Behavioral science Neurochemistry 2 Serotonin Dr.Ahmed
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
• 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.
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