Exam 5 Drugs and Behavior

Serotonin (5-HT)

A monoamine neurotransmitter with only metabotropic receptors. Synthesis is limited by tryptophan availability.

Changes in Tryptophan Levels

A decrease in tryptophan is when you consume an amino acid rich food without tryptophan. An elevation is due to eating a food with tryptophan.

Tryptophan Depletion

Linked in early studies to increases in aggression and impulsivity. Later studies are moderated by the type of impulsivity and the individual.

Serotonin Storage

Vesicular Monoamine Transport pumps into vesicles. Vesicular storage prevents degradation.

Serotonin Release

Inhibited by autoreceptor activation. Terminal autoreceptors are direct inhibition. Somatodendritic autoreceptor decreases action potentials.

Serotonin Metabotropic Receptors

5-HT1 inhibits adenylyl cyclase and cAMP formation and stimulates potassium channels. 5-HT2 activates PKC and increases calcium (atypical antipsychotics)

Serotonin Signal Termination

Reuptake via the serotonin transporter (SERT) or enzymatic degradation via monoamine oxidase intracellulary on mitochondria. These are the primary target of antidepressants

What is genetic variation in SERT associated with?

Affective Disorder

What is serotonin mainly involved in?

Heavily involved in mood regulation and impulse control.

Three types of depression treatments

SSRI, MAOI, Tricyclics

Major Depressive Disorder

Dysphoric mood or loss of interest in activities for several weeks. Can also include fatigue, inability to concentrate, and sleep or appetite disturbances.

Epidemiology of Major Depressive Disorder

Peak onset age in mid to late thirties. There is a significant increase in suicide rates.

Monoamine Hypothesis of Depression

Depression is related to a deficit of monoamines at critical synapses. Monoamine agonists are drugs to relieve depression. Monoamine antagonists exacerbate symptoms.

Serotonergic Dysfunction

Depressed patients have reduced plasma concentrations of tryptophan, 5-HT1 receptors, and serotonin transporters.

Chronic Antidepressants

Increases synaptic 5-HT, down regulate 5-HT2 receptors, and up regulate the 5-HT1 receptors.

Neurogenesis Hypothesis

Hippocampus structural changes lead to decreased neurogenesis. Stress decreases neurogenesis and antidepressants increase it. Latency of drug effects can reflect the maturation period of new neurons.

Which types of antidepressants hit catecholamines as well?

MAOI and Tricyclics

Monoamine Oxidase Inhibitor Mechanism

Inhibit the monoamine oxidase enzyme, which breaks down serotonin, norepinephrine, and dopamine.

Tricyclics and Heterocyclics Mechanism

Inhibits the reuptake of serotonin, norepinephrine, and/or dopamine.

Selective Serotonin Reuptake Inhibitors Mechanism

Block the reuptake of serotonin, having little effect on norepinephrine or dopamine synapses.

MAOIs general effects

Cause a moderately delayed normalization of mood with less depressive ideation, increased energy, confidence and self esteem, and elevates mood. All are irreversible when they covalently bond to the MAO.

MAOI interactions

MAOIs inhibit other liver enzymes, causing interactions with foods containing tyramine, which is toxic when it builds up. Leads to impaired metabolism of barbiturates, alcohol, and opioids.

When are MAOIs used?

When all other treatments are not working.

Different Tricyclic Antidepressants

They differ in potency for antidepressant effects with relatively equal efficacy.

Tricyclic Efficacy

They are efficacious in treating major depression and are effective in preventing new episodes. They have no abuse potential and don’t cause euphoria.

Absorption of Tricyclics

Readily absorbed after oral administration, have long half lives so they can be taken once a day. Decreased side effects when taken at bedtime.

Distribution of Tricyclics

Extensively bound to plasma proteins and are very lipophilic.

Metabolism of Tricyclics

Rates of metabolism are determined by individual genetics. There are active and inactive metabolites. Demethylated metabolites of the tertiary amines are active.

Excretion of Tricyclics

Less that 5% of the drug is excreted unchanged

Pharmacodynamics of Tricyclics

TCAs block uptake of monoamines, but potency and selectivity varies greatly for norepinephrine vs serotonin. Either selective for NERT, selective for SERT, or nonselective for both.

Increased Synaptic Levels in TCA

Synaptic levels of neurotransmitters increase quickly. Clinical efficacy takes weeks to occur despite increasing neurotransmitter availability.

Side Effects of TCA

Anticholinergic: Dry mouth, constipation, blurred vision, urinary retention, dizziness, confusion. Antihistaminergic: weight gain, sedation. Antiadrenergic: orthostatic hypotension, cardiac depression or arrhythmias.

SSRI Introduction

Same efficacy as TCA, onset of 2-3 weeks. Reduces adverse effects.

SSRI Treatment Efficacy

SSRIs are similar to TCAs at treating major depression, but less side effects. SSRIs are best at treating panic disorders and OCD. SSRIs and MAOIs are best for specific phobias.

What was the first SSRI?

Fluoxetine/Prozac

SSRI Pharmacokinetics

Large plasma protein depot binding, peak levels at 8 hours with oral dosing, long but variable half life.

SSRI Mechanism of Action

Selective blockade of 5-HT reuptake, all SSRIs inhibit the serotonin transporter. Acutely have little effect on 5-HT synaptic levels due to action of autoreceptors.

Autoreceptors in SSRIs

Primary: impulse mediating autoreceptors. Secondary: release modulating autoreceptors.

Chronic Use of SSRIs

Feedback systems become desensitized, firing rate of raphe neurons return to normal, increases neuroplasticity and neurogenesis

LSD

Classified as a psychedelic hallucinogen, but rarely produces them and is more of an illusiogenic drug.

What is LSD synthesized from?

Lysergic acid derived from ergot, which is a grain fungus on rye. They didn’t think it had any effects in early animal testing

LSD History

Discovered in 1938 by Alfred Hofmann in a research program for ergot medical uses. A needle poke introduced Hofmann to the effects of LSD in humans.

Timothy Leary

Founded the league for spiritual discovery, which is a religion declaring LSD as the holy sacrament.

What schedule is LSD?

Schedule III

LSD Route of Administration

Sublingual or oral, liquid solution is dried on blotter paper and dissolves on the tongue.

LSD Pharmacokinetics

LSD is 2-5 thousand times more active than mescaline. A single dose can have between 100-500 mcg, but threshold effects can be felt at 25 mcg. Effects begin 30-90 minutes after ingestion and average duration is 6-8 hours.

LSD Pharmacodynamics

Serotonin system is most commonly implicated with LSD. Binds multiple different serotonin receptors with both agonist and antagonist effects.

Therapeutic effects of LSD

Visual and auditory illusions, time distortion, increased emotionality, mystic/religious out of body experience, synesthesia

What are LSD effects altered by?

Expectations, environment, and mood

Common acute adverse effects of LSD

Increased heart rate and BP, flushing, sweating, exhaustion, headache, confusion, illusions, self harm

Rare acute adverse effects of LSD

Impaired balance and coordination, convulsions, pins and needles

Long term adverse effects of LSD

Flashbacks, weakness, persistent exhaustion, depression, impaired concentration

LSD Tolerance

Develops and disappears rapidly. Within a few days of repeated doses, initial dose becomes ineffective. Absence for a few days restores full CNS sensitivity to the drug

LSD Cross Tolerance

Partial cross tolerance among LSD, mescaline, and psilocybin

LSD Withdrawal

Virtually no withdrawal syndrome

What is MDMA structurally similar to?

Methamphetamine

MDMA Route of Administration

Often oral with small tablets. They are often laced with other drugs like caffeine, amphetamines, meth, ketamine

MDMA History

Synthesized in 1912 as diet pills. 1953 was tested as a truth serum in army. 1977 was used as a psychotherapeutic tool. 1985 drug was banned and became schedule I.

How many people 12 or older have tried MDMA?

Over 11 million

MDMA Absorption and Elimination

Absorbed from the intestinal tract, peaks in blood in 1.5-3 hours. Broken down metabolically in the liver by first order kinetics. Elimination is slow and half life is about 8 hours.

MDMA Pharmacokinetics

Affects 5-HT, DA, and NE. Unlike meth and amphetamine, it affects 5-HT more than DA. Blocks reuptake and reverses the SERT, releasing 5-HT into synapse. Releases oxytocin and caused rapid acute increase in extracellular 5-HT.

Short term “positive” MDMA effects

Mental stimulation, emotional warmth, empathy, decreased anxiety, increased sensory perception

Short term “negative” MDMA effects

Sadness, anxiety, irritability, sleep disturbances, aggression, lack of appetite, nausea, blurred vision, heart failure

Long term effects of MDMA

Depletion of 5-HT and neurotoxicity

Lethal side effects of ecstasy

When a person overdose it can cause fast heart beat, high BP and body temp. Deaths are usually caused by overheating and dehydration.

MDMA Tolerance/Withdrawal

Hard to assess tolerance, but there is self reported increases. Depression is a withdrawal symptom

Opioids

A class of psychoactive drugs grouped by drug target/opioid receptor. There is a long history, as well as synthetic and natural compounds (opioids vs opiate)

Opiates

Natural compound from poppy plants. 10% of the pod left after flowering is psychoactive.

Poppy Tears

They are superficial cuts with a knife that dry as sticky brown resin. This is scraped off as raw opium.

History of Natural Opiates

Very long history going back to prehistoric cave paintings, neolithic villages, and ancient Egypt and Asia minor. Hippocrates used it to induce sleep and reduce pain. Ancient Rome used it as medicine and poison.

Natural Opiates 16th Century vs 19th Century

In the 16th century, lots of medical potions and elixirs contained opium, like Laudanum. In the 19th century, there were opium wars and the hypodermic needle was developed leading to addiction concerns

Morphine

The most potent opiate. Morphine dependence is fostered by the hypodermic needle and “Soldiers disease” in civil war

Heroin

Made of boiled morphine and acetic acid, is five times more potent than morphine. Was marketed as nonaddictive to reduce morphine usage

Semisynthetic opiates/opioids derived from morphine/codeine

Heroin, hydromorphone, hydrocodone, oxycodone

What are opioids?

Fully synthetic opioids aren’t derived from the opium plant, like fentanyl and methadone

Opioid route of administration

All routes except sublingual, most medical opioids come in multiple preparations like tablets, solution, time release tablets. They are orally bioavailable.

Morphine Pharmacokinetics

Common medical routes of admin are oral solutions, tablets and capsules which can also be crushed for injections, and IV solutions. When morphine is abused it is typically injected IV for the rush

Heroin Pharmacokinetics

Pure heroin (white powder) is dissolved with a weak acid for injection. Hydrochloride salt is brown and readily water soluble. Black tar isn’t completely acetylated and is typically smoked

Heroin and Spoons

Heroin is heated in spoons or foil for inhaling the smoke or as part of the injection process. To inject, it is heated before and after adding weak acid and water

Morphine Biodistribution

Spreads throughout the body but very little crosses the blood brain barrier

Opioid Chemistry

Greatly affects drug potency, morphine has multiple polar groups. Masking them makes the drug more potent and cross the BBB better

What is heroin metabolized into?

Morphine

Elimination and Metabolism of Opioids

Varies widely between compounds. Half life for morphine is three hours, heroin is three minutes, and methadone is 8 hours.

What did Candace Pert discover?

She found the endogenous opioid system drug target. Discovered radioactive binding assays as a grad student, advisor got the Nobel prize

What are the three kinds of opioid receptors?

Mu, kappa, and delta. All have further subtypes

Endogenous opioid receptors

All are G protein coupled metabotropic receptors and decrease neural activity/excitability. Often tied to GIRK

What is GIRK?

G protein coupled inwardly rectifying K+ channel

What does GIRK do concerning opioids?

Pushes neuron to the resting potential and prevents action potential.

Mu receptor

Named because of its activation by morphine. Mediates euphoria, sedation, GI side effects, respiratory depression, and spinal/supraspinal analgesia.

Delta Receptor

Mediates spinal/supraspinal analgesia, olfaction, cognitive function, and overlaps mu receptor binding.

Kappa Receptor

Named due to activation by ketocyclazocine. Mediates the aversive effects like sedation, dysphoria, paranoia, hallucinations, and delirium.

Neuropeptide Neurotransmitters Synthesis

Propeptide gene is transcribed and expressed. The propeptide is cut up by peptidases into different neuropeptides. Some neuropeptides have nonprotein chemical groups added

What are the broad classes of endogenous opioid peptides?

Enkephalins, endorphins, and dynorphins

Enkephalins

Largely act on delta receptors and are widely distributed to brain, nervous, endocrine, reproductive, and immune systems. Have a strong neurotransmitter and neuromodulator role.

Endorphins

Ligands at both delta and mu receptors. More localized effects on hypothalamus, pituitary, reproductive, and immune systems. Has a strong neurohormone role

Dynorphins

Act on Kappa receptors. Found across CNS and PNS, endocrine and reproductive systems, and is less widely spread than enkephalins. Has a neurotransmitter and neuromodulator role.P

Pure opioid receptor agonist

Full efficacy at mu receptors, but can also be agonists at delta and kappa receptors.

Partial opioid receptor agonists

Partial agonist at the mu receptor, but often small efficacy overall

Mixed opioid receptor agonist-antagonist

Agonists at some receptors and antagonists at others which limits overall efficacy

What are the typical desired effects of opioid agonists?

Analgesia, euphoria, drowsiness, relaxation, warm sensation, overall indifference