3 курс / Фармакология / Essential_Psychopharmacology_2nd_edition

FIGURE 5 — 64. The monoamine hypothesis of gene action in depression, part 2. If BDNF is no longer made in appropriate amounts, instead of the neuron prospering and developing more and more synapses (right), stress causes vulnerable neurons in the hippocampus to atrophy and possibly undergo apoptosis when their neurotrophic factor is cut off (left). This, in turn, leads to depression and to the consequences of repeated depressive episodes, namely, more and more episodes and less and less responsiveness to treatment. This may explain why hippocampal neurons seem to be decreased in size and impaired in function during depression on the basis of recent clinical neuroimaging studies.

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FIGURE 5 — 65. Classically, substance P was thought to be involved in the pain response because it is released from neurons in peripheral tissues in response to inflammation, causing "neurogenic" inflammation and pain. Furthermore, substance P is present in spinal pain pathways, which suggests a role in central nervous system—medicated pain. Unfortunately, however, antagonists to substance P's receptors were unable to reduce neurogenic inflammation or pain of many types in human testing.

drugs might be effective in reducing emotional distress has nevertheless spawned a race to find antagonists for all three of the known neurokinins to see if they would have therapeutic actions in a wide variety of psychiatric disorders. Substance P and its related neurokinins are present in areas of the brain such as the amygdala that are thought to be critical for regulating emotions (Fig. 5—66). The neurokinins are also present in areas of the brain rich with monoamines, which suggests a potential regulatory role of neurokinins for monoamine neurotransmitters already known to be important in numerous psychiatric disorders and in the mechanisms of action of numerous psychotropic drugs. Thus, antagonists to all three important neurokinins are currently in clinical testing of various states of emotional dysfunction, including depression, anxiety, and schizophrenia. Over the next few years it should become apparent whether this strategy can be exploited to generate truly novel psychotropic drugs acting on an entirely new neurotransmitter system, namely, the neurokinins.

FIGURE 5-66. Substance P and its related neurokinins are present in areas of the brain such as the amygdala that are thought to be critical for regulating emotions. The neurokinins are also present in areas of the brain rich in monoamines, which suggests a potential regulatory role of monoamine neurotransmitters, which are already known to be important in numerous psychiatric disorders and in the mechanisms of action of numerous psychotropic drugs.

Substance P and neurokinin 1 receptors. The first neurokinin was discovered in the 1930s in extracts of brain or intestine. Since it was prepared as a "powder," it was called substance P. This molecule is now known to be a string of 11 amino acids (an undecapeptide) (Fig. 5—67). This is in sharp contrast to monoamine neurotransmitters, which are modifications of a single amino acid.

The following are some of the differences between the synthesis of neurotransmitter by a monoaminergic neuron and by a peptidergic neuron. Whereas monoamines are made from dietary amino acids, peptide neurotransmitters are made from proteins that are direct gene products. However, genes are not translated directly into peptide neurotransmitters but into precursors of the peptide neurotransmitters. These precursors are sometimes called "grandparent" proteins, or pre-propeptides. Further modifications convert these grandparent proteins into the direct precursors of peptide neurotransmitters, sometimes called the "parents" of the neuropeptide, or the propeptides. Finally, modifications of the parental peptide produces the neuropeptide progeny itself.

For neurons utilizing substance P, synthesis starts with the gene called preprotachykinin A (PPT-A) (Fig. 5—68). This gene is transcribed into RNA, which is then "edited," or revised by cutting and pasting, like revising a manuscript or a

FIGURE 5-67. Shown here are the amino acid sequences for the three neurokinins substance P, neurokinin A (NK-A) and neurokinin B (NK-B). Substance P has 11 amino acid units and NK-A and NK-B each have 10. Several of the amino acids are the same in these three peptides.

FIGURE 5 — 68. Substance P neurons and neurokinin 1 receptors, part 1. For neurons utilizing substance P, synthesis starts with the gene called pre-protachykinin A (PPT-A). This gene is transcribed into RNA, which is then "edited" to form three alternative mRNA splice variants, alpha, beta, and gamma. The actions of the mRNA version called alpha-PPT-A mRNA are shown here. This mRNA is then transcribed into a protein called alpha-PPT-A, which is substance P's "grandparent." It is converted in the endoplasmic reticulum into the "parent" of substance P, called protachykinin A (alpha-PT-A). Finally, this protein is clipped even shorter by another enzyme, called a converting enzyme, in the synaptic vesicle and forms substance P itself.

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videotape. Thus, this process is sometimes called "splicing" of the RNA. This leads to different versions of RNA called alternative mRNA splice variants.

The mRNA version called alpha-PPT-A mRNA goes on to be transcribed into a protein called alpha-PPT-A, which is substance P's grandparent (Fig. 5—68). It is much longer than substance P itself, as it contains a longer string of amino acids. The alpha-PPT-A grandparent protein needs to be cut down to size by an enzyme in the endoplasmic reticulum called a signal peptidase. Thus, pro-tachykinin A (alpha- PT-A) protein is formed, the parent of substance P. Finally, alpha PT-A is clipped even shorter by another enzyme in the synaptic vesicle called a converting enzyme, and forms substance P itself (Fig. 5 — 68).

Substance P can also be formed from two other proteins, called beta-PPT-A and gamma PPT-A (Figs. 5—69 and 5—70). These proteins come from different mRNA splice variants, but the same precursor PPT-A gene. Not only can substance P be formed from these proteins, but so can another important neurokinin, called neurokinin A (NK-A) (Figs. 5-71 and 5-72). Thus, substance P can be formed from three proteins derived from the PPT-A gene, namely, alpha, beta, and gamma PPT-A (Figs. 5-68 to 5-70), and NK-A can be formed from two of these, beta and gamma PPT-A (Figs. 5-71 and 5-72).

Substance P is released from neurons and prefers to interact selectively with the neurokinin 1 (NK-1) subtype of neurokinin receptor (Figs. 5-68 to 5—70). Inter-

FIGURE 5-69. Substance P and neurokinin 1 receptors, part 2. Substance P can also be formed from two other proteins, called beta-PPT-A, shown here, and gamma PPT-A, shown in Figure 5 — 70. These proteins come from different mRNA splice variants but the same precursor PPT-A gene.

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FIGURE 5—70. Substance P and neurokinin 1 receptors, part 3. Shown here is how substance P is formed from gamma PPT-A. Thus, substance P can be formed from three proteins derived from the PPT-A gene, namely, alpha, beta, and gamma PPT-A (see also Figs. 5 — 68 and 5 — 69). When substance P is released from neurons, it prefers to interact selectively with the neurokinin 1 subtype of neurokinin receptor (Figs. 5—68 to 5 — 70). However, there is a mismatch in the brain between the locations of substance P and the NK-1 receptors, suggesting that substance P acts preferentially by volume neurotransmission at sites remote from its axon terminals rather than by classical synaptic neurotransmission.

estingly, however, there is a bit of a mismatch in the brain between where substance P is located and where the NK-1 receptors are located. This may suggest that substance P acts preferentially by volume neurotransmission at sites remote from its axon terminals rather than by classical synaptic neurotransmission.

Neurokinin A and neurokinin 2 receptors. Neurokinin A (NK-A) is another member of the neurokinin family of peptide neurotransmitters. It is a peptide containing 10 amino acid units (decapeptide), with 5 amino acid units the same as in substance P, including 4 of the last 5 on its N-terminal tail (Fig. 5 — 67). As mentioned above, it is formed both from the beta and the gamma PPT-A proteins derived from the PPT-A gene (Figs. 5—71 and 5—72). The beta and gamma PPT-A proteins are the grandparents of NK-A and are cut down to size just as described for substance P, eventually forming the peptide neurotransmitter NK-A.

This neurokinin prefers a different receptor than does substance P. Thus, NK-A specifically binds the NK-2 receptor (Figs. 5—71 and 5—72). There are few NK-A receptors in the brain of rats, so the guinea pig is a closer model to humans, with

FIGURE 5 — 71. Neurokinin A and neurokinin 2 receptors, part 1. Neurokinin A can be formed from two of the same proteins that form substance P, namely beta and gamma PPT-A. The formation of neurokinin A from beta PPT-A is shown here.

NK-A receptors also in peripheral tissues such as the lung. As for substance P, there is a mismatch between the neurotransmitter and its receptor anatomically, which suggests the important role of nonsynaptic volume neurotransmission for NK-A as well. However, the anatomical distribution of NK-A is different from that of substance P, and the anatomical distribution of NK-2 receptors is different from that of NK-1 receptors.

Neurokinin B and neurokinin B receptors. The third important member of the neurokinin neurotransmitter family is neurokinin B (NK-B). Like NK-A, it is a ten amino acid peptide (decapeptide). Six of the ten amino acids in NK-B are the same as in NK-A, and four of the last five amino acids in the N-terminal tail of NK-B are identical to substance P (Fig. 5—67).

Neurokinin B is formed from a gene called PPT-B, which is different from that from which substance P and NK-A are derived. However, the process of converting the PPT-B protein into NK-B is analogous to that already described for substance P and NK-A (Fig. 5 — 73). NK-B prefers its own unique receptors, called NK-3 receptors (Fig. 5—73). Neurokinin B and its NK-3 receptors are also mismatched, and in different anatomical areas from substance P, NK-A, and their NK-1 and NK-2 receptors, respectively.

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FIGURE 5 — 72. Neurokinin A and neurokinin 2 receptors, part 2. Shown here is the formation of

NK-A from the gamma PPT-A protein. The beta and gamma PPT-A proteins are the "grandparents" of NK-A and are cut down to size just as described for substance P, eventually forming the peptide neurotransmitter NK-A. Neurokinin A specifically binds to the NK-2 receptor. As for substance P, there is a mismatch between this neurotransmitter and its receptor anatomically, suggesting the important role of nonsynaptic volume neurotransmission for NK-A as well. However, the anatomical distribution of NK-A is different from that of substance P, and the anatomical distribution of NK-2 receptors is different from that of NK-1 receptors.

Summary

In this chapter we have introduced two major psychopharmacological themes, namely, the affective disorders and the monoamine and neuropeptide neurotransmitters. We have described the clinical features, epidemiology, and longitudinal course of various types of depression, including the impact that treatments are having on the long-term outcome of affective disorders. We have also described the three monoamine neurotransmitter systems—noradrenergic, dopaminergic, and seroto-nergic. Specifically, the synthesis, metabolism, transport systems, and receptors for each monoaminergic system have been outlined and then applied to the leading theories for the biological basis of depression. These theories of depression are the monoamine hypothesis, the neurotransmitter hypothesis, and the pseudomonoamine hypothesis of defective signal transduction and gene expression. Finally, we have introduced a new family of neurotransmitters and their receptors, called neurokinins, of which substance P is the most prominent member.

FIGURE 5—73. Neurokinin B and neurokinin 3 receptors. The third important member of the neurokinin neurotransmitter family is NK-B, which is formed from a gene, called PPT-B, which is different from the gene from which either substance P or NK-A is derived. However, the process of converting the PPT-B protein into NK-B is analogous to that already described for substance P and NK-A. Neurokinin B prefers its own unique receptors, called NK-3 receptors. Neurokinin B and its NK-3 receptors are also mismatched and are located in different anatomical areas from substance P, NK-A, and their NK-1 and NK-2 receptors, respectively.

The material in this chapter should provide the reader with the basis for understanding the pharmacologic basis of the treatment of depression discussed in the following two chapters. It should also provide useful background information about the monoamine neurotransmitter systems that serve as the pharmacological basis for several other classes of psychotropic drugs.