Kaplan + Sadock's Synopsis of Psychiatry, 11e

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1.4 Neurophysiology and Neurochemistry

Numerous lines of evidence have suggested a role for nitric oxide in the regulation of sleep–wake cycles. nNOS expressing neurons occur in several areas that initiate REM sleep, including the pons, dorsal raphe nucleus, laterodorsal tegmentum, and pedunculopontine tegmentum. In animal models, microinjection of compounds that release nitric oxide result in decreased wakefulness and increased slow wave sleep. Consist- ent with this, NOS inhibitors show a trend toward decreasing slow wave and REM sleep. Studies of NOS-deficient mice suggest that nitric oxide may serve a more complex role than merely promoting sleep. nNOS- deficient animals also show reduced REM sleep; however, inducible nitric oxide synthase (iNOS)–deficient mice demonstrate the reverse, suggesting a complex interplay between NOS enzymatic isoforms. Nitric Oxide and Mood Disorders.  NOS-expressing neurons are well represented in areas implicated in depression, including the dorsal raphe nucleus and prefrontal cortex. A role for nitric oxide has been suggested in antidepressant response, as SSRI antidepressants can directly inhibit NOS activity. More- over, in animal studies such as the forced swim test, NOS and soluble guanylyl cyclase inhibitors can achieve antidepressant- like effects. Plasma nitric oxide levels were elevated in patients with bipolar disorder compared to healthy controls. However, in depressed subjects, studies have found decreased nitric oxide levels and increased plasma nitrite, a byproduct of nitric oxide. Reduced NOS has also been described in the paraventricular nucleus of patients with schizophrenia and depression com- pared to controls. Nitric oxide has been questioned as to its ability to regulate neurotransmission at serotonin, norepinephrine, and dopamine nerve termini. However, there has been no clear consensus, and nitric oxide appears to be able to increase or decrease activity at these neurons depending on the timing of its activation and the region of the brain studied. Nitric Oxide and Schizophrenia.  Nitric oxide has been investigated as a candidate molecule contributing to symptoms of schizophrenia. Two genetic studies have identified schizo- phrenia-associated single nucleotide polymorphisms (SNPs) in CAPON, a protein that associates with nNOS. SNPs in nNOS itself have been associated with schizophrenia, although others have not been able to reproduce such findings. Changes in NOS levels have been reported in postmortem brain samples of indi- viduals with schizophrenia. Abnormalities have been noted in the cortex, cerebellum, hypothalamus, and brainstem, although no specific trend can be discerned. Elevated NOS activity has been noted in platelets from drug-naive and drug-treated indi- viduals with schizophrenia. Some investigators find increased nitric oxide activity and others the reverse. In autopsy samples, schizophrenic patients were found to have abnormally localized NOS expressing neurons in the prefrontal cortex, hippocampus, and lateral temporal lobe, consistent with abnormal migration of these neuronal types during development. In a rat model, pre- natal stress led to reduced NOS expressing neurons in the fascia dentate and hippocampus. Neuropathological Roles of Nitric Oxide.  Abundant evidence exists that nitric oxide is a direct participant in a vari- ety of neuropathic events. Superoxide, a byproduct of cellular metabolism, can react with nitric oxide to form peroxynitrite (chemical formula ONOO − ). This labile and toxic compound forms chemical adducts with protein tyrosine residues, a

Neuropeptide Y (NPY) is a 36 amino acid peptide found in the hypothalamus, brainstem, spinal cord, and several limbic structures and is involved in the regulation of appetite, reward, anxiety, and energy bal- ance. NPY is colocalized with serotonergic and noradrenergic neurons and is thought to facilitate the containment of negative effects following exposure to stress. Suicide victims with a diagnosis of major depres- sion are reported to have a pronounced reduction in NPY levels in the frontal cortex and caudate nucleus. Furthermore, CSF NPY levels are decreased in depressed patients. Chronic administration of antidepres- sant drugs increases neuropeptideY concentrations in the neocortex and hippocampus in rats. Plasma NPY levels were found to be elevated in soldiers subjected to the “uncontrollable stress” of interrogation, and NPY levels were correlated with the feelings of dominance and con- fidence during the stress. In addition, low NPY response to stress has been associated with increased vulnerability to depression and PTSD. The discovery that gases could function as neurotransmit- ters revealed that highly atypical modes of signaling existed between neurons. In the early 1990s, nitric oxide was the first gas to be ascribed a neurotransmitter function and proved to be an atypical neurotransmitter for several reasons. First, it was not stored in or released from synaptic vesicles, as it was a small gas it could freely diffuse into the target neuron. Second, its tar- get was not a specific receptor on the surface of a target neu- ron, but intracellular proteins whose activity could directly be modulated by nitric oxide, leading to neurotransmission. Nitric oxide also lacks a reuptake mechanism to remove it from the synapse. Although enzymatic inactivation of it is postulated to exist, nitric oxide appears to have a very short half-life of a few seconds. Nitric oxide was initially discovered as a bactericidal com- pound released from macrophages, and as an endothelial cell it derived relaxation factor allowing for the dilation of blood vessels. A role for nitric oxide in the brain followed, revealing a role for the gas in neurotransmission, learning and memory processes, neurogenesis, and neurodegenerative disease. Nitric Oxide and Behavior Nitric oxide neurotransmission can play a role in behavior, as neuronal nitric oxide synthase (nNOS)–deficient male mice display exaggerated aggressive tendencies and increased sex- ual activity. In female mice the contrary is true, as they have reduced aggression. As manic bipolar patients may show both hypersexuality and aggression, the nitric oxide pathway may participate in the psychopathology of affective states. In the periphery, nNOS localizes to neurons that innervate blood vessels of the penis, including the corpus cavernosa. Stimulation of these nerves releases nitric oxide, leading to cyclic guanosine mono- phosphate (cGMP) formation, blood vessel wall relaxation and vaso- dilation, penile engorgement, and initial erection. The sustained phase of erection also depends on nitric oxide; turbulent blood flow leads to phosphorylation of eNOS and sustained nitric oxide production. Drugs used in treatment of erectile dysfunction—sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra)—act to inhibit phosphodi- esterase type 5 (PDE5), an enzyme that degrades cGMP in the penis (Fig. 1.4-12), thereby potentiating nitric oxide neurotransmission and penile erection. Novel Neurotransmitters Nitric Oxide