Neurochemistry 2

Serotonin

Serotonin, an indolamine, plays a role in mood, sleep,pain sensitivity, appetite, sexuality, and impulse control
tryptophan is converted to serotonin (5-hydroxytryptamine) by the enzyme tryptophan hydroxylase as well as by an amino acid decarboxylase.
It catalyzed by MAO to 5-HIAA
5-HT may be inactivated by reuptake into the presynaptic neuron(TCAD &SSRI inhibit this process).

most serotonergic cell bodies in the brain are located in the dorsal raphe nucleus in the upper pons and lower midbrain
there more than 11 different type of 5-HT receptors.the predominant action of 5-HT on receptors is inhibition.

Increased brain serotonin concentrations are associated with positive effects like improved mood and sleep, as well as negative effects like decreased sexual function (particularly delayed orgasm) and, in high concentrations, psychotic symptoms(atypical antipschotic act on this)

Decreased serotonin availability is associated with depression of mood, poor impulse control, violent behavior, alcoholism, chronic pain syndromes, sleep disorders, and anxiety disorders like OCD.
Through different mechanisms, all antidepressant medications currently in use increase the availability of serotonin and other biogenic amines in the synaptic cleft

Acetylcholine

Acetylcholine is used by nerve-skeleton-muscle junctions.
Cholinergic neurons synthesize ACh from acetyl coenzyme A and choline using the enzyme choline acetyltransferase. The enzyme acetylcholinesterase (AChE) breaks ACh down into choline and acetate
cholinergic mechanisms are critical in cognitive functioning
Alzheimer's disease, Down's syndrome, movement disorders, and sleep disorders are related to decreased availability of ACh


blocking the action of AChE with drugs such as donepezil (Aricept) and rivastigmine (Exelon) can delay progression of the disease
Muscarinic ACh receptors play a greater role in behavior and in the side effects of psychoactive agents than nicotinic ACh receptors
Blockade of muscarinic receptors with drugs such as antipsychotics and tricyclic antidepressants results in the classic anticholinergic side effects seen with use of these drugs, including dry mouth, blurred vision, urinary hesitancy, and constipation.

Amino acid neurotransmitters

Amino acid neurotransmitters like g-aminobutyric acid (GABA), glycine, and glutamate are involved in most synapses in the brain
G-Aminobutyric acid is the principal inhibitory neurotransmitter in the CNS and is associated with the symptoms of anxiety. The effectiveness of the antianxiety agents, like the benzodiazepines (diazepam ) and barbiturates, involves their ability to increase the affinity of GABA for its binding site, allowing chloride to enter the neuron. As a result, the neuron becomes hyperpolarized and inhibited, decreasing neuronal firing and ultimately decreasing anxiety.

Glycine is an inhibitory neurotransmitter found primarily in the spinal cord. It works on its own and as a regulator of the excitatory neurotransmitter glutamate
Glutamate has been associated with epilepsy, neurodegenerative illnesses, memory formation, mechanisms of cell death, and schizophrenia. Symptoms of schizophrenia have been linked to alterations in the major glutamate receptor, N-methyl-D-aspartate (NMDA).
Drugs that block NMDA induce psychotic symptoms in healthy volunteers
genes linked to the development of schizophrenia are associated with disruption of the NMDA-receptor pathway .

Neuropeptides

Neuropeptides that act on behavior include the endogenous opioids, the enkephalins and endorphins.
These neurotransmitters are produced by the brain itself, serve to decrease pain and anxiety, and have a role in addiction and mood
Placebo effects (i.e., subjective responsiveness to inactive pharmacologic agents) may be mediated by the endogenous opioid and dopaminergic systems

the biosynthesis of a neuropeptide involves transcription of an mRNA from a specific gene, translation of a polypeptide preprohormone encoded by that mRNA, and then posttranslational processing involving proteolytic cleavage of the preprohormone to yield the active neuropeptide
released peptides are degraded into smaller fragments and, eventually, into single amino acids by specific enzymes termed peptidases.


Thyrotropin-Releasing Hormone(TRH)
TRH is widely distributed in the CNS
TRH receptor is a G-protein–coupled receptor
TRH stimulation test revealed blunting of the TSH response in approximately 25 percent of euthyroid patients with major depression.
TSH blunting is a reflection of pituitary TRH receptor downregulation as a result of hypersecretion of endogenous TRH
There are elevations of CSF TRH concentration which may be relatively specific to depression

Corticotropin-Releasing Factor(CRF)

CRF is the primary hypothalamic ACTH secreting hormone
it also functions as an extrahypothalamic neurotransmitter in a CNS network that,apparently, coordinates global responses to stressors
CRF plays a complex role in integrating the endocrine, autonomic, immunological, and behavioral responses of an organism to stress
. adult animals exposed to maternal separation early in life, an animal model for early adverse childhood experiences, exhibit elevated CRF concentrations and exaggerated HPA response to stress

Hyperactivity of the HPA axis is one of the most consistent finding in major depression .

The reported HPA axis alterations in major depression include:
hypercortisolemia
resistance to dexamethasone suppression of cortisol secretion
blunted ACTH responses to intravenous CRF challenge
elevated CSF CRF concentrations.
the elevated CSF CRF concentrations in drug-free depressed patients are significantly decreased after successful treatment with electroconvulsive therapy (ECT) and antidepressant drugs.


Oxytocin and Vasopressin
alterations in CSF vasopressin concentrations found in major depression, bipolar disorder, schizophrenia, anorexia, and Alzheimer’s disease
Oxytocin has role in facilitating specific, complex social behaviors
It facilitates female sexual behavior, increases social interest, and facilitates the onset of maternal behavior
OT is involved in the regulation of the social brain, suggesting that dysregulation of this peptide could explain social deficits in psychiatric disorders such as autism

Neurotensin

NT is colocalized in certain subsets of dopamine neurons and is coreleased with dopamine in the mesolimbic and medial prefrontal cortex dopamine-terminal regions that are implicated as the site of dopamine dysregulation in schizophrenia.
Both antipsychotic drugs and NT neurotransmission enhance sensorimotor gating.
Sensorimotor gating is the ability to screen or filter relevant sensory input, deficits of which may lead to an involuntary flooding of indifferent sensory data

Cholecystokinin is often colocalized with dopamine in the VTA neurons and it decrease dopamine release
Infusions of a CCK fragment induce panic in healthy individuals
patients with panic disorder exhibit increased sensitivity to the CCK fragment
testosterone level tends to be correlated with aggression in humans. Testosterone is important for sexual desire in men and women.

Estrogen and Progesterone

modulate spatial cognition and verbal memory and are involved in impeding age-related neuronal degeneration. There is also increasing evidence that estrogen administration may decrease the risk and delay onset of dementia of the Alzheimer’s type in postmenopausal women, but acute treatment in dementia has been ineffective in reducing symptoms. Estrogen has mood-enhancing properties and can also increase sensitivity to serotonin, possibly by inhibiting monoamine oxidase

MELATONIN

is a pineal hormone that controls photoperiodically medicated endocrine events .
It also modulates immune function, mood, and reproductive performance; is a potent antioxidant and free-radical scavenger; and may have oncostatic effects. Melatonin has analgesic effects .
Altered secretory patterns and levels of melatonin found in unipolar and bipolar depression, seasonal affective disorder, bulimia, anorexia, schizophrenia, panic disorder, and obsessive compulsive disorder.
Melatonin is useful in the treatment of circadian phase disorders, such as jet lag
intake of melatonin increases the speed of falling asleep, as well as its duration and quality.