It is natural for us to think of the brain as a large computational device that processes information analogously to a computer. In this view, which we like to call the electrophysiological point of view, the basic elements are the neurons that receive inputs from other neurons and, via action potentials, send information to other neurons. There are then two fundamental classes of biological (and mathematical) questions. How do individual neurons receive and process their inputs and decide when to fire? How do connected sets of neurons perform information processing functions that individual neurons cannot do? The electrophysiological point of view is natural for two reasons. First, we have had great success in building computational machines and we understand completely how they work. If brains are like our computational devices then we can use computational algorithms as metaphors and examples of what must be going on in the brain. Secondly, the electrophysiological point of view fits well with our modern scientific method of trying to understand complex behavior in the large as merely the interaction of many fundamental parts (the neurons) whose behavior we understand very well. The electrophysiological point of view is perfect for mathematical analysis and computation. One need not deal with the messy details of cell biology, the existence of more than 50 identified neurotransmitters, changing gene expression levels, the influence of the endocrine system, or the fact that neurons come in a bewildering variety of different morphological and physiological types. All of these things appear, if they appear at all, as parameters in models of neurons, or as parameters in local or global network simulations. In particular, the chemistry of neurotransmitters themselves is not very important, since their only role is to help the electrophysiological brain transmit information from one neuron to the next.
There is a different point of view that we call the pharmacological view of the brain. It has been known for a long time that not all neurons are engaged in the one-to-one transfer of information to other neurons. Instead, groups of neurons that have the same neurotransmitter can project densely to a distant volume (a nucleus or part of a nucleus) in the brain and when they fire they increase the concentration of the neurotransmitter in the extracellular space in the distant volume. This increased concentration modulates the electrophysiological neural transmission in the distant region by binding to receptors on the cells in the target region. This kind of neural activity is called volume transmission. It is also called neuromodulation because the effect of the neurotransmitter is not one-to-one neural transmission but instead the modulation of other transmitters that are involved in one-to-one transmission. Some examples of volume transmission are the dopaminergic projection to the striatum in the basal ganglia from the cells of the substantial nigra pars compacta (SNc) and the serotonergic projection to the striatum from the dorsal raphe nucleus (DRN). Projections of norepinepherine (NE) neurons from the locus coeruleus to the cortex play an important role in initiating and maintaining wakefulness. This cell group globally innervates large parts of the brain and the spinal cord and gives rise to fine varicose NE terminal networks of low to moderate densities present all over the cerebral and cerebellar cortices.
There are many pieces of evidence that suggest that volume transmission plays a fundamental role in the functioning of the brain. Dopamine (DA) has been linked to fundamental brain functions such as motivation, pleasure, cognition, memory, learning, and fine motor control, as well as social phobia, Tourette’s syndrome, Parkinson’s disease, schizophrenia, and attention deficit hyperactivity disorder. In most experiments it is the concentration of dopamine in a particular nucleus that is important. Similarly, serotonin (5HT) has been linked to feeding and body weight regulation, aggression and suicidality, social hierarchies, obsessive compulsive disorder, alcoholism, anxiety disorders, and affective disorders such as depression. Many pharmaceutical drugs and recreational drugs have been shown to act by binding to certain receptors and thus changing the local concentrations of various neurotransmitters in regions of the brain. For example, the immediate effect of selective serotonin reuptake inhibitors (SSRIs) is to inhibit the reuptake of 5HT after it has been released thus increasing its concentration in the extracellular space in certain brain regions. Adenosine is an important neuromodulator. Caffeine binds to adenosine receptors and cocaine blocks the reuptake of DA, 5HT, and norepinepherine.
Furthermore, various morphological and physiological features of the brain are consistent within the idea that the purpose of some neurons is to change the local biochemistry at distant regions of the brain. Often the projections are dense in the target volume suggesting that the idea is to change the local concentration at all parts of the target region simultaneously by the same amount. There are 50 or more types of receptors for 5HT in the brain, suggesting that this great variety allows the concentration of 5HT to modulate neurons in different ways depending on what receptors they express. The 5HT neurons in the dorsal raphe nucleus (DRN) have very thin unmyelinated axons and release 5HT from many small varicosities rather than synapses, suggesting that their purpose is not one-to-one neural transmission. 5HT neurons in different parts of the DRN project to many different brain regions that frequently project back, suggesting that the DRN is differentially changing the local biochemistry in many distinct regions. There is a long list of different DA receptors. For example, in the striatum, the DA projections from the SNc inhibit medium spiny neurons in the indirect pathway by binding to D2 receptors while the same neurons excite medium spiny neurons in the direct pathway by binding to D1 receptors.
Notice that what is important in volume transmission is that local groups of neurons project to distant nuclei and change the local biochemistry there. That is, they project changes in biochemistry over long distances. Of course they do this by firing action potentials. But the action potentials do not carry information in the usual sense; their only purpose is to allow the neurons to project biochemistry over long distances. This is the pharmacological view of the brain. To understand the brain one must understand both the electrophysiology and the pharmacology, and how they affect each other.
For an excellent review of volume transmission with a historical perspective and many examples, see:
Fuxe, A. B. Dahlstrom, G. Jonsson, D. Marcellino, M. Guescini, M. Dam, P. Manger, L. Agnati. The discovery of central monoamine neurons gave volume transmission to the wired brain. Prog. Neurobiol., 90(2010), 82–100.
