lecture 19: Inhalents, GHB, and Anabolic- Androgenic Steroids

Where do you find inhalants?

in everyday household items, they are legal and can be bought at retail stores

who are the typical users for inhalants?

children and adolescents

-between the ages of 12 and 16
- abuse by young ppl is a global problem

what form are inhalants in?

- Volatile Liquids or gasses
- fuels
- halogenated hydrocarbons
- anesthetics
- Nitrites

what is toluene?

Toluene is in spray paint, adhesives, marker pens, lighter fluid. - They have strong smell, easily assessable and cheap.

what are volatile solvents?

liquids at room temp that give off fumes that can be huffed
- nail polish remover, air fresheners, moth balls degreasing agents

what are fuels?

they fall under volatile liquids or gasses that include automobile fuels, fuels for lamps and heating supplies, lighter fluids and propellants (found in spray cans)

Halogenated hydrocarbons

Hydrocarbon molecules with one or more chlorine or fluorine atoms
- used as refrigerants, solvents, degreasers, adhesives, propellants ect.

what are anesthetics?

the Nitrous oxide (laughing gas)
- in dentistry and whipped cream cans.
- chloroform and ether. used in animal anesthetics and lab research.

what are nitrites?

they are used to heighten sexual arousal and pleasure
- their subjective effects are caused by dilating blood vessels and causing muscle relaxation (thts why gay men use it the most)
- members of this group include amyl nitrite ("poppers") and butyl nitrite.

How are inhalants absorbed? Do they cross the blood brain barrier?

easily absorbed through the lungs --> bloodstream--> into the brain.

- act very acutely and quickly. effects also dissipate very quickly

how are inhalants measured?

parts per million ppm

why are inhalants a global problem?

they are inexpensive and easily accessible.

- countries that are around many factors it becomes a environmental issue and an occupational issue if you work in the factories from constant inhalation although it might not be intentional drug seeking.

-they are also known to be a gateway drug.

are effects of inhalants long acting or short?

they are acute and short acting.

what are the effects acutely?

- similar to alcohol intoxication; euphoria (high feelings) stimulation and disinhibition, followed by drowsiness and lightheadedness.

what are the effects at greater exposure? (repeated exposure)

- strong depressant effects-- slurred speech, poor coordination, ataxia, lethargy.
(sometimes but rare sensory distortions and hallucinations)

what are the effects at very high doses?

- can lead to anesthesia, loss of consciousness and coma

is there a difference with frequency of use?

yes
- Low-frequency users: Mainly positive effects
- High Frequency users: mixture of positive and aversive effects irritably depression and suicide

is there a high dependency on inhalants?

most users do not become dependent but some develop tolerance and dependence. most transition to other drugs, gateway drug

is there withdrawal symptoms with inhalants? what are they?

- nausea, fatigue, irritability, anxiety, sleep disturbances and cravings

whats the mechanism of action?

its not well understood.
But, when talking about toluene
- the actions of the mesolimbic dopamine system is being released from the VTA onto the NAcc and the prefrontal cortex is activated by toluene

where is toluene highest concentration in? (suggesting where its having its acute effects)

high uptake in the striatum, thalamus, and deep cerebellar nuclei.
this is where they're binding/interacting

what are the class of inhalants considered?

CNS Depressants, similar to ethanol (alcohol)

when talking about toluene where does it bind? what does it do?

- toluene binds to the same receptors as ethanol, the GABA A receptor, where its enhancing inhibitory GABA A receptor activity and glycine receptor function.

- it inhibits activity of NMDA receptors (just like ethanol)

- it inhibits activity of nicotinic cholinergic receptors. (ethanol does not do this)

how else do inhalants influence?

since they act in the VTA they are shown to influence several voltage-gated ion channels

what are the effects of prolonged exposure to toluene and other inhalants?

affect ion channels in a very different way vs acute.
- counterregulatory response occurs in which function and expression of GABAA receptors is reduced and function and expression of the NMDA receptors is enhanced

what is sudden sniffing death syndrome? how does it happen?

can happen with a single use and can be fatal. causes cardiac arrhythmia.

what damage does repeated use have?

damage heart, liver, kidney, lungs, and bone
- chronic inhalation can also impair growth

when it effects bone marrow what disease does it cause?

bone marrow toxicity causes anemia in chronic users

what does nitrous oxide specifically effect?

inactivates vitamin B12, causing anemia (like alcohol)

inhalants have high lipid content where do they collect?

they collect in lipid matter, what matter, and cause neuronal destruction, myelin destruction and degeneration

what are the neuronal result of problematic chronic toluene use?

- apathy and inattention
- memory impairment
-visuospatial dysfunction

think about brain damage is occurring and effecting cognitive and motivational impairment

- cognitive function can be recovered if use it stopped over a period of years

what can cause permanent brain damage

sniffing leaded gasoline. cannot be revered. not common bc lead is taken out of our gas

do inhalents cross the placental barrier? how does it effect fetus?

inhalants do cross placental barrier. infants are born prematurely with low birth weights and can have physical malformations of the head and face similar to children of alcoholic women

What is GHB?

Hydroxybutyrate. structurally similar to GABA A

how GHB found in the brain?

GABA A is broken down to--> succinic semialdehyde via GABA Aminotransferase which is further broken down to ---> GHB via succinic semialdehyde reductase

what is the relationship of GHB and GABA?

GHB can be copackaged with GABA by VIAAT (the vesicular inhibitory amino acid transporter)
in extreme cases they can be associated with excitotoxicity related to GABA signaling

how was GHB discovered?

in search for a GABA analog

why was GHB sold as a dietary supplement for body builders?

helps promote sleep so muscles are able to physically get bigger.

what are the effects of GHB

relaxation, euphoria, sexual arousal

why is GHB used as a club drug?

because its like a date rape drug, it doesn't make you party but given to someone puts them to sleep.

how is GHB sold?

solution in water. it has no color or odor.

how is GHB absorbed? does it cross the blood brain barrier?

it is absorbed from the GI tract and readily crosses the blood-brain barrier

what are the effects of GHB under low doses and high doses?

under low doses:
Produce an alcohol-like experience. Mild euphoria, relaxation and social disinhibition

high doses:
cause lethargy, ataxia, slurring of speech, dizziness, nausea and vomiting.

how does GHB look with overdose?

very dangerous.
- causes respiration depression
- causes unconsciousness or comatose (coma)
- seizures may occur

how does GHB effect lab animals?

GHB-induced inhibition of DA release causes
- Hypolocomotion (shaking/flinching)
- catalepsy (muscular rigidity and immobility)
Decreases in NMDA receptors and toxic effects of hippocampus cause
- impaired spatial learning in rats given

what do toxic effects on the hippocampus and reduced NMDA receptor expression and nerve cell loss cause?

impaired spatial learning in rats given repeated moderate doses of GHB

does GHB have rewarding and reinforcing effects? (in lab animals)

GHB does give rewarding and reinforcing effects when tested at appropriate doses and under the right experimental conditions.

when compared to lever press for cocaine they did not always respond to GHB. (usually want cocaine but this proves individual based)

what does GHB activate?

GABA B metabotropic receptors
- acts as a allosteric modulator
- GHB is a weak agonist

what happens if you lack GABA B receptors and take GHB? (lab animal studies)

- GHB still has binding sites but the GHB does not give any effects

what can block GHB effects?

GABA B antagonists

what cannot block GHB effects?

GHB receptor antagonist
- a GHB receptor antagonist cannot block the effects
of GHB because the GHB site is not the GABA site.
- GHB is a negative allosteric modulator

in Europe what are the medical uses of GHB?

- used to treat narcolepsy
- as an IV anesthetic
- in some cases treatment for alcohol withdrawal (like the BDZs)

what is reported by recreational users of GHB?

- Initial positive effects; euphoria
- during the come down--> unpleasant effects such as weakness and anxiety

what are the risks when using GHB?

- Intoxication is similar to alcohol-- Drinking while driving
- Overdose is possible
- tolerance
- withdrawal symptoms

is there tolerance built to GHB?

Yes the more you use the more tolerant you become the higher risk you are for respiratory depression and heart failure ect.

is overdose possible with GHB? is it fatal?

Yes overdose of GHB is similar to alcohol, causes:
- unconsciousness or coma
- respiratory depression
- bradycardia
- hypotension

what does withdrawal of GHB look like?

similar to other drugs.
- anxiety
- agitation
- tremor
-tachycardia
-insomnia
- confusion
in extreme cases-- hallucinations and delirium

what is AAS?

anabolic-androgenic steroids
- steroid hormones used to increase muscle mass (anabolic) and have masculinizing, or testosterone-like, properties (androgenic)

what is the anabolic part?

the increasing muscle mass is the anabolic part

what is the androgenic part?

the masculinizing or testosterone like properties

are the AAS drugs addictive?

evidence shows that they are abused and could produce an addiction like dependence
- the dependence itself does not produce a state of euphoria and the drugs themselves generally dont interfere with daily function
- they are not considered drugs of addiction under the DSM

what about AAS is structure is important?

they are very structurally similar to testosterone

why do individuals use the drug AAS?

increase muscle mass which give more strength and enhance performance

the androgenic actions are the ones that are getting taken advantage of therapeutically but cause the side effects for individuals that are using these for performance enhancing drugs like athletic performance.
the masculinizing the testosterone like properties are often the side effects

what increases when taking AAS drugs?

- muscle strength
- muscle volume
- sexual function DOES NOT change

what kind of action do AAS have?

AAS have Androgenic action

- they are agonists at androgen receptors which are present in many tissues including skeletal muscle.

in the inactive state where are the androgen receptors located?

In the cytoplasm of the cell

the steroid hormone binds to the androgen receptor in the cytoplasm where --> causes translocation of the receptor to the nucleus--> where it acts as a regulator to gene transcription---> the main genes it effects are the ones involving muscle mass, and protein synthesis to increase muscle mass

to the nucleus where it regulates transcri

Where is the steroid hormone (from the AAS drug) binding to initially?

the androgen receptor in the cytoplasm

after the steroid hormone binds to the androgen receptor in the cytoplasm where does the androgen receptor translocate?

to the nucleus

what happens when the androgen receptor goes to the nucleus?

it regulates gene transcription

when the androgen receptor is in the nucleus and is regulating gene transcription what genes is it effecting and why?

the main genes it effects are the ones involving muscle mass, and protein synthesis to increase muscles

what are other effects of anabolic steroids?

- Increase proliferation of satellite cells in muscle that are necessary for the formation of new muscle fibers

- promote differentiation of local stem cells into muscle cells while inhibiting an alternate differentiation pathway into adipose (fat) cells.

can effect other genes like

- cardiovascular
- effects on liver
- effects on the skin and hair
- growth effects and behavioral effects

what are the behavioral effects of AAS drugs?

Roid rage
- increased sex drive
- mood changes (depression and mania)
- increased anxiety, irritability. and aggressiveness
- dependence

is there withdrawal effects on AAS drugs?

yes typical withdrawal symptoms.

what are the reinforcing effects of AAS?

seeing yourself grow and get big. more motivational no euphoric high

what are the two metabolites of testosterone?

1. 5α-reductase
2. Aromatase

What does 5α-reductase do?

converts testosterone to 5α-dihydrotesterone (DHT), more potent than testosterone as an androgen receptor agonist

what does Aromatase do?

converts

testosterone ---> estradiol = to estrogenic hormone

how do u mediate the subjective and behavioral effects of AAS

by androgen receptors but also by estrogen receptors in the brain

what happens with long term exposure of interactions of AAS

likely to cause interaction of AAS with other molecular targets.

what is the main use for testosterone?

male hypogonadism

what is male hypogonadism?

Failure of the testes to produce testosterone, sperm, or both)

what is primary hypogonadism?

rare genetic mutation or diseases cause the testes to be unresponsive to LH and FSH
- the hypothalamus pituitary gland is producing LH and FSH but the testes are unresponsive to it.

what is secondary hypogonadism?

trauma or mutations or diseases that effect the hypothalamus causes pituitary damage resulting in severe reduction in LH and FSH secretion.

what are symptoms of hypogonadal men?

1. poor libido (low sex drive)
2. erectile dysfunction
3. sterility
4. loss of muscle mass
5. other adverse effects

is testosterone replacement therapy used in women?

in postmenopausal women.

- after menopause woman's gonadal hormones decline

-->using testosterone treatment therapy helps improve sexual function and musculoskeletal health in postmenopausal women.

what systems do AAS drugs effect?

- Dopaminergic
- Serotonergic
- Vasopressin