Like many aspects of schizophrenia, there are no definitive answers in regard to the biochemical mechanisms underlying the auditory hallucinations associated with this disease. However, research extending over the past century has illuminated many possible explanations. While these explanations are limited by the complexity and unanswered questions surrounding the brain and behavior, they do provide an impetus for further research as well as insight for current treatments. Currently, one of the most promising and well-researched theories involves a malfunction in the circuitry of the neurotransmitter dopamine. This theory is not specific to auditory hallucinations because the exact mechanisms of these hallucinations remain unclear. However, because there is a strong correlation between the two, the theory will be presented on this page in the context of auditory hallucinations.
As is often the case in the discovery of the molecular mechanisms of a disease, preliminary insight is gained through examination of the molecular actions of exogenous chemicals that either mimic aspects of a disease, or treat its symptomatic manifestations. The first breakthrough with schizophrenia came with the discovery that certain drugs found effective in the treatment of anxiety before surgery also proved to be powerful antipsychotics. Among the first of these drugs discovered was chlorpromazine, originally used by Henri Laborit, a French surgeon, to relieve undesirable side effects of anesthesia. Laborit felt that histamine release from mast cells contributed to anxiety and chose chlorpromazine based on its known antihistaminergic effects. However, he soon found that this drug was highly effective in treating the symptoms of anxiety, and proposed its use with psychotic patients. In 1951, John Delay and Pierre Deniker were the first to explore clinical applications for patients of schizophrenia and met with definitive success. While many assumed that the effects of chlorpromazine were achieved through its action as a tranquilizer or general sedative, by 1964 researchers began to recognize its effects were specific to the psychotic symptoms of schizophrenia.
Once the effects of chlorpromazine were widely accepted,
researchers started to pry into the molecular nature of these effects, hoping to
reveal the secrets of the psychosis that had eluded them for so long.
Following the assumption that an exogenous compound can only exert an effect by acting at pre-existing receptors within the
body, researchers looked for endogenous
compounds that shared similar chemical properties with chlorpromazine. What they found was dopamine.
Dopamine is a natural neurotransmitter and will be discussed further in a
moment.
Adapted from Kandel’s Principles of Neural Science.
Although they are not identical in structure it is easy to see how they might be recognized by the same receptor. In fact, it is this difference in structure that allows the receptor to recognize chlorpromazine, but not to be activated by it. In this way, chlorpromazine acts as an antagonist at dopamine receptors. Once this connection was made, people recognized that the side affects of chlorpromazine and other similar drugs resembled the primary symptoms of Parkinson’s disease, which was known at the time to be caused by too little dopamine in pathways associated with movement and motor control. This further supported the need for research involving the possible role of dopamine, and has lead to a wealth of newfound information involving dopamine receptors and dopaminergic pathways.
The neurotransmitter dopamine belongs to the catecholamine group that, in turn, belongs to the wider group of neurotransmitters: the monoamines. A monoamine is any molecule that contains a single amine group (—NH2). Therefore, all catecholamines will contain one amine group, but what is the unifying characteristic of catecholamines that chemically differentiates them from other monoamines? Looking at the picture below, which shows three of the most well known catecholamines, it is clear that they all have a similar “base” known as the “cathechol nucleus” which is composed of a benzene ring with two adjacent hydroxyl groups (—OH).
While Dopamine has clearly been implicated as a possible
effector molecule for the psychosis associated with schizophrenia, it is
important to note that it does not exert uniform effects in the brain, and it is
not expressed ubiquitously. In
fact, it is primarily restricted to four pathways within the brain, known as the
dopaminergic pathways. This
includes the tuberoinfundibular, nigrostriatal, mesocortical, and mesolimbic
systems. These different systems
are associated with different aspects of perception and behavior.
The tuberoinfundibular system is a minor player, and will not be included
here in the discussion of the pathways.
The nigrostriatal pathway originates in the most rostral division of the brain stem known as the midbrain, and its projections terminate in the striatum of the brain. The striatum is composed of the caudate nucleus and the putamen and is a key component of the basal ganglia, a region associated with the control of normal voluntary movement.
It is this pathway that is thought to be greatly altered in
patients with Parkinson's Disease, as evidenced by the severe motor disturbances connected to it.
The mesocortical pathway originates in the ventral
tegmental area where the cell
bodies are located and its projections (axons)
extend all the way to the frontal cortex. Here
they have an excitatory effect, playing a role in the formation of short-term
memories, planning, strategy, problem solving, as well as reinforcement in
learning.
The cell bodies of the mesolimbinc pathway also originate in the ventral tegmental area while their axons project to areas of the limbic system including the nucleus accumbens, amygdala, and hippocampus. This pathway is an integral part of the limbic system and also plays a major role in reinforcing behavior.
Adapted from Kandel’s Principles of Neural Science.
Given the complexity of the effects that dopamine is able
to exert, it is not surprising to learn that there are six major types of
dopamine receptors. These receptors
subtypes are numbered accordingly as D1, D2, D3,
D4, and D5, with D2 having two different
subtypes of its own (hence the six types total).
These two subtypes (for D2) vary only slightly, with one
having a long chain facing the cytosol of the cell while the other has a short
chain here. All of these receptor
subtypes are composed of a seven
membrane-spanning G-protein linked receptor.
However, once activated they lead to different downstream molecular
events, and can be divided into two groups based on this.
The D1 and D5 receptors activate adenylyl
cyclase leading to the
production of cyclic
adenosine monophosphate (cAMP). Because
they are so similar, many texts will refer to the D1 and D5 receptors
as D1A and D1B, respectively.
The diagram below is a summary of the molecular events that
lead to dopamine release. As a bit
of background, an increase of Ca2+ (as shown by the little red dots )
within the cell is a common trigger for the release of a neurotransmitter.
More importantly, the diagram shows that the D1 and D5 receptors
activate (indicated by the +) adenylyl cyclase (AC) leading to the production of
cAMP. The D2, D3, and
D4 receptors, on the otherhand, inhibit it, as indicated by the ---]
sign shown below.
cAMP is a second
messenger that activates other molecules within a cell, causing the cell
to undergo certain changes in response to the increased presence of cAMP.
What changes occur following the binding of dopamine and resulting
increase or decrease in cAMP is not currently well understood.
Adapted from
Kandel’s Principles of Neural Science.
All of these receptors are expressed in high levels within the cerebral cortex and the hippocampus. However, unlike the D1 and D5 receptors, D2, D3, and D4 are found in the greatest numbers in neurons of the caudate nucleus, putamen, and nucleus accumbens. The D2 subtype is especially prevalent in the caudate and putamen and given the high specificity of many antipsychotics for this receptor, as well as the important role of these areas in motor function, it makes sense that one of the common side effects of the drugs is motor dysfunction. (For more information, see Treatments section) This is further supported by the fact that antipsychotic drugs that are specific for both the D3 and D4 receptors do not give rise to such side effects. The D2 and D3 receptors are of particular interest because they are also able to act as inhibitory autoreceptors, thus controlling the release of dopamine induced by the action potential.
Because so much evidence implicates the role of dopamine in the positive symptoms of schizophrenia, many drugs have been created and implemented that interfere with the efficacy of dopamine. (For more information, see Treatments). For example, a-methyltyrosine directly prevents the synthesis of dopamine, while resperine and tetrabenazine prevent its (and that of other monoamines) vesicular storage and perphenazine and haloperidol directly block dopamine receptors.
Auditory hallucinations are one of the most salient features of schizophrenia and are thought to be paralleled by a number of illegally abused substances, including cocaine, phencyclidine (PCP), and MDMA (methylenedioxymethanphetamine – also known as “ecstasy”). Examining the molecular effects of these drugs should only increase our understanding of the mechanisms of hallucinations associated with schizophrenia. Indeed, all of three of these drugs have been shown to act in an agonistic fashion towards the dopamine system. For example, PCP (“angel dust”) has been shown to increase the release of dopamine in the nucleus accumben, and when clozapine (a drug used in the treatment of schizophrenia) was administered following a dose of PCP, the symptoms associated with “angel dust” were negated. Similarly, “ecstasy” has been shown to act at the synapse of dopaminergic neurons not only preventing the reuptake of dopamine, but interfering with the dopamine transporters (responsible for dopamine reuptake) in such a way as to increase its release. As a result, dopamine stays in the synaptic cleft where it continues to exert an effect when it would normally have been removed from the synapse and thus unable to act on the receptors of the postsynaptic neuron. Cocaine has also been implicated in the inhibition of dopamine reuptake. Another interesting parallel between schizophrenia and hallucinogenic drugs is the feeling of euphoria reported by many schizophrenic patients just prior to the onset of symptoms.
The diagram below is a summary of
the previous two sections, and was adapted from Kandel’s Principles of
Neural Science.
It is now widely accepted that dopamine is involved in many
of the symptoms of schizophrenia, but exactly how it exerts these effects is not
well understood because there are many points where a malfunction could occur
leading to the increase dopaminergic activity observed in the brains of
schizophrenic patients. For
example, the dysfunction could be due to an increase in dopamine release, or
perhaps an increase in the postsynaptic response, or even the prolonged
activation of postsynaptic receptors.
In order to isolate a mechanism, experiments have focused in different
aspects of dopaminergic transmission. For
example, Laruelle et al. (1996) performed an experiment in which PCP was
injected intravenously into patients with schizophrenia, and the resulting
release of dopamine was measured using a machine similar to a PET scanner.
What they found was that schizophrenic patients showed an increased
release of dopamine when compared to normal patients, suggesting that an
underlying problem in the brains of schizophrenics lies in excessive release of
dopamine. These researchers were
also able to positively correlate the release of dopamine with the severity of
positive symptoms (such as auditory hallucinations).
There is also the theory that the brains of schizophrenic
patients contain more dopamine receptors than normal patients.
Postmortem measurements in the brains of deceased schizophrenic patients
and PET
scans after
treatment with radioactive ligands
for dopamine have, unfortunately, yielded mixed results.
Some researchers have found a marked increase in D2 receptors
(see below) while others have not. One
explanation for such conflicting results might lie in the area of the brain most
researchers examine: the striatum. This is the region associated with motor control, and it is
perhaps not as important as the mesolimbic dopaminergic system in schizophrenia.
MRI
image adapted from Haines’ Neuroanatomy.
Ventricles are located in the center, and appear black, while the
striatum stained in the previous figure, can be clearly seen with respect to the
surrounding anatomy.
Interestingly,
studies of the drugs used to treat schizophrenia show a strong positive
relationship to their affinity for the D2 receptor.
The graph below shows the effectiveness of the drug, as indicated by the
dose required for an equal response in a patient, along the X-axis.
This means that the farther away from the origin you go, the higher the
needed dose, and the less effective the drug is overall.
Similarly, the Y-axis shows the quantity of the drug needed to fill half
of the receptors, thus indicating the drugs “binding affinity.”
The higher the affinity the drug has for the receptor, the lower it will
appear on the y-axis. Thus, you can clearly see that the drugs with the lowest
dosages have the highest affinity for the D2 receptor.
Such a strong correlation is very important in the world of pharmacology.
Adapted
from Kandel’s Principles of Neural Science.
It is widely known that one of the reasons that cocaine is
so addictive is that it activates the reinforcing pathways of brain such as the
mesolimbic system. It is thought
that a similar mechanism might underlie the irrational thought patters and
hallucinations associated with schizophrenia.
The argument presented is that we are all prone to random irrational
thoughts that surface, or imagined bizarre comments, but we are able to
recognize their insignificance as well as their inappropriateness.
However, in the minds of those individuals with schizophrenia, it is
thought that these irrational, sometimes paranoid thoughts and auditory
hallucinations are ironed into the preexisting circuitry and perpetuate
themselves through a hyperactive
mesolimbic system. But just what
does this hyperactivity stem from? Especially
considering the fact that in some areas of the brain, such as the frontal
cortex, the dopaminergic systems are hypoactive.
To explain this, researchers such as Weinberger (1987) have proposed a
loop between the dopaminergic circuits. In
this situation, a problem arising in the projections to the prefrontal cortex
results in hypoactivity in this area. The
theory continues that because activity of the prefrontal normally inhibits
dopamine release to the limbic areas, a decrease in activity of the frontal
cortex will result in an increase in activity in the limbic system.
The resulting increase in the limbic areas then leads to the expression
of positive symptoms such as auditory hallucinations.
Adapted from Kandel’s Principles of Neural Science.