin, E., Neely, A.S., Larsson, A., Bäckman, L. & Nyberg, L. (2008). Transfer of learning after updating training mediated by the striatum. Science, 320, 1510-1512. Abstract

Seamans, J.K. and Yang, C.R. (2004). The principal features and mechanisms of dopamine modulation in the prefrontal cortex. Progress in Neurobiology, 74, 1-57. Abstract

View all comments by Michael J. Frank

Related News: Cognition and Dopamine—D1 Receptors a Damper on Working Memory?

Comment by:  Terry Goldberg
Submitted 3 March 2009
Posted 3 March 2009

This is an important article that describes profound changes in the dopamine D1 receptor binding potential after working memory training in healthy male controls. The study rests on prior work that has demonstrated changes in brain volume with practice (e.g., Draganski and May, 2008), and dopamine can be released at the synapse in measurable amounts even during, dare I say, fairly trivial activities (e.g., playing a video game (Koepp et al., 1998). The present study demonstrated that binding potential of D1 receptors decreased in cortical regions (right ventrolateral frontal, right dorsolateral PFC, and posterior cortices) with training, and the magnitude of this decrease correlated with the improvement during training. Binding potential of D2 receptors in the striatum did not change. Unfortunately, D2 receptors in the cortex could not be measured with raclopride.

Two points come to mind. One is theoretical—how long would such a change remain, i.e., is it transient or is it fixed? This has implications for understanding practice-related phenomena and their transfer or consolidation. The second is technical. A number of studies have shown that practice can change not only the magnitude of a physiologic response, but also its location (see Kelly and Garavan for a review, 2005). Thus, the circuitry involved in learning a task may be different than the circuitry involved in implementing a task after it is well learned. By constraining areas to those activated in fMRI during initial working memory engagement, it is possible that other critical areas were not monitored for binding potential changes.

References:

Draganski B, May A. Training-induced structural changes in the adult human brain. Behav Brain Res . 2008 Sep 1 ; 192(1):137-42. Abstract

Kelly AM, Garavan H. Human functional neuroimaging of brain changes associated with practice. Cereb Cortex . 2005 Aug 1 ; 15(8):1089-102. Abstract

Koepp MJ, Gunn RN, Lawrence AD, Cunningham VJ, Dagher A, Jones T, Brooks DJ, Bench CJ, Grasby PM. Evidence for striatal dopamine release during a video game. Nature . 1998 May 21 ; 393(6682):266-8. Abstract

View all comments by Terry Goldberg