The cause of schizophrenia is not due to increased dopamine concentration in certain brain pathways. I wish it was like that! We would already have the key to heal these sick ..... Unfortunately, the aetiology of this disease is still unclear. We only know that many factors come into play: genetic predisposition, protective factors, negative factors, precipitating factors, etc. If we administer antipsychotics that have the ability, with different mechanisms, to decrease dopamine activity in the mesolimbic system vs D2 receptors, we have the effect to make to decrease or eliminate the positive symptoms of psychosis, especially hallucinations and delusions. But this is not because the levels of dopamine are higher than normal.

Unfortunately the most antipsychotics are not very selective and therefore they determine a dopaminergic deficiency also in other brain areas, especially in the tuberinfundibular, mesocortical and nigrostriatal system, giving as result the well-known side effects, which are respectively hyperprolactinaemia, negative symptoms and parkinsonism.

The only exception to all that could be the last born, the only atypical third generation antipsychotic: Aripiprazole. This drug would seem not to cause all of these side effects. We are still evaluating it in clinical practice

"According to some references, schizophrenia and behavioral disorders cause excessive brain production of dopamine."

Isn't it the other way round?

Really, excessive dopamine production causes these illnesses.

But, what is the destiny of dopamine after using antagonist drugs?

An antagonist of dopamine receptors competes with endogenous dopamine and does not change its levels, but its postsynaptic receptor signaling (unless we do not speak about antagonist of presynaptic dopamine autoreceptors). Striatal synaptic dopamine is metabolised via the dopamine transporter (DAT). But what mechanism will reduce the hyperdopaminergic state - I can not say with certainty. Does anyone know it?

Thank you for these clarifications Michal.

The cause of schizophrenia is not due to increased dopamine concentration in certain brain pathways. I wish it was like that! We would already have the key to heal these sick ..... Unfortunately, the aetiology of this disease is still unclear. We only know that many factors come into play: genetic predisposition, protective factors, negative factors, precipitating factors, etc. If we administer antipsychotics that have the ability, with different mechanisms, to decrease dopamine activity in the mesolimbic system vs D2 receptors, we have the effect to make to decrease or eliminate the positive symptoms of psychosis, especially hallucinations and delusions. But this is not because the levels of dopamine are higher than normal.

Unfortunately the most antipsychotics are not very selective and therefore they determine a dopaminergic deficiency also in other brain areas, especially in the tuberinfundibular, mesocortical and nigrostriatal system, giving as result the well-known side effects, which are respectively hyperprolactinaemia, negative symptoms and parkinsonism.

The only exception to all that could be the last born, the only atypical third generation antipsychotic: Aripiprazole. This drug would seem not to cause all of these side effects. We are still evaluating it in clinical practice

To Francesco Lusciano: also pimavanserin as a 5-HT2A antagonist may be of interest

Thank you Anthony and Francesco for your help.

"But this is not because the levels of dopamine are higher than normal."

I think all auditory hallucinations start off in the inner ear when it is in a temporary hypersensitive state. There is a continuum from noises > tinnitus > music > speech sounds > voices. One strong pieces of supporting evidence is that the brain circuits/regions for tinnitus (of known otological origin) are identical to the brain areas for dopamine. It follows that the most likely relevant site of action of dopamine or anti-dopamine drugs is the inner ear, not the brain.

So, is there any evidence to disprove this, or is it certain that it is the direct action of the anti-psychotics in the brain that is crucial?

Hallucinations may occur for each of the 5 senses, even though auditory hallucinations are more common in schizophrenic patients. However hallucinations are not always present in these patients and we do not need them to be present to diagnose schizophrenia also according to DSM-5. Furthermore I'd wonder why the dopaminergic drugs and the levodopa itself don't have the effect of inducing hallucinations under this hypothesis?

This may happen instead with other types of substances, eg the

so-called hallucinogens, such as LSD

To Anthony Gordon: To say that auditory hallucinations begin in the inner ear is the same as saying that visual hallucinations begin in the eye. Of course, it is a cortico-subcortical matter or dysfunction of neuronal pathways to which the hyperdopaminergic state also contributes.

To Francesco Lusciano: Psychostimulants are also dopaminergic agents and may cause psychosis. In the case of levodopa, a certain disruption of some neuronal circuits is necessary (for example, in Parkinson's disease) and it may cause visual hallucinations.

To Michal Gordon: I agree with you, however I was referring to therapeutic dosages and ideal conditions at all when talking about dopaminergic agents

OK, tkank you

"same as saying that visual hallucinations begin in the eye."

Some certainly do. See Charles Bonnet syndrome. Just as at least some auditory hallucinations begin in the ear, as reported by distinguished clinicians for at least two centuries. So there is no logical or physiological objection to stating that all auditory hallucinations start in the ear. Rather than arguing about this, all that is needed to shoot this theory down are some non-otological cases with proven brain damage. I can't find any.

"though auditory hallucinations are more common in schizophrenic patients."

This alone is enough to sink the cortical theory of hallucination generation. As B Rush noted, ear disease is commoner than eye disease in the insane.

Your discussion is very very interesting!

So, if I understand correctly the cause of disease is not well known, and it has many suggestions.

Do you know if dopamine produced in the brain could cross its barrier into the blood?

Short answer for where DA goes after being released into synaptic cleft is DA is recycled into vesicles by neuronal re-uptake, as well as degraded by uptake into glial cells. See this paper about DA metabolism, Meiser et al. Cell Communication and Signaling 2013, 11:34

Thank you Zhimin for your answer and for the reference.

Dopamine can't cross BBB (Blood Brain Barrier). That's why in PD therapy we administer L-dopa instead of dopamine.

(DA biosynthesis: L-phenylalanine ⇒ L- tyrosine ⇒ L-DOPA ⇒ dopamine)

The natural degradation of dopamine in inactive metabolites can take place in two distinct ways and involves three enzymes : monoamine oxidase (MAO), the catechol-O-methyltransferase (COMT) and the aldehyde dehydrogenase. Both modes of natural degradation lead to the formation of homovanilic acid (HVA).

"Do you know if dopamine produced in the brain could cross its barrier into the blood?"

But what is happening in the ear?

As I have noted above, I think auditory hallucinations emerge from a hypersensitive state of the inner ear, aka endolymphatic hydrops, the pathological basis of Meniere's disease. One manifestation of this increased sensitivity, even in the very earliest stage of hydrops, is a marked susceptibility to a wide range of drugs and toxins. Here is evidence for breakdown in the blood-labyrinth barrier:

The blood labyrinthine barrier in the human normal and Meniere’s disease macula utricle

• Gail Ishiyama,...
• Scientific Reports 7, Article number: 253 (2017)
• doi:10.1038/s41598-017-00330-5...

Published online: 21 March 2017

Abstract

The ultrastructural organization of the blood labyrinthine barrier (BLB) was investigated in the human vestibular endorgan, the utricular macula, using postmortem specimens from individuals with documented normal auditory and vestibular function and surgical specimens from patients with intractable Meniere’s disease. Transmission electron microscopic analysis of capillaries located in the normal human utricular stroma showed vascular endothelial cells with few pinocytotic vesicles, covered by a smooth and uniform basement membrane surrounded by pericyte processes. Meniere’s disease specimens revealed differential ultrastructural pathological changes in the cellular elements of the microvasculature. With moderate degeneration of the BLB, there were numerous vesicles within the vascular endothelial cells (VECs), with increased numbers at the abluminal face, pericyte process detachment and disruption of the perivascular basement membrane surrounding the VECs. With severe degeneration of the BLB, there was severe vacuolization or frank apparent necrosis of VECs and loss of subcellular organelles. A higher severity of BLB degenerative changes was associated with a higher degree of basement membrane thickening and edematous changes within the vestibular stroma. This study presents the first ultrastructural analysis of the capillaries constituting the BLB in the human vestibular macula utricle from normal and Meniere’s disease."

I agree with you Anthony, such disease may occur due to ear or other dysfunctions. However, I have to stay in my field of study: "dopamine".

Thank you Francesco for your clarification.

Now, an other question is also important: what can induce excessive dopamine production? (like hormones or other substances)

I consider it necessary to point out to all those who are discussing that the hyperdopaminergic state is extremely complex even without nosological classifying it into a disorder (such as schizophrenia). So if Anthony G Gordon says that auditive hallucinations emerge from the hypersensitive state of the inner ear, I have to disagree with him. Maybe in some exceptional cases. But it is rather a matter of associative auditive or multimodal cortex. Anthony G Gordon is looking for the cause of hallucinations at the very opposite end!

To Naïrouz Benzeggouta: This is a beautiful question. We know about many drugs that lead to a hyperdopaminergic state. They are not only non-specific dopamine agonists such as cocaine and amphetamine, but also hallucinogens that are 5-HT2A receptor agonists, or even cannabinoids (THCs) that are CB1 receptor agonists. Even more interesting, however, is the question of why is the hyperdopaminergic state endogenously induced. The cause is a dysregulation of dopamine synthesis and release, which can have really many causes (only very briefly: GABA hypofunction, NMDA hypofunction, etc)

"Anthony G Gordon is looking for the cause of hallucinations at the very opposite end! "

So where are the reported cases of top end auditory hallucinations in neurological patients with normal inner ear function. Just one case would be good here. In the absence of such cases, all the neuroscience focused on the cortex is wasted.

Incidentally, I think the immediate mechanism of AHs is the same, whether that person is normal, psychotic, intoxicated, etc, or has any other medical condition.

An other question worries me, schizophrenic people are afraid of something in their life, is there any relation somewhere with adrenaline which is released with fear and stress?

It certainly has a lot of common with noradrenaline. Personally, I understand the stress axis activation and fear generation as secondary to the delusional mood or the delusional thought content that occurs (like hallucinations) just as a result of the subcortical hyperdopaminergic state that leads to aberrant salience attribution also to irrelevant stimuli.

All of us are concerned by this problem, chemist, biologist, physician...

Do you think if we can join traditional to modern medicine we can find solutions to this problem?