Genetics, Anatomy, and Biochemistry of Behavior

د.وليد عزيز العميدي

Genetics, Anatomy, and Biochemistry of Behavior
I. BEHAVIORAL GENETICS
A. There is a genetic component to the etiology of psychiatric disorders such as schizophrenia) and mood disorders .
B. Specific chromosomes have been associated with other disorders with behavioral symptoms (Table 4-1).
















C. Studies for examining the genetics of behavior
1. Family risk studies compare how frequently a behavioral disorder or trait occurs in the relatives of the affected individual (proband) with how frequently it occurs in the general population.
2. Twin studies
a. Adoption studies using monozygotic twins or dizygotic twins reared in the same or in different homes are used to differentiate the effects of genetic factors from environmental factors in the occurrence of psychiatric and neuropsychiatric disorders.
b. If there is a genetic component to the etiology, a disorder may be expected to have a higher concordance rate in monozygotic twins than in dizygotic twins (i.e., if concordant, the disorder occurs in both twins).
II. BEHAVIORAL NEUROANATOMY
The human nervous system consists of the central nervous system (CNS) and the peripheral nervous system (PNS).
A. The CNS contains the brain and spinal cord.
1. The cerebral cortex of the brain can be divided
a. Anatomically into at least four sets of lobes: frontal, temporal, parietal, and occipital, as well as the limbic lobes (which contain medial parts of the frontal, temporal, and parietal lobes and include the hippocampus, amygdala, fornix, septum, parts of the thalamus, and cingulate gyrus and related structures)
b. By arrangement of neuron layers or cryo architecture
c. Functionally into motor, sensory, and association areas
2. The cerebral hemispheres
a. The hemispheres are connected by the corpus callosum, anterior commissure, hippocampal commissure, and habenular commissure.
b. The functions of the hemispheres are lateralized.
1. The right, or nondominant, hemisphere is associated primarily with perception; it also is associated with spatial relations, body image, and musical and artistic ability.
2. The left, or dominant, hemisphere is associated with language function in about almost all right-handed people and most left-handed people.
c. Sex differences in cerebral lateralization. Women may have a larger corpus callosum and anterior commissure and appear to have better interhemispheric communication than men. Men may have better-developed right hemispheres and appear to be
better at spatial tasks than women.
3. Brain lesions caused by accident, disease, surgery, or other insult are associated with particular neuropsychiatric effects (Table 4-2)















B. The PNS contains all sensory, motor, and autonomic fibers outside of the CNS, including the spinal nerves, cranial nerves, and peripheral ganglia.
1. The PNS carries sensory information to the CNS and motor information away from the CNS.
2. The autonomic nervous system, which consists of sympathetic and parasympathetic divisions, innervates the internal organs.
3. The autonomic nervous system coordinates emotions with visceral responses such as heart rate, blood pressure, and peptic acid secretion.
4. Visceral responses occurring as a result of psychological stress are involved in the development and exacerbation of some physical illnesses .
III. NEUROTRANSMISSION
A. Synapses and neurotransmitters
1. Information in the nervous system is transferred across the synaptic cleft (i.e., the space between the axon terminal of the presynaptic neuron and the dendrite of the postsynaptic neuron).
2. When the presynaptic neuron is stimulated, a neurotransmitter is released, travels across the synaptic cleft, and acts on receptors on the postsynaptic neuron. Neurotransmitters are excitatory if they increase the chances that a neuron will fire and inhibitory if they decrease
these chances.
B. Presynaptic and postsynaptic receptors
are proteins present in the membrane of the neuron that can recognize specific neurotransmitters.
1. The changeability of number or affinity of receptors for specific neurotransmitters (neuronal plasticity) can regulate the responsiveness of neurons.
2. Second messengers. When stimulated by neurotransmitters, postsynaptic receptors may alter the metabolism of neurons by the use of second messengers, which include cyclic adenosine monophosphate (cAMP), lipids (e.g., diacylglycerol), Ca2+, and nitric oxide.
Classification of neurotransmitters. Biogenic amines (monoamines), amino acids, and peptides are the three major classes of neurotransmitters.
D. Regulation of neurotransmitter activity
1. The concentration of neurotransmitters in the synaptic cleft is closely related to mood and behavior. A number of mechanisms affect this concentration.
2. After release by the presynaptic neuron, neurotransmitters are removed from the synaptic cleft by mechanisms including:
a. Reuptake by the presynaptic neuron
b. Degradation by enzymes such as monoamine oxidase (MAO)
3. Availability of specific neurotransmitters is associated with common psychiatric conditions (Table 4-3). Normalization of neurotransmitter availability by pharmacological agents is associated with symptom improvement in some of these disorders.


IV. BIOGENIC AMINES
A. Overview
1. The biogenic amines, or monoamines, include catecholamines, indolamines, ethyl amines, and quaternary amines.
2. The monoamine theory of mood disorder hypothesizes that lowered monoamine activity results in depression and elevated levels in mania.
3. Metabolites of the monoamines are often measured in psychiatric research and diagnosis because they are more easily measured in body fluids than the actual monoamines
(Table 4-4)







B. Dopamine
1. Dopamine, a catecholamine, is involved in the pathophysiology of schizophrenia and other psychotic disorders, Parkinson disease, mood disorders, the conditioned fear response , and the "rewarding" nature of drugs of abuse .
2. Synthesis. The amino acid tyrosine is converted to the precursor for dopamine by the enzyme tyrosine hydroxylase.
3. Receptor subtypes. At least five dopamine receptor subtypes (D1–D5) have been identified; the major site of action is D2 for traditional antipsychotic agents and D1 and D4 as well as D2 for the newer "atypical" antipsychotic agents .
4. Dopaminergic tracts
a. The nigrostriatal tract is involved in the regulation of muscle tone and movement.
1. This tract degenerates in Parkinson disease.
2. Treatment with antipsychotic drugs, which block postsynaptic dopamine receptors receiving input from the nigrostriatal tract, can result in Parkinson-like symptoms.
b. Dopamine acts on the tuberoinfundibular tract to inhibit the secretion of prolactin from the anterior pituitary.
1. Blockade of dopamine receptors by antipsychotic drugs prevents the inhibition of prolactin release and results in elevated prolactin levels.
2. This elevation in turn results in symptoms such as breast enlargement, galactorrhea, and sexual dysfunction.
c. The mesolimbic-mesocortical tract is associated with psychotic disorders.
1. This tract may have a role in the expression of emotions since it projects into the limbic system and prefrontal cortex.
2. Hyperactivity of the mesolimbic tract is associated with the positive symptoms of schizophrenia; hypoactivity of the mesocortical tract is associated with the negative symptoms of schizophrenia .
C. Norepinephrine,
a catecholamine, plays a role in mood, anxiety, arousal, learning, and memory.
1. Synthesis
a. Like Dopaminergic neurons, noradrenergic neurons synthesize dopamine.
b. Dopamine ?-hydroxylase, present in noradrenergic neurons, converts this dopamine to norepinephrine.
2. Localization. Most noradrenergic neurons (approximately 10,000 per hemisphere in the brain) are located in the locus ceruleus.
D. Serotonin,
an indolamine, plays a role in mood, sleep, sexuality, and impulse control. Elevation of serotonin is associated with improved mood and sleep but decreased sexual function (particularly delayed orgasm). Very high levels are associated with psychotic symptoms.
Decreased serotonin is associated with poor impulse control, depression, and poor sleep.
1. Synthesis. The amino acid tryptophan is converted to serotonin (also known as 5-hydroxy-tryptamine [5-HT]) by the enzyme tryptophan hydroxylase as well as by an amino acid decarboxylase.
2. Localization. Most serotonergic cell bodies in the brain are contained in the dorsal raphe nucleus.
3. Antidepressants and serotonin. Heterocyclic antidepressants (HCAs), selective sero-tonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAOIs) ulti-mately increase the presence of serotonin and norepinephrine in the synaptic cleft .
a. HCAs block reuptake of serotonin and norepinephrine, and SSRIs such as fluoxetine (Prozac) selectively block reuptake of serotonin by the presynaptic neuron.
b. MAOIs prevent the degradation of serotonin and norepinephrine by MAO.
E. Histamine
1. Histamine, an ethylamine, is affected by psychoactive drugs.
2. Histamine receptor blockade with drugs such as antipsychotics and tricyclic antidepressants is associated with common side effects of these drugs such as sedation and increased appetite leading to weight gain.
F. Acetylcholine (Ach)
a quaternary amine, is the transmitter used by nerve-skeleton-muscle junctions.
1. Degeneration of cholinergic neurons is associated with Alzheimer disease, Down syndrome, and movement and sleep disorders (e.g.,decreased REM sleep,).
2. Cholinergic neurons synthesize Ach from acetyl coenzyme A and choline using choline acetyltransferase.
3. The nucleus basalis of Meynert is a brain area involved in production of Ach.
4. Acetylcholinesterase (AchE) breaks Ach down into choline and acetate.
5. Blocking the action of AchE with drugs such as donepezil (Aricept), rivastigmine (Exelon), and galantamine (Reminyl) may delay the progression of Alzheimer disease but cannot reverse function already lost.
6. Blockade of muscarinic Ach receptors with drugs such as antipsychotics and tricyclic antidepressants results in the classic "anticholinergic" adverse effects seen with use of these drugs, including dry mouth, blurred vision, urinary hesitancy, and constipation.
7. Anticholinergic agents are commonly used to treat the Parkinson-like symptoms caused by antipsychotic agents.
V. AMINO ACID NEUROTRANSMITTERS
These neurotransmitters are involved in most synapses in the brain and include glutamate, ?aminobutyric acid (GABA), and glycine.
A. Glutamate
1. Glutamate is an excitatory neurotransmitter that may be toxic to neurons (exitotoxicity) and thereby contribute to the pathophysiology of disorders such as schizophrenia, Alzheimer disease, and other neurodegenerative illnesses.
2. Memantine (Namenda), a blocker of the N-methyl-d-aspartate (NMDA) receptor, a type of glutamate receptor, has been approved to treat Alzheimer disease and may prove useful also in the treatment of schizophrenia.
B. GABA
1. GABA is the principal inhibitory neurotransmitter in the CNS. It is synthesized from glutamate by the enzyme glutamic acid decarboxylase, which needs vitamin B6 (pyridoxine) as a cofactor.
2. GABA is closely involved in the action of antianxiety agents such as benzodiazepines (e.g., diazepam [Valium]) and barbiturates (e.g.,secobarbital [Seconal]). Benzodiazepines and barbiturates increase the affinity of GABA for its GABAA binding site, allowing more chloride to enter the neuron. The chloride-laden neurons become hyperpolarized and inhibited, decreasing neuronal firing and ultimately decreasing anxiety. Anticonvulsants also potentiate the activity of GABA.
C. Glycine
is an inhibitory neurotransmitter that works on its own and as a regulator of glutamate activity.
VI. NEUROPEPTIDES
A. Endogenous opioids
1. Enkephalins, endorphins, dynorphins, and endomorphins are opioids produced by the brain itself that decrease pain and anxiety and have a role in addiction and mood.
2. Placebo effects may be mediated by the endogenous opioid system. Prior treatment with an opioid receptor blocker such as naloxone may block placebo effects.
B. Other neuropeptides
have been implicated in the following conditions:
1. Schizophrenia (cholecystokinin [CCK] and neurotensin)
2. Mood disorders (somatostatin, substance P, vasopressin, oxytocin, and corticotropin-releasing factor [CRF])
3. Huntington disease (somatostatin and substance P)
4. Alzheimer disease (somatostatin)
5. Anxiety disorders (substance P and CCK)
6. Physical and mental pain and aggression (substance P)
7. Obesity (neuropeptide Y)