Dopamine is the new serotonin: everyone is talking about it. Depending on what authority you read, dopamine is central to schizophrenia, ADHD, depression, sexuality, and cognition.

Dopamine (DA) is one of the catecholamines, a family of neurotransmitters within the larger category of monoamines. Like all monoamines, dopamine has a single amine (NH2) attached to a benzene ring, along with some methyl groups (CH3) that vary in configuration, giving different monoamines their properties.

Until fairly recently, dopamine was viewed as uninteresting in itself, and worth studying only because it is a precursor of norepinephrine. Here’s that synthetic pathway that has haunted you ever since your first biochemistry course: Tyrosine to Dopa to Dopamine to Norepinephrine to Epinephrine.

The Dopamine Hypothesis of Schizophrenia
Although dopamine was first synthesized in 1910, it didn’t gain fame in psychopharmacology circles until patients with amphetamine addictions began to develop psychotic symptoms that mimicked schizophrenia. Since amphetamine acts largely by increasing dopamine levels, psychiatrists began to discuss the “dopamine hypothesis,” namely, that too much dopamine in the brain causes schizophrenia.

But, in 1976, blaming psychosis on “too much” DA was shown to be an oversimplification. That was the year that Philip Seeman discovered a dopamine receptor in animal brains (for references on the history of dopamine research, see Brit J Pharmacology 2006;147:S136-S144). He showed that DA bound to this receptor (which was later named “D2”), and, perhaps more revolutionary, he showed that the antipsychotic haloperidol could shove DA off the receptor. Thus, it appeared that antipsychotics worked by blocking D2 receptors. This knowledge led to a refinement of the DA hypothesis: schizophrenia was not simply a disorder of too much dopamine, but rather too much dopamine attaching to the specific DA receptor now named D2.

But over time, even this theory began to look simplistic. Antipsychotics led many patients to develop troubling movement disorders (labeled “extrapyramidal symptoms” to distinguish these involuntary movements from the voluntary movements arising from our pyramidal tract), implying that blocking DA receptors in certain brain regions was undesirable. Eventually, researchers hypothesized that the antipsychotic effect of these medications occurred when they blocked D2 in the mesolimbic pathways, and that the extrapyramidal symptoms occurred because of D2 blockade in the nigrostriatal pathway, where it is required for fluid movement. This resulted in a “brain region” revision of the DA hypothesis.

Along came the atypicals, medications that get around the movement problems because, in addition to blocking D2, they also block a serotonin receptor, 5HT2A. And what does serotonin have to do with anything? Serotonin and DA have a seesaw relationship with one another: when serotonin goes up, it decreases DA release via feedback inhibition. Thus, blocking serotonin receptors cause extra DA release, partly compensating for the DA blockade. When this happens in the nigrostriatal pathway, the negative effects of antipsychotics on movement are prevented. Of course, this same thing may happen in mesolimbic pathways, but this appears not to substantially interfere with the antipsychotic properties of these drugs, for as-yet unclear reasons ( Br J Psychiatry 2002; 181:271-275).

Recently, another brain region entered the DA conversation: the mesocortical circuit, made up of neurons going from the limbic system to cortex. Some research indicates that, in schizophrenia, this pathway is dopamine-deficient. If true, this might explain the negative symptoms that characterize schizophrenia, including cognitive deficits and lack of motivation.

This piece of information led to the more sophisticated version of the DA hypothesis that is in vogue currently: Schizophrenia is a disorder of excess DA in the mesolimbic circuit, insufficient DA in the mesocortical circuit, and normal DA in the nigrostriatal circuit (which we should just leave alone).

You can now understand why Bristol-Myers Squibb, the makers of Abilify (aripiprazole), have been so keen to portray Abilify as a “dopamine stabilizer.” According to Abilify’s website (abilify.com), this drug may act as a D2 blocker where there’s too much DA (the mesolimbic pathway) and a D2 stimulator where there isn’t enough (the mesocortical pathway). Indeed, Abilify has an anecdotal reputation of being a “stimulating” atypical, but there are as yet no controlled studies to endorse Abilify as being more effective for negative symptoms than any of the other atypicals.

What about all the other DA receptors? Currently, five have been discovered (D1 through D5), and the possibilities for drug development are tantalizing. D4, for example, occurs in the limbic region and not in the striatal regions. So a selective D4 blocker would be ideal. Unfortunately, nobody has been able to synthesize one. D3 is quite plentiful in the prefrontal cortex, so how about a combination D3 agonist (for negative symptoms) and a D2 antagonist (for psychotic symptoms)? No such creature exists now, but we’ll let you know when it appears in some company’s pipeline.

Dopamine and ADHD
Much is made of how stimulants increase DA, the mechanism being a combination of immediate release from storage vesicles and more gradual DA reuptake blockade. Since stimulants increase dopamine, it’s tempting to see ADHD as a dopamine-deficiency disorder. But several pieces of evidence are at odds with this idea.

First, if you give kids with ADHD pure dopamine (in the form of L-dopa, which crosses the blood brain barrier), it doesn’t help (see Biol Psychiatry 2005;57:1385-1390 for a good review of research described in this section). Second, drugs that have little effect on DA are often effective in ADHD. The most obvious example of this is Strattera (atomoxetine), which is a selective norepinephrine (NE) reuptake blocker.

In fact, all stimulants increase levels of NE as well as DA, and so most experts see ADHD as a complicated disorder involving both of these neurotransmitters. Indeed, the data on ADHD is so confusing and contradictory that one researcher, Anthony Grace at the University of Pittsburg, convincingly argues that ADHD is a disorder of both too much and too little DA (see article mentioned above for references).

How could this make sense? Because there are two different sources of DA in the brain: a “tonic” pool of the stuff that is always bathing the neurons, and a “phasic” burst during which lots of DA is released at once. According to Grace’s theory, the phasic DA bursts cause people to be especially impulsive and inattentive. The presence of sufficient tonic DA creates a negative feedback loop that minimizes the phasic bursts. Stimulants may work, in part, by increasing the tonic pool of DA and thereby putting a brake on periodic DA bursts.

Bottom line? We’re still far from the point where we can confidently predict a drug’s effectiveness based on its neurochemical profile.

TCPR Verdict:
Dopamine: A complicated celebrity