If you were to ask five scientists back in 1975 to identify which neurotransmitter system is most strongly implicated in schizophrenia, you would probably get a single answer: dopamine. Today, you might get five different answers, and it's unlikely that any of them would start with the letter D.

Indeed, one thing is clear today about the molecular basis of schizophrenia: It's much more complicated than scientists once thought. A number of different systems have been linked to the disorder, and while no one yet knows which one might sit at the top of a molecular cascade - or even if a molecular cascade exists - every scientist tends to support one system over the others. "People choose their favorite abnormality, and then focus on that," says Daniel Javitt, director of the program in cognitive neuroscience and schizophrenia at New York University's Nathan Kline Institute in Orangeburg.

When neuroscientists showed in the 1970s that antipsychotic drugs block dopamine D2 receptors in subcortical brain regions, researchers began focusing primarily on dopamine and its associated brain regions in their efforts to understand schizophrenia. Clinicians soon realized, however, that these drugs, while successful at inhibiting schizophrenia's positive symptoms of psychoses, hallucinations, and delusions, they hardly improved cognitive deficits and negative (social) symptoms. "You kind of [had to] scratch your head and say, 'hmm, maybe we've been barking up the wrong tree for a long time,'" says Joe Coyle, a psychiatrist at Harvard Medical School. Clearly, other systems were involved, and this discovery led researchers to branch out in different directions.

Some continued to study the dopamine system, finding that whereas the positive symptoms of schizophrenia are associated with an overabundance of dopamine and D2 receptors in the subcortical regions, a deficit of dopamine in the cortex, combined with an overabundance of cortical dopamine D1 receptors, might cause the associated cognitive deficits. Anissa Abi-Dargham, a psychiatrist and radiologist at Columbia University, says that high levels of the D1 receptor (important for the working memory and executive functions) might be compensating for low levels of cortical dopamine. The net result, however, is an overall deficiency in cortical dopamine signaling. She admits, however, that "evidence for dopamine dysregulation in the cortex is more recent and needs more work and more clarification" than the dopamine problems in the subcortical regions.

That dopamine and its receptors are overabundant in one brain region and deficient in another might seem counterintuitive, but it can be explained by a circuitry model that 2000 Nobel laureate Arvid Carlsson developed. The model suggests, says Abi-Dargham, that the same weakness in the cortex - a deficiency in N-methyl-D-aspartic acid (NMDA) receptor-mediated transmission - actually causes a lack of dopamine in the cortex and too much dopamine in the striatum.

The model suggests that dopamine abnormalities might lie downstream of problems in the glutamate-NMDA system, and indeed, a number of scientists are focusing on this possibility. Glutamate, the most abundant excitatory neurotransmitter in the brain, binds to two types of receptors: Ionotropic receptors form ion channel pores and include NMDA receptors and AMPA receptors. Metabotropic receptors are indirectly linked with ion channels. In the 1970s, studies showed that patients who use ketamine or phencyclidine (PCP), drugs that block NMDA receptors, exhibit symptoms that closely match those of schizophrenia, suggesting that perhaps a deficiency in NMDA function is involved in the disorder.^1,2 "They have positive symptoms, they have negative symptoms, they have cognitive deficits that look very much like what you see in schizophrenia," says NYU's Javitt.

For example, NMDA receptors are involved in the formation of memories but not in the retention of old memories; similarly, patients with schizophrenia have trouble forming, but not retaining, memories, Javitt says. NMDA receptors are also involved in pitch matching in the auditory cortex and in certain visual tasks, and schizophrenia patients have trouble detecting changes in pitch and in performing certain visual tasks.

Article continued below Schizophrenia in the prefrontal cortex

Postmortem studies have reported that subjects with schizophrenia have (1) fewer neurons in the mediodorsal (MD) thalamic nucleus; (2) diminished density of certain parvalbumin-positive synapses where MD neurons project into the prefrontal cortex (PFC); (3) lower spine density on the basilar dendrites of deep layer 3 pyramidal neurons, the principal targets of excitatory synaptic projections from the MD; (4) reduced mRNA expression of GABA-synthesizing glutamic acid decarboxylase (GAD67) in a subset of PFC GABAneurons; (5) decreased density of GABA transporter (GAT-1)-immunoreactive axon cartridges, the axon terminals of GABAergic chandelier neurons, which synapse exclusively on pyramidal neurons; and (6) decreased dopamine innervation in layer 6, where pyramidal neurons provide corticothalamic feedback projections.

Source: Neuron, 28;325-34, 2000.

To confirm that these symptoms are caused by the drug itself rather than by factors associated with drug abuse, John Krystal, a clinical pharmacologist and psychiatrist at Yale University, administered low doses of ketamine to healthy subjects in 1992 and achieved similar results.³ Krystal points out, however, that administering ketamine is not the same thing as having schizophrenia. "It mainly produces this one effect of blocking NMDA glutamate receptors, and schizophrenia is very likely to affect, in primary ways, multiple systems of the brain."

Some studies suggest that chronic NMDA receptor deficits do affect multiple brain systems, including dopamine. Research shows, for example, that disturbances in glutamate and NMDA function can lead to the type of dopamine dysregulation seen in schizophrenia,⁴ that overstimulation of dopamine D2 receptors affects NMDA function adversely in subcortical regions,⁵ and that stimulating NMDA receptors increases dopamine D1 levels,⁶ according to Abi-Dargham.

Genetic evidence also points to the glutamate system. Genes for dysbindin and neuregulin 1, proteins that indirectly modulate NMDA function, have both been implicated in schizophrenia. Harvard's Coyle points out that of 15 schizophrenia-associated genes mentioned in a recent peer-reviewed journal article, "About five of them were within two degrees of separation of the NMDA receptor."⁷

That said, most of the evidence implicating NMDA in schizophrenia has been based on pharmacologic evidence, says David Lewis, a psychiatrist at the University of Pittsburgh. "There really is no body of literature directly showing that the NMDA receptor is altered in the illness," he says. "It's an important and interesting hypothesis, [and] there are some data that are consistent with it, but it doesn't have the sine qua non of a pathological entity yet." (For more on Lewis' GABA research, see sidebar.)

Evidence also exists for the cholinergic system's involvement in schizophrenia. This system uses acetylcholine as its primary neurotransmitter, which binds to both muscarinic and nicotinic receptors. Eighty percent of schizophrenics smoke, possibly due partly to the metabolic boost that decreases the intensity of side effects associated with their medications, and also because smoking activates deficient nicotinic receptors (Studies have shown that there is decreased alpha7 nicotinic receptor binding in certain parts of the brain in schizophrenics.^8-10. Other studies suggest that sensory gating, a function related to attention and the ability to filter out extraneous information, is deficient in individuals with schizophrenia; the alpha7 receptor also mediates this process.¹¹ Abnormal muscarinic cholinergic receptors have been implicated in the disorder, too. "The implication is that [for] those patients who do not respond well to a dopamine antagonist, adding a cholinergic agent could be beneficial," says Rajiv Tandon, a psychiatrist at the Florida Department of Children and Families in Tallahassee.

With so many discrete systems implicated in schizophrenia, it's difficult to know what might ultimately "cause" the disorder. "[Some] people say schizophrenia is a glutamate disease, ... [while others] say it's a GABA disease, and [still others] say it's a dopamine disease," says Lewis. Yet, he says that these different molecular views can be integrated. Some of the most exciting areas of research today, he says, involve finding ways in which these different systems might converge upon a common problem in cortical circuitry; doing so would obviously have profound implications for treatment development.

The key lies in using a combination of different approaches, such as imaging, animal studies, and postmortem studies, to decipher which of the findings represent causes, consequences, compensations, and confounds. For instance, explains Lewis, if a scientist sees that two findings are correlated, such as NMDA hypofunction and deficits in GABA synthesis, he or she could decrease the function of NMDA receptors in animal models to determine whether a GABA deficit ensues, or vice versa. If one change consistently follows the other but not the other way around, then causality begins to become clearer.

Tandon agrees that it's crucial to look at the big picture. "It's one illness we're talking about, so we've really got to try to pull all these findings together," he says. "Efforts to pull all these together [and] organize them around some conceptual framework, that's something I think we need to be spending a little more time and effort on," he says.