3.3 Neurotransmitters Made from Fats

Synthesis

The two currently best studied endocannabinoid neurotransmitters (there are at least seven) are anandamide and 2-AG (2-arachidonoyl-glycerol); 2-AG occurs at much higher levels in the brain than anandamide (Lu and Mackie, 2016). The production, synthesis and release of anandamide and 2-AG occur independently within the cell, suggesting that 2-AG and anandamide can be recruited differentially from the same postsynaptic neuron depending on the type of presynaptic signaling. The synthesis of both endocannabinoid neurotransmitters begins with phospholipid components of the neural membrane (Figure 3.21). Diacylglycerol (DAG) is produced first followed by enzymatic conversion into 2-AG via the enzyme diacylglycerol lipase (DAGL). A different membrane phospholipid is converted into N-arachidonoyl phosphatidylethanolamine (NAPE) which is then enzymatically converted into anandamide by the enzyme phospholipase D (PLD).

Figure 3.21 Synthesis of arachidonic acid and prostaglandins

Unlike the other neurotransmitters discussed thus far, these two endocannabinoids are not stored in synaptic vesicles. The depolarization of a postsynaptic neuron leads to Ca2+ influx through voltage-gated channels and causes the enzymatic de novo generation and the release of endocannabinoids such as anandamide. Once produced they are released to flow in reverse direction (retrograde neurotransmission) across the synapse to find their receptors on the pre-synaptic side of the synapse (Figure 3.22).

Figure 3.22 Retrograde neurotransmission Retrograde neurotransmitters are not packaged in vesicles. Instead, they are released by the postsynaptic cell and signal on receptors on the presynaptic cell.

Receptors

Two different types of endocannabinoid receptors are located throughout the brain and body. Anandamide binds best to CB1 receptors, while 2-AG binds best with the CB2 receptors (Figure 3.23).

Figure 3.23 Function of endocannabinoid receptors

The type 1 receptors are densely distributed in several brain regions; the type 2 receptor is found at much lower levels in the brain. The type 1 receptor is among the most abundant G protein–coupled receptors in the brain. Anandamide and 2-AG also prevent the release of both glutamate and GABA, thus altering the balance of excitation and inhibition throughout the brain.

Inactivation of endocannabinoids

Anandamide is inactivated by either reuptake or catabolism by the enzyme fatty acid amide hydrolase (FAAH). 2-AG is inactivated by either reuptake or sequential catabolism by both FAAH and monoacylglycerol lipase (MAGL). The major product of this catabolism is arachidonic acid, which can be used to produce prostaglandins (see next section).

The functions of endocannabinoids

At the synaptic level, anandamide and 2-AG act retrogradely on pre-synaptic receptors to inhibit the release of a variety of neurotransmitters by altering the function of potassium and voltage-gated calcium channels. At the systems level, endocannabinoids influence appetite, mood, stress reduction, and the brain’s inflammatory response. The endocannabinoids enhance goal-seeking behaviors by augmenting the actions of dopamine within the brain’s pleasure centers in the ventral forebrain.

Synthesis

Prostaglandins are synthesized from the fatty acid arachidonic acid via the enzyme cyclooxygenase (COX). Every prostaglandin contains 20 carbon atoms that includes a single 5-carbon ring. They are found throughout the body and brain. Like the endocannabinoids, prostaglandins are not stored in vesicles; they are produced on demand when they are needed and then released into the extracellular space via a specific protein transporter. Prostaglandins are not reused by the neurons. Prostaglandins are oxidized by NAD+-dependent 15-hydroxyprostaglandin dehydrogenase and then reduced by NADPH/NADH dependent delta13-15-ketoprostaglandin reductase.

Functions of prostaglandins

The variety of prostaglandins that exist and their wide distribution in the brain underlies their variety of functions. Glia release prostaglandins to activate pro-inflammatory cascades. Some prostaglandins are neuroprotective from the effects of hypoxia or ischemia. The sexual differentiation of the brain may depend on the actions of prostaglandins. Acutely, fever-producing agents induce the production of prostaglandins in the hypothalamus, altering body temperature regulation. In contrast, chronic inflammatory processes associated with prostaglandins may underlie the development of depression (Regulska et al., 2021). Generally, the level of most prostaglandins is kept quite low in the brain.

Synthesis

Acetylcholine (commonly abbreviated ACh) is made by transferring a molecule of acetic acid on to a molecule of choline that is derived from the fatty acid lecithin (steps 1 and 2 in Figure 3.24). This conversion occurs via the action of an enzyme called choline acetyltransferase (Picciotto et al., 2012). The acetyl is derived from a molecule of sugar, usually glucose, that is initially modified inside the mitochondria. The brain needs sugar (usually in the form of glucose) to function normally. Once inside the brain, only a very small percentage of the dietary sugar is used to produce acetylcholine. The brain typically has a constant and ample supply of choline. Choline can be easily obtained from the diet, such as from eggs and baked goods. Despite this fact, many health foods stores sell choline powder to gullible customers, claiming that consuming more choline will somehow enable their brains to make more acetylcholine. Given the vital role of acetylcholine in learning and memory, this is an appealing claim. Regrettably, it has no basis in fact. For adults, the brain responds only to deficits in choline, not surpluses, in the diet. It has a ready source of choline in the diet or stored in the liver and, in fact, never develops a deficit in choline, even in patients with Alzheimer’s disease. Thus, consuming extra choline does not induce your brain to make more acetylcholine. Instead, it only results in a gaseous by-product that you exhale and that smells like rotting fish. Rather than enhancing your cognitive abilities, choline supplements merely generate a terrible case of bad breath.

Once acetylcholine is produced, it is transported into synaptic vesicles (step 3 in Figure 3.24). The vesicles containing acetylcholine fuse with the presynaptic membrane of the axon terminal in response to an action potential (step 4 in Figure 3.24). Each vesicle releases about 10,000 acetylcholine molecules into the synapse. Some of these acetylcholine molecules will bind to protein receptors on the surface of the nearby neuron (step 5 in Figure 3.24). Ultimately, all of them are inactivated by an enzyme.

Figure 3.24 Acetylcholine lifecycle

Inactivation of Acetylcholine

Released acetylcholine molecules are quickly inactivated by the enzyme acetylcholinesterase (step 7 in Figure 3.24). Acetylcholinesterase has one of the fastest reaction rates of any of our enzymes, breaking up each molecule in about 80 microseconds (Taylor, 1991). Acetylcholinesterase breaks the acetylcholine into a molecule of acetate and choline. About forty percent of the choline will be reabsorbed into the axon terminal by specialized transport proteins and reused to produce more acetylcholine (step 8 in Figure 3.24). The remaining choline molecules and acetate will diffuse into the extracellular space and ultimately be removed from the brain. Knowledge about the chemistry and function of acetylcholinesterase led to the development of drugs that inhibit the enzyme acetylcholinesterase and greatly increase the amount of acetylcholine in the synapse. Today, acetylcholinesterase inhibitors are common treatments for Alzheimer’s disease. In theory, the drugs should compensate for the loss of acetylcholine neurons in these patients; in practice, the drugs provide little clinical benefit because too few healthy acetylcholine neurons are still present in the brain.

Receptors

Once released into the synapse, the neurotransmitter acetylcholine can act on two quite different protein receptors that have been designated, as have most receptors, according to the compounds that were originally used to study them—in this case, muscarine and nicotine (Figure 3.25).

Figure 3.25 ACh channels

Most of the acetylcholine receptors in the brain are the muscarinic subtype, whereas less than 10% are nicotinic. They differ in size, structure, and mechanism of action; yet they both respond to acetylcholine. Nicotinic acetylcholine receptors are simple ligand-gated fast-opening ion channels that are also responsive to nicotine. Most of the nicotine receptors in the body live in the neuromuscular junction (see Chapter 10 Motor Control). Nicotine receptors allow the passage of sodium, potassium or calcium ions and typically produce depolarization. Muscarinic acetylcholine receptors are G-protein-linked receptors that activate other ionic channels via a second messenger cascade. These receptors are responsive to muscarine and can produce either depolarization or hyperpolarization depending on the nature of the ionic channel linked to the G-protein complex.

The functions of acetylcholine

Within the human brain are numerous acetylcholine pathways that influence the function of the cortex, hippocampus, and many other subcortical regions (Figure 3.26).

Figure 3.26 Acetylcholine system anatomy

Within these various regions, the actions of acetylcholine enable you to learn and remember, to regulate your attention and mood, and to control how well you can move. Thus, anything that affects the function of acetylcholine neurons has the potential to affect all these brain functions. Sometimes we can learn much about the role of a particular neurotransmitter system by investigating what happens when it is injured or diseased. In the brains of people with Alzheimer’s disease, for example, acetylcholine neurons that project into the hippocampus and cortex degenerate. The loss of normal acetylcholine function in the cortex may be why patients with Alzheimer’s disease have difficulty paying attention to their environment. The loss of acetylcholine projections into the hippocampus may underlie the profoundly debilitating memory loss that is the hallmark of this disease (see Chapter 18 Learning and Memory).