The chemistry of motivation.
A recent paper got me interested in the dopamine neurotransmitter system. There are a limited number of neurotransmitters, (roughly a hundred), which are used for all communication at synapses between neurons. The more common transmitters are used by many cells and anatomical regions, making it hazardous in the extreme to say that a particular transmitter is "for" something or other. But there are themes, and some transmitters are more "niche" than others. Serotonin and dopamine are specially known for their motivational valence and involvement in depression, schizophrenia, addiction, and bipolar disorder, among many other maladies.
This paper described the reason why cancer patients waste away- a syndrome called cachexia. This can happen in other settings, like extreme old age, and in other illnesses. The authors ascribe cachexia (using mice implanted with tumors) to the immune system's production of IL6, one of scores of cytokines, or signaling proteins that manage the vast distributed organ that is our immune system. IL6 is pro-inflammatory, promoting inflammation, fever, and production of antibody-producing B cells, among many other things. These authors find that it binds to the area postrema in the brain stem, where many other blood-borne signals are sensed by the brain- signals that are generally blocked by the blood-brain barrier system.
The binding of IL6 at this location then activates a series of neuronal connections that these authors document, ending up inhibiting dopamine signaling out of the ventral tegmental area (VTA) in the lower midbrain, ultimately reducing dopamine action in the nucleus accumbens, where it is traditionally associated with reward, addiction, and schizophrenia. These authors use optically driven engineered neurons at an intermediate location, the parabrachial nucleus, (PBN), to reproduce how neuron activation there drives inhibition downstream, as the natural IL6 signal also does.
 |
| Schematic of the experimental setup and anatomical locations. The graph shows how dopamine is strongly reduced under cachexia, consequent to the IL6 circuitry the authors reveal. |
What is the rationale of all this? When we are sick, our body enters a quite different state- lethargic, barely motivated, apathetic, and resting. All this is fine if our immune system has things under control, uses our energy for its own needs, and returns us to health forthwith, but it is highly problematic if the illness goes on longer. This work shows in a striking and extreme way what had already been known- that prominent dopamine-driven circuits are core micro-motivational regulators in our brains. For an effective review of this area, one can watch a video by Robert Lustig, outlining at a very high level the relationship of the dopamine and serotonin systems.
 |
| Treatment of tumor-laden mice with an antibody to IL6 that reduces its activity relieves them of cachexia symptoms and significantly extends their lifespans. |
It is something that the Buddhists understood thousands of years ago, and which the Rolling Stones and the advertising industry have taken up more recently. While meditation may not grant access to the molecular and neurological details, it seems to have convinced the Buddha that we are on a treadmill of desire, always unsatisfied, always reaching out for the next thing that might bring us pleasure, but which ultimately just feeds the cycle. Controlling that desire is the surest way to avoid suffering. Nowhere is that clearer than in addiction- real, clinical addictions that are all driven by the dopamine system. No matter what your drug of choice- gambling, sugar, alcohol, cocaine, heroin- the pleasure that they give is fleeting and alerts the dopamine system to motivate the user to seek more of the same. There are a variety of dopamine pathways, including those affecting Parkinson's and reproductive functions, but the ones at issue here are the mesolimbic and mesocortical circuits, that originate in the midbrain VTA and extend respectively to the nucleus accumbens in the lower forebrain, and to the cerebral cortex. These are integrated with the rest of our cognition, enabling motivation to find the root causes of a pleasurable experience, and raise the priority of actions that repeat those root causes.
So, if you gain pleasure from playing a musical instrument, then the dopamine system will motivate you to practice more. But if you gain pleasure from cocaine, the dopamine system will motivate you to seek out a dealer, and spend your last dollar for the next fix. And then steal some more dollars. This system shows specifically the dampening behavior that is so tragic in addictions. Excess activation of dopamine-driven neurons can be lethal to those cells. So they adjust to keep activation in an acceptable range. That is, they keep you unsatisfied, in order to allow new stimuli to motivate you to adjust to new realities. No matter how much pleasure you give yourself, and especially the more intense that pleasure, it is never enough because this system always adjusts the baseline to match. One might think of dopamine as the micro-manager, always pushing for the next increment of action, no matter how much you have accomplished before, no matter how rosy or bleak the outlook. It gets us out of bed and moving through our day, from one task to the next.
In contrast, the serotonin system is the macro-manager, conveying feelings of general contentment, after a life well-lived and a series of true accomplishments. Short-circuiting this system with SSRIs like prozac carries its own set of hazards, like lack of general motivation and emotional blunting, but it does not have the risk of addiction, because serotonin, as Lustig portrays it, is an inhibitory neurotransmitter, with no risk of over-excitement. The brain does not re-set the baseline of serotonin the same way that it continually resets the baseline of dopamine.
How does all this play out in other syndromes? Depression is, like cachexia, at least in part syndrome of insufficient dopamine. Conversely, bipolar disorder in its manic phase appears to involve excess dopamine, causing hyperactivity and wildly excessive motivation, flitting from one task to the next. But what have dopamine antagonists like haloperidol and clozapine been used for most traditionally? As anti-psychotics in the treatment of schizophrenia. And that is a somewhat weird story.
Everyone knows that the medication of schizophrenia is a haphazard affair, with serious side effects and limited efficacy. A tradeoff between therapeutic effects and others that make the recipient worse off. A paper from a decade ago outlined why this may be the case- the causal issues of schizophrenia do not lie in the dopamine system at all, but in circuits far upstream. These authors suggest that ultimately schizophrenia may derive from chronic stress in early life, as do so many other mental health maladies. It is a trail of events that raise the stress hormone cortisol, which diminishes cortical inhibition of hippocampal stress responses, and specifically diminishes the GABA (another neurotransmitter) inhibitory interneurons in the hippocampus.
It is the ventral hippocampus that has a controlling influence over the VTA that in turn originates the relevant dopamine circuitry. The theory is that the ventral hippocampus sets the contextual (emotional) tone for the dopamine system, on top of which episodic stimulation takes place from other, more cognitive and perception-based sources. Over-activity of this hippocampal regulation raises the gain of the other signals, raising dopamine far more than appropriate, and also lowering it at other times. Thus treating schizophrenia with dopamine antagonists counteracts the extreme highs of the dopamine system, which in the nucleus accumbens can lead to hallucinations, delusions, paranoia, and manic activity, but it is a blunt instrument, also impairing general motivation, and further reducing cognitive, affect, parkinsonism, and other problems caused by low dopamine that occurs during schizophrenia in other systems such as the meso-cortical and the nigrostriatal dopamine pathways.
Manipulation of neurotransmitters is always going to be a rough job, since they serve diverse cells and pathways in our brains. Wikipedia routinely shows tables of binding constants for drugs (clozapine, for instance) to dozens of different neurotransmitter receptors. Each drug has its own profile, hitting some receptors more and others less, sometimes in curious, idiosyncratic patterns, and (surprisingly) across different neurotransmitter types. While some of these may occasionally hit a sweet spot, the biology and its evolutionary background has little relation to our current needs for clinical therapies, particularly when we have not yet truly plumbed the root causes of the syndromes we are trying to treat. Nor is precision medicine in the form of gene therapies or single-molecule tailored drugs necessarily the answer, since the transmitter receptors noted above are not conveniently confined to single clinical syndromes either. We may in the end need specific, implantable and computer-driven solutions or surgeries that respect the anatomical complexity of the brain.
- Thoughts about corruption.
- The Fed is extraordinarily powerful.
- But our Stable Genius is going downhill.
- The real deal with autism.
