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Dopamine is a fundamental neurotransmitter and hormone. You may know it as one of the neurotransmitters associated with the limbic system, being released during eating and sex, which causes a sensation of pleasure. But it is more than just a hedonistic chemical, actually many of the functions of the brain are dependent on dopamine. Memory, attention and problem solving revolve around dopamine to control the flow of information from other areas of the brain to the frontal lobes. As a hormone, dopamine acts a precursor to noradrenaline and adrenaline and thus increases heart rate and blood pressure during sympathetic nervous system response.

For this purposes of this post, dopamine is an important neurotransmitter that regulates behavioral responses. In brains of people with deficiencies in dopamine levels, attention deficit hyperactivity disorder is an all too common diagnosis. Low levels of dopamine also cause social withdrawal, apathy, and anhedonia. Furthermore, social anxiety is associated with neurons that are unable to bind dopamine. When dopamine is unregulated and in excess, extraversion or gregarious and assertive behaviors are observed.

Before I jump deep into the post, let me first run down some neuron physiology. Without an understanding about how neurons and their associated chemicals function, it’s hard to comprehend how a mutation in any one of the components leads to neurological, cognitive and behavioral disorders. Neurons are specialized cells of the nervous system that are depolarizable and this ability allows signal to be transduced. Signals come in two forms, graded or action potentials. I won’t get into the nitty gritty of how potentials are formed but just know that once graded potentials reach a threshold, an action potential is generated that rushes down the axon of a neuron. Action potentials are an all or none response.

Neuron SynapseThe action potential travels down axon to the presynaptic terminal where it causes channel proteins to open. The presynaptic terminals contain vesicles chock full of neurotransmitters. The opening of channel proteins influences the vesicles full of neurotransmitters to fuse with the presynaptic membrane. The neurotransmitter is released into the space between the presynaptic membrane called the synaptic cleft and it targets its reciprocal receptor on the postsynaptic membrane of the next neuron. The effect of the neurotransmitter on the postsynaptic membrane will depend on the nature of the neurotransmitter, the nature of the postsynaptic receptors, and whether the postsynaptic ion channels are voltage-gated or chemically-gated. In dopamine’s case, it is hypothesized to provide a teaching signal to parts of the brain responsible for acquiring new behavior.

To clean up the neurotransmitters, specialized proteins called transporters function to re-uptake the bound neurotransmitters back into the neuron. I imagine them as vacuums. In dopamine’s case, a specific transporter exits, and is called the dopamine transporter… but we’ll be calling it DAT. Since DAT cleans up dopamine, and inactivates its function, it is critical in regulating (stopping) the network of effects dopamine is responsible for. Any mutation in the DAT gene that also changes the amino acid composition of the transporter ultimately affects the ability of the protein to stop dopamine’s effects.

In humans, the DAT gene is fairly large, around 64,000 base pairs long and consists of 15 exons. Evidence for the associations between DAT and dopamine related disorders have come from a genetic polymorphisms studies of the DAT gene. Currently mutations in DAT are implicated in a number of dopamine related disorders such as attention deficit hyperactivity disorder, bipolar disorder, clinical depression, and alcoholism.

Because DAT modulates the extent of dopamine activity on the receptor, it becomes an excellent candidate to study how variants of DAT effect behavior and ultimately if the variants offer an selective advantage. In what I consider a really awesome paper in the journal, Molecular Biology and Evolution, a half dozen geneticists at the University of Pittsburg, studied DAT for sequence variation in populations of two different macaque species and humans. They calculated the extent of the different combinations of DAT alleles in their populations that would be more or less frequent than what’s expected from a random formation of haplotypes. The amount of non-random associations between polymorphisms at different loci are measured by the degree of linkage disequilibrium, which is the basically the probability to find same set of alleles at two or more loci. The key word here is non-random. In order to study whether or not a mutation in the DAT gene has any affects on survivability, we need to figure out the random variants from the ones that are seemingly selected for.

The paper, “Sequence Variation in the Primate Dopamine Transporter Gene and Its Relationship to Social Dominance,” tells us how they went about doing that. First they sampled about 760 monkeys but only 23 humans. They designed primers for the DAT gene and each exon was sequenced. That’s a lot of sequencing, if my estimations are correct, that’s around 12,000 different reactions. But I don’t know that for sure. Either way, 78 polymorphisms were identified but only two functional variants were linked to high social rank. Social rank was observed through the level of dominance (aggressive, use of attack gestures, actions, and vocalizations more frequently, and consistently defeat individuals of lower rank).

What I’m kinda iffy on is how they identified the variants, located in 5′ UTR, if they only sequenced the exons. Regardless, they realized that heterozygous individuals, with one copy of the minor 5′ UTR allele, were more likely to be of subordinate rank than those who were homozygous for the major allele. In other words,

“the odds that a subordinate individual possesses at least one copy of the minor allele… are one and a half to nearly twice the odds of it being homozygous… In contrast, subordinates were significantly less likely to be heterozygous than homozygous.”

The two DAT 5′ UTR variants fall at a putative transcription factor–binding site. They don’t get deep into a discussion on how the variants affect the transcription factor-binding site (other than the minor allele abolishes the core sequence) nor what the putative transcription factor that binds to it, which would be two a really cool study in itself. If one could take the 2 variants and compare how levels of gene expression vary, then we can get an idea if the homozygous alleles allow for less DAT to be transcribed and ultimately allow for more dopamine to float around causing extraversion and socially dominant behavior. But they do identify NFAT as a regulator,

“…these transcription factors thus play a crucial role in shaping long-term changes in neuronal function. They are also sensitive to secondary messenger systems activated by brain-derived neurotrophic factor (BDNF) which regulates expression of the dopamine D3 receptor. It is thus possible that NFAT and/or BDNF also modulates expression of DAT. “

I consider this study extremely enlightening in understanding the biological mechanisms behind primate social behavior and ultimately evolution. See we have behavior, social dominance, that for the most part we think has evolutionary significance and has something to do with dopamine and the regulation of this neurotransmitter. In order to figure out if the two are linked, one needs to correlate that a variation in any portion of the gene that regulates dopamine activity (DAT) is linked to a heterozygote or homozygote state.

In this case, Robert Ferrell and his lab identified a difference in an area slightly upstream of DAT that controls the rate it is transcribed in macaques. By looking at the variants in each individual and the observations of the social behavior, his lab figured out heterozygous individuals we’re as bossy. Pretty amazing, if you ask me. But this putative binding site is not found in the homologous region of human DAT, which is also really interesting! Has social dominance by way of the dopamine network not been positively selected or lost in the human lineage? Or have we humans found another biochemical pathway to influence dominant behavior?