Stress and Anxiolytics Flashcards
stress exists when
animal is in a state of
homeostatic imbalance
or psychological uncertainty (real or imagined)
stimuli that produce stress are
called
stressors
homeostatic disturbance
food deprivation, cold, shock, etc.
psychological uncertainty (real or imagined)
a stimulus that is unexpected or uncontrollable
Humans are different because….
humans (at least) are able to contrive stressors at a purely psychological level (e.g., What if, right now, someone is breaking into my car?)
when faced with a stressor, the brain…..
…..evaluates the situation to see how serious it is and whether or not the situation has been faced in the past.
coping strategy
- what the brain does when brain a stressor is experienced
- exhibits a rapid increase in alertness and enhanced cognitive function…these changes facilitate your ability to gather information, integrate it
1) ideally, coping strategies are…..
and
2) when this does not happen…….
1) activated quickly, are effective, and then
are terminated rapidly.
2) because coping strategy is ineffective or because the stress is too intense or repeatedly presented, changes in the brain compromise an animal’s subsequent ability to deal with stress
CNS STRESS RESPONSE
brain is critically dependent upon the hypothalamic-pituitary-adrenal axis (HPA axis),
which mediates the body’s
response to stress.
also relies on AMYGDALA AND HIPPOCAMPUS
CNS STRESS RESPONSE Cycle
- the amygdala starts the stress response;
it receives inputs from many different brain regions, including much of the neocortex, and is responsible for “affective tags” that color our cognitive processing - in the presence of a stressor, the amygdala excites neurons in the hypothalamus, causing the release of corticotrophin-releasing hormone (CRH) into the hypothalamic-pituitary portal system
- CRH leads to ACTH release from neurons in the anterior pituitary into the general circulation
- ACTH from the anterior pituitary leads to cortisol release from cortex of the adrenal glands; cortisol is one
of the signatures of the body’s stress
response - elsewhere, the locus coeruleus is activated by the amygdala, the hypothalamus, the cingulate gyrus, and the prefrontal cortex (all involved in the assessment of stressors)
- LC activation causes release of norepinephrine throughout the brain, increasing the excitability of neurons and thus facilitating information processing throughout the brain
- at the same time, the sympathetic nervous system activates cells in the medulla of the adrenal glands, causing the release of epinephrine (adrenaline) into the general circulation
What does the combination of cortisol and adrenaline do?
- together, adrenaline (increased heart rate; pupil dilation; increased respiration; altered blood flow) and cortisol (altered metabolism; temporary immune suppression/anti-inflammatory effects) dramatically alter the body and brain’s physiology to enable an animal to best deal with the presentation of a stressor
- the hippocampus is excited by elevations in cortisol, NE, and glutamatergic inputs from throughout the brain
- it projects to the hypothalamus and activates GABA neurons there, which decrease hypothalamic activity.
- thus, the hippocampus is ONE of the brakes for the HPA axis
Pharmacotherapy
aims at reducing activation of “stress circuits” throughout the brain.
Pharmacotherapy targets 2 key transmitter
systems…
-GABA agonists: including ethanol and barbiturates; most the clinically more useful are benzodiazepines such as Valium.
- all enhance GABA activity by
acting at modulatory binding sites on GABA-A receptors
Benzodiazepines
can be administered orally, IM, IV, or via mucosal membranes (e.g., rectal suppository)
- potent GABA-A agonist; only effective when GABA is also present (works by increasing GABA binding at receptor), which is why the drugs are very safe
- (Valium - ED50 anxiety = 2 mg; LD50 = 1000mg ; TI = 500).
- TI greatly reduced if combined with ethanol or other sedative hypnotics
-highly lipid soluble; effective within 10-15 min; can have a lot of depot binding
(depending on fat solubility)
- metabolized in liver by cytochrome P-450 enzymes; 95% excreted in urine; metabolites are also psychoactive. Induction of liver enzymes is limited, meaning there is less tolerance and less x-tolerance with other drugs.
- act at GABA-A receptors throughout CNS to reduce activity of the amygdala, prefrontal cortex, hippocampus, hypothalamus, brainstem regions involved in
Serotonin agonists
such as Prozac (SSRI; blocks reuptake of 5HT) or buspirone (directly activates 5HT-1A receptors)
- the anti-anxiety effects of these drugs take up to 8 weeks to be expressed (the classic monoamine start-up phenomenon)
- this may be due to increased cortisol receptors in the hippocampus or decreased sensitivity of presynaptic autoreceptors on 5-HT neurons themselves.
