Introduction
Recall that when the action potential reaches the terminal buttons, neurotransmitters (NTs) are released; this is the means of intercellular communication. The NTs travel across the synapse and depolarize the postsynaptic cell. Such is the nature of a chemical synapse. There is also electrical synapses, in which direct electrical coupling between the membranes of adjacent neurons occurs by the way of gap junctions. Gap junctions contain channels that allow ions responsible for depolarization to flow from one cell to the next. While some electrical synapses do exist in vertebrates (mostly at dendrodendritic synapses), their role is poorly understood and so the mechanisms for chemical synapses are the focus of this module.
The effect of a neurotransmitter (either an excitatory or an inhibitory influence on the post synaptic cell, i.e. EPSP or IPSP) can not be determined independently of the receptors available for binding on the target site. This point explains why some NTs have different effects in different areas of the brain.
Related to neurotransmitters are neuromodulators. These substances are essentially long distance NTs which regulate various behavioral and mood states. Neuromodulators are not restricted to the synaptic cleft and may activate neuron receptors not located at the synapse (as well as synaptic receptors). When a neuromodulator travels to other organs via the bloodstream it is more commonly referred to as a hormone. Besides the range distinctions between transmitters and modulators/hormones, there is also a temporal one: NTs have a very short latency before action and their effects are soon reversible, whereas modulators/hormones have long latency and long periods of influence.
The first person to show that there are neurotransmitters in the brain was Otto Loewi in the 1920's. He took the heart out of an animal (specifically a pig) leaving the vagus nerve intact, and placed it in a petri dish. He then stimulated the vagus nerve to demonstrate that with a raise in heart rate the vagus nerve will release the substance acetylcholine, inhibiting the heart. He then transferred the surroundings from the first petri dish to a second for testing with no stimulation.
Neurotransmitters are released by the presynaptic cell's terminal boutons when an action potential occurs in that cell. The NT molecules are emptied from their storage sites, called vesicles, through exocytosis into the synaptic cleft where they diffuse over a very short distance to where the post-synaptic cell's dendrite, axon or soma (synapses can involve any of the three). The vesicles serve to facilitate transportation of the NTs within the neuron and protect them from intracellular degradative enzymes. Appropriate levels of NT at the receptor sites may then induce a response of either an excitatory or an inhibitory nature on the target cell. Formally, there are five commonly accepted criteria that must be satisfied for a substance to be regarded as a NT. First :the substance has to be present at the terminal bouton. Second: the neuron must be able to synthesize the substance. Most 'NTs are manufactured in the cell body and then transported to the boutons in vesicles that hold them, where they wait for a signal, the action potential, to be emptied. The third: the substance is released when the action potential reaches the terminal bouton. Electrical signals as opposed to changes in temperature or pH are required for release. Ca2+ influx, as witnessed during the post AP depolarization phase, is the factor controlling transmitter release through exocytosis of the vesicles with the cell membrane. Fourth:a physiological response from the post synaptic cell must be elicited by the substance. Either an EPSP or IPSP must be observed. Often, a NT will effect not only the post-synaptic cell but also the pre-synaptic cell by way of feedback to its autoreceptors. This feedback is generally of an inhibitory nature and is necessary for avoiding overexpenditure of a NT for a given fining. Fifth: the substance's induced response must have a mechanism for termination. The autoreceptors described above help prevent the pre-synaptic cell from releasing NTs longer than is needed. What about the NTs that have already been released- how do they get inactivated? Most synapses employ two strategies. First, there is chemical deactivation in which other chemicals in the gap may deactivate the NT. Second, the pre-synaptic cell may use a reuptake mechanism that brings the molecules in question back into the terminal button so that they may be used again later (See figure 7.1).
There are molecules that can act like neurotransmitters, agonists, or inhibit the activity of NTs called antagonists. An agonist is any chemical substance which binds to the receptors of a NT and has the same effect as the NT. An antagonist is a substance which binds to the receptor but has a blocking effect on the response.
The brain has over 100 types of neurotransmitters. Why so many? Evidence has mounted in support of three theories. One is that EPSPs and IPSPs are not all the same; there are functional advantages to having some post-synaptic influences persist and others be transient. Thus, there is a need for some NTs that are longer acting than others. There is also an evolutionary explanation, which simply states that over the course of time the brain has introduced new and more complex NTs while retaining the older and simpler ones (presumably, for those older and more primitive functions). Lastly, the brain shows a great deal of specialization. The different systems of the brain perform their services in different ways, which could conceivably justify having different NTs of preference for each system.
Despite the abundance of different NT molecular structures that have been observed, there are only three categories, or families, of NTs: amino acids, biogenic amines, and neuropeptides. These NT families are found in concentrations of micromolar (10-6 M), nanomolar (10-9 M), and picomolar (1012 M) quantities respectively. Reviewing the functional properties of each of these three NT categories will suggest things about how the CNS subsystems associated with each operate.
NTs may express their effects via one of two messenger systems. Using the first messenger system (ionotropic receptors), NTs bind directly to a receptor, causing a change in an associated ion channel's permeability in the cell's membrane, i.e. allowing Na+ channels to open so that depolarization takes place. The first messenger system is fast because it is direct.
The ion channels opened by the first messenger system in the postsynaptic cell depend on part on the concentration of NT present as does the magnitude of the resulting depolarization. Generally, small concentrations open only Na+ channels while larger concentrations open both the Na+ and Ca++ channels.
An important example of dual channel type usage occurs when K/Q receptors and NMDA receptors are simultaneously bound to by glutamate. The Na+ channels are opened by binding to the K/Q receptors; the Ca++ channels open when the NT binds to an NMDA receptor, resulting in that channel's releasing a blocker Mg++ and thereby opening up. What's the functional advantage of having two channels in this example? The NMDA channel opens only when there is an excess of NT, such that the K/Q channels are already opened. Therefore, the NMDA channels open when the cell is already excited to begin with. The inflow of Ca++ to a cell that is depolarized induces certain lasting changes in the membrane's potential and response behavior---long term potentiation, or LTP, which is believed to be necessary for the creation of memory. (Note that a long term potentiation occurs despite the short durations of first messenger system NTs; the action of the transmitters is quick and brief but the result of having the two charnels open simultaneously is a physiological change in the cell that will last for a long term.) More will be said about LTP in the hippocampus module.
NTs that use the first messenger system are referred to as classical neurotransmitters. These transmitters have unconditioned effects in that their straightforward actions do not depend on the presence of other NTs. ("Classical" and "unconditional effects" may be taken as synonyms, but neither is a synonym with "the first messenger system" since it is possible to have these effects with the other messenger system, as will be made clear next.)
The second messenger system (metabotropic receptors), also requires binding between a NT and a receptor, however the receptor is not directly coupled to the ion channel. After the NT binds to the receptor, a G protein, located between the receptor and the channel, activates an enzyme that converts a substrate into a second messenger (the NT was the first messenger). Generally, that substrate is ATP, or adenosine triphosphate, and the second messenger is cyclic adenosine monophosphate, or cAMP. The phosphates lost by ATP go to the proteins that make up the ion gates; the gates become phosphorylated. It is the interactions between the cAMP and the membrane's proteins along with the phosphorylation of those proteins which finally opens the ion channels. The second messenger system takes considerably longer because of the additional reaction sequences it requires. It also exhibits its influence over a longer period of time.
Modulatory effects, when they arise, are associated with the second messenger system. It is possible for this system to have non-modulatory/classical effects, like the first messenger system, however second messenger systems are generally associated with modulatory actions. These modulatory effects result from a NT's ability to influence the actions of other NTs. Thus, a NT using a second messenger mechanism to elicit modulatory NT effects is said to be conditional since the actions of the modulating NT must require the presence of another NT to be modulated. Those NTs behaving conditionally are nonclassical (these terms are synonyms). NTs producing modulatory effects are more commonly called neuromodulators. Modulatory actions would seem to be necessary if a system were to alter the focus or intensity of normally occurring function. Thus, one would expect mood and arousal states to involve the second messenger system.
It is important to remember that the initial ions that either messenger system allow to flow in represent the fluctuations in voltage associated with the "summation of NT phase" and not with the depolarization phase: the AP occurs when many more Na+ channels open after the Na+ ions let In by the messengers systems succeed in perturbing the membrane's potential to the threshold value.
The amino acid NTs are referred to as classical/unconditional NTs and typically use the more straightforward first messenger system. Biogenic amines use the second messenger system, and thus are capable of both modulatory/conditional and classical/unconditional effects, although the former actions are significantly more common with them. Neuropeptides have been shown to use both first and second messenger systems; since their time course generally is intermediate to classical and modulatory NTs and since one type of action (classical/unconditional vs. modulatory/conditional) is not observed more frequently than the other, they are best regarded as a distinct class of their own as opposed to predominantly class) cal or modulatory.
Amino acids are the building blocks of proteins, but in the present context only single molecules of a given amino acid are used. The amino acid NTs and their effects (excitatory +, inhibitory -) are: glutamate (+), GABA (-), glycine (-), and aspartane (+). The receptors associated with the amino acids NTs are the NMDA, Q (Quisqualate), K (Kainate), and the GABAa and GABAb receptors. The amino acids are classical, first messenger NTs. Because they are classical, we can expect the effect of any one of them (+/-) to always be the same. Because they use the first messenger system, we can expect their effects to occur very quickly, to have short durations, and to be unconditional. The amino acid NTs are the ones most commonly found in the cortex, and therefore can be associated with the hierarchical circuit design characteristic of this brain region.
The biogenic amines, also known as monoamines, NTs are norepinephrine (NE), dopamine (DA), acetylcholine (ACh), and serotonin (5-Ht). These NTs use the secondary messenger system, and therefore are capable of both modulatory and classical effects, although both the former is more common. Biogenic amine transmitter actions depend on the receptors present, and each NT of this class is associated with its own receptor types. Acetylcholine binds to both muscarinic and nicotinic receptor types; the effect is excitatory for muscarinic and inhibitory for nicotinic. Norepinephrine binds to alpha and beta receptors, producing an inhibitory effect with each type. Dopamine and serotonin are also inhibitory NTs binding to D1-D5 and S1, S2 receptor types respectively.
The chlorinergic system (consisting of the circuits of cells using acetylcholine) provides a good example of how second messenger NT may be either modulatory or classical in effect. When the receptors involved are muscarinic, the actions are conditional; when the nicotinic receptors are used, unconditional actions occur.
Biogenic amines are slow acting but have long durations. They are associated with single-source divergent circuits since those are the designs that enable a single cell to influence many others as would be needed if the source cell were responsive for modulating the activity levels of the target cells. Therefore, areas concerned with controlling levels of alertness, arousal and mood could be expected to be influenced by biogenic amines. The locus ceruleus is one example of a nucleus involved in these general functions, and in fact it makes extensive use of the biogenic amines. The locus ceruleus, located in the brainstem, contains only a few thousand cells but still manages to contact virtually the entire brain so as to control our arousal states, a testament to the resourcefulness of the single-source divergent design. Further evidence that these transmitters are involved in mood states comes from scientific literature on psychoactive drugs, where support is mounting for theories of how the effects of such drugs are mediated via the biogenic amine NTs.
The neuropeptide receptors are endorphins, vasonessin, substance P, CCK, CRF, and VIP. These NTs can elicit either excitatory or inhibitory effects with the following receptor types: mu, sigma, kappa, epsilon, and delta. The neuropeptides are capable both classical and modulatory effects, occurring with roughly equal frequency, over a characteristically intermediate time course. They are associated with local circuits and so are found in cells with short axons, their effects being localized to the immediate area.
It is possible for a cell to use or express two types of neurotransmtters. Dale's principle states, incorrectly, that a neuron is capable of releasing only one type NT at all its terminals and that if the NT is released at one site, then it will be released at all sites. It is known, however that co-localization can take place between a neuropeptide and either a biogenic amine or an amino acid, a situation in which the same cell is releasing two distinct NTs, with each release being independent. This is possible because either the AP does travel to all ends but the receptors have different sensitivities or the branches have different diameters which determines the path of the AP.