Psychiatric Pharmacology

What are the targets of CNS drugs?

Ion channels (mediate changes in excitability from neurotransmitters), neurotransmitter receptors (physiologically respond to activation by neurotransmitters), and transport proteins (clear released transmitter from extracellular space)

facts regarding the BBB

protects the brain from toxins which complicates drug delivery - lipophilic molecules diffuse freely across the BBB and accumulate in the brain, it is relatively impermeable to neurotransmitters

what are neurons?

primary signaling cells of the brain; electrically active, variety of ion channels and transport proteins, stimulation causes nerve impulses or action potentials, and results in release of neurotransmitters

what are synapses?

sites of intraneuronal communication

what are synaptic vessels?

contain proteins for storage, secretion, and reaccumulation of neurotransmitters

when do neurons release NTs?

they release in response to rapid rise/fall in membrane potential (aka action potential)

T/F: the brain loves fatty (lipophilic) molecules

true

rapid influx of which ions leads to depolarization?

positively charged (Na+/K+) 

rapid efflux of which ions leads to repolarization?

efflux of negatively charged chloride ions

when do ion channels on membranes open?

when membrane potential increases (depolarization) which regulates the electrical excitability of neurons

T/F: transmembrane transport of ions permit resting cells to maintain steady-state concentrations

true

T/F: influx of Na+/K+ results in hyperexcitatbility

true

T/F: blockade of chloride ions results in hyperexcitability

true

what is the role of chloride channels?

maintain resting potential and are responsible for inhibitory postsynaptic potential and dampen neuronal excitability

_______________ results in continuation of the nerve impulse

depolarization (+)

______________ leads to diminished signaling

hyperpolarization (-)

after NT are released from the synapse where can/do they go?

they can interact with receptors post synaptically, act through second messengers, reuptake into the nerve terminal, enhance more exocytosis, gobbled up by monoamine oxidase, or deactivated by glial cells

which neurotransmitters are based in the CNS?

amino acids (glutamate, aspartate, GABA, glycine, beta-alanine, taurine), acetylcholine, monoamines, neuropeptides, purines, gases

which amino acids are excitatory?

glutamate and aspartate

which amino acids are inhibitory

GABA, glycine, beta-alanine, taurine

role of glutamate

important in learning and memory

what can happen in glutamate excitotoxicity?

ischemia or hypoglycemia in the brain which can lead to cell death

what is the role of GABAa?

major inhibitory receptor in CNS (effects of benzos and barbiturates); sedative-hypnotic, muscle relaxant, anxiolytic, amnesic, anticonvulsant

what is the role of the GABAa1 subunits?

drug target for “z-drugs” as hypnotics, minimal anticonvulsant/muscle relaxant effect

where does acetylcholine have most of its effects?

autonomic nervous system

which receptors does acetylcholine interact with?

nicotinic and muscarinic

where are nicotinic receptors located?

skeletal muscle, ganglia, adrenal gland, CNS (hippocampus, cortex, striatum)

where are muscarinic receptors located?

M1-M5 are all found in the CNS and have roles in cognitive function, motor control, appetite regulation, nociception, and more!!!!

what does M2 agonism lead to?

decreased heart rate (located in heart as well as CNS)

what does M3 agonism lead to?

increased GI motility, increased urination, bronchoconstriction, pupillary constriction, increased secretory gland secretions, and vasodilation

T/F: many antidepressants and antipsychotics are muscarinic agonists

false

what is the role of muscarinic antagonists?

effective in PD tremor, extrapyramidal symptoms from antipsychotics

T/F: antipsychotics with muscarinic action have less risk of EPS

true

what QUICKLY degrades acetylcholine

acetylcholinesterase 

what are the four catecholamines?

dopamine, norepinephrine, epinephrine, serotonin

T/F: histamine is a catecholamine

false

examples of monoamines include:

dopamine, norepinephrine, epinephrine, serotonin, histamine, and trace amines

what are the 3 dopamine pathways in the CNS?

nigrostriatal, mesocortical/mesolimbic, tuberoinfundibular

what is the nigrostriatal pathway?

regulator of movement, degenerates in Parkinson’s Disease

what is the mesocortical/mesolimbic pathway?

involved in motivation and reward -- dysfunction is associated with addiction, schizophrenia, and psychoses

what is the tuberoinfundibular pathway?

involved in the release of hormones (mainly prolactin), regulates blood supply to the pituitary.

T/F: administered dopamine does not cross the BBB

true

the dopamine transport protein (DAT) is expressed in:

mesostriatal, mesolimbic, and mesocortical dopamine pathways

what are dopamine neurons strongly influenced by?

excitatory glutamate and inhibitory GABA input (glutamate enables burst like firing of dopaminergic

where are D1 receptors located?

mostly within the CNS, also kidney, retina, and cardiovascular (cerebral cortex regulates cognition)

where are D2 receptors located?

striatum, nucleus accumbens, prefrontal cortex, basal ganglia.

role of D2 receptors?

reward and motivation, motor control/coordination, working memory, attention.

where are D3 receptors located?

limbic region of the brain — nucleus accumbens, substantia nigra, ventral tegmental area

what is a possible drug target for substance use disorders?

D3 receptors

where are D4 receptors located?

retina, hypothalamus, prefrontal cortex, amygdala, hippocampus

where are D5 receptors located?

hippocampus, substantia nigra, hypothalamus, striatum, cerebral cortex, nucleus accumbens, olfactory tubercle — regulates neuronal circuitry controlling learning and memory

T/F: D1 receptor agonism causes vasodilation, decreases in BP, and increases in cardiac contractility

true

T/F: activation of D2 receptors decreases prolactin

true

D1 and D2 receptors modulate release of ______________________

norepinephrine and dopamine

why is dopamine often used at very high concentrations (IV)?

activates adrenergic receptors causing vasoconstriction and increased blood pressure which treats severe congestive heart failure, sepsis, or cardiogenic shock

T/F: drugs of abuse increase DA in nucleus accumbens

true

what is dopamine’s role in cognition/memory?

D1 receptor activity in prefrontal cortex required for optimum performance in learning and memory (too little is associated with learning deficits and decreased cognition while too much impairs function)

facts regarding dopamine agonists

treats PD, restless leg syndrome, and hyperprolactinemia (least subtype selectivity)

facts regarding dopamine antagonists:

treat schizophrenia, bipolar disorders, and N/V (more selective)

what are partial agonists?

occupy the receptor but do not achieve the same effect as full agonists, and antagonize the binding of other antagonists and full agonists

examples of dopamine partial agonists include:

atypical antipsychotics (second gen antipsychotics)

how do partial dopamine agonists work?

diminishes dopamine hyperfunction by competing for DA receptor binding, enhances dopaminergic neurotransmission in PFC by acting as an agonist which manages positive and negative symptoms

what is the primary catecholamine in the peripheral nervous system (acts in innervated tissues)

norepinephrine

examples of a1 agonists

epinephrine, phenylephrine

examples of a1 antagonists

prazosin, doxazosin, tamsulosin

examples of a2 agonists (associated on glial and vascular elements and neurons)

epinephrine, norepinephrine, clonidine, guanfacine

examples of beta agonists

epinephrine, norepinephrine

examples of beta antagonists

carvedilol, metoprolol, propranolol

facts regarding epinephrine:

is the primary neurotransmitter released by adrenal medulla which is secreted into the blood circulation and its effects are dependent on concentration

T/F: epinephrine has complex effects on organs such as the heart, vascular, and smooth muscle

true

T/F: epinephrine is a potent stimulant on a-b-adrenergic receptors

true

what are the effects of histaminergic receptors in the CNS?

arousal, body temperature, vascular dynamics.

what manages histamine storage?

vesicular monoamine transporter (VMAT2)

what are the types of histamine receptors?

H1, H2, H3, H4

facts regarding H1 receptors:

Widely distributed in the brain, linked to neuroendocrine, behavioral, and nutritional control. Receptor anomalies are linked to behavioral state abnormalities (receptor blockers cause sedation)

facts regarding H2 receptors:

Involved in gastric acid secretion, smooth muscle relaxation (dyspepsia/acid reflux treatment). CNS involvement regulates neuronal physiology and plasticity (inhibition blocks pain)

facts regarding H3 receptors:

Regulates serotonergic, cholinergic, noradrenergic, and dopaminergic NT release. Therapeutic target for obesity, movement disorders, schizophrenia, ADHD, and wakefulness

facts regarding H4 receptors:

expressed on hematopoietic cells - limited CNS activity, mostly allergy, asthma, and antipruritic properties

what is the role of 5HT1 receptors?

modulates K/Ca channels

facts regarding 5HT2A:

expressed in almost every tissue and cell in body (responsible for many ADRs of psych meds)

role of 5HT3 receptors

located in GI tract and in areas of CNS responsible for vomiting - is an antiemetic drug target.

where is 5HT4 located?

hippocampus and GI tract (facilitates peristalsis)

T/F: released 5HT elicits an aggregation response

true

5HT causes ____________ of blood vessels in the splanchnic, renal, pulmonary, and cerebal vasculature

contraction

motility of gastric and smooth muscle is enhanced via signaling of _____

5HT

T/F: activation of 5HT2A receptors leads to pro-inflammatory responses

true

T/F: depletion of 5HT at most receptors leads to drowsiness

false

T/F: low 5HT increases impulsivity and aggression 

true

facts regarding trace amines

have a short half-life and are rapidly metabolized by monoamine oxidase

examples of trace amines:

Phenethylamines, phenylethanolamine, tyramine, tryptamine, N-methyltyramine, octopamine, synephrine, and 3-methoxytyramine

facts regarding trace amine-associated receptors (TAARs), especially TAAR1?

modulate monoaminergic activity which is activated by amphetamine and psychostimulants (is a target for treatment of addiction and schizophrenia)

what are peptides?

modulators of neurotransmitters and are not directly inhibitory/excitatory

What affects do peptides have?

analgesia, social behaviors, learning, memory

what are purines?

adenosine, ATP, UDP, and UTP which are extracellular signaling molecules

which cannabinoid receptors are throughout the brain?

CB1

which cannabinoid receptors are in immune cells?

CB2

facts regarding lipid mediators

Arachidonic acid: metabolites from cyclooxygenase, lipoxygenase, and CYP450’s involved with long-term potentiation and other forms of neuronal plasticity

what is nitric oxide involved in?

long term potentiation, neurotransmitter release, enhancement of glutamate toxicity

what is carbon monoxide’s role?

generated in neurons and acts as an intracellular messenger

how are NTs converted to inactive compounds?

via enzymes such as acetylcholinesterase and monoamine oxidase