PBSI 336 -- EXAM 4 (minus marijuana)

What are the effects of repeated cannabis use while still using the drug?

- Amotivational syndrome (similar to depression)

- Impaired attention and memory

- Reproductive system impairments in males

i. Lower testosterone, sperm counts, and sperm motility

Spice and K2

herbs laced with synthetic cannabinoids sold under several names

- Marketed as "safe" legal alternatives to marijuana

- But not safe or legal!

potential causes of consuming Spice and K2

intoxication, withdrawal, psychosis, and overdosedeath

cannabinoid (CB) receptors

where mj interacts

- CB1 cannabinoid receptors: located on presynaptic terminals for retrograde signaling

- The endogenous ligands for CB receptors (CB1 andCB2) are endocannabinoids.

Endocannabinoids (endogenous cannabinoids) -- 2 types

high lipid solubility

1. Anandamide: partial agonist for CB1 receptors

2. 2-AG: full agonist for CB1 and CB2

Endocannabinoids are lipid neurotransmitters andretrograde messengers, this means...

No vesicles -- Too lipid soluble to be stored in vesicles

- Synthesized on demand in the post-synaptic side of the synapse

endocannabinoids travel retrogradely to the pre-synaptic terminal and bind to ____ receptors

CB1

Inactivation: enzymatic degradation

two known cannabinoid receptors

CB1 and CB2

- both metabotropic, coupled to Gi (inhibitory)

- CB1 expression in brain and spinal cord

- CB2 expression mostly in immune system

CB1 receptor

expressed at high levels in CNS

- important for rewarding effects and "high" from cannabis

- most abundant GCPR in mammalian brain

function of Gi coupled protein from CB1

reduces activity of voltage-gated Ca2+ channels, thus inhibiting calcium-mediated nt release

Endocannabinoids are involved in both STD and LTD

short-term plasticity (seconds to minutes) and long-term plasticity (hours +)

- LTP/LTD, a component of learning

Endocannabinoids are the principal components of ____ ____ ____.

retrograde synaptic signaling

Low doses of THC:

- conditioned place preference (CPP)

- self-administration

High doses of THC:

- conditioned place aversion (CPA)

- no self-administration

CB1 agonists increase DA firing in ___ and increase DA release in ___ -- via disinhibition

VTA, NAc

disinhibition: inhibition of GABA inputs onto DA neurons

Animals will self-administer ___ _____ (likeTHC or 2-AG) directly into VTA or NAc

CB1 agonists

Cannabinoids injected into NAc cause

pleasureable reaction to taste

- MUNCHIES

Cannabinoids Injected into hippocampus cause deficits in...

working memory

- Blocked by CB antagonist rimonabant into hippocampus

Endocannabinoid roles

Endocannabinoids are normally involved in reward, feeding, and learning.

CB1 antagonists or CB1 gene knockout:

- Block self-administration of THC -- but also decrease self-administration of other drugs: alcohol, opioids, cocaine, nicotine

- Decrease sensitivity to all rewards (food or drugs) and decrease NAc dopamine release

In animals, CB1 antagonist ___ decreased food consumption.

AM6545

- due to effects causing reduced motivation and reward

CB1 knockout mice show normal fear learning but impaired ____ _____

extinction learning

- they keep freezing at sound of tone even after several tones without footshock

experiment indicates that endocannabinoids are important for what kind of learning?

extinction learning (probably due to role in LTD at synapses)

CB1 knockout mice also show enhanced retention of other types of memory:

retain recognition memory for longer

THC effects in mice:

- Rewarding

- Increases feeding (pleasure)

- Impairs learning/memory

- Hypoalgesic (reduced pain)

**All blocked by CB1 antagonist

CB1 antagonist or knockout effects:

- Reduces reward

- Decreases feeding (motivation)

- Impairs extinction learning

- Hyperalgesic (enhanced pain)

the effects of THC and CB1 antagonist/knockout indicate that...

THC mimics and amplifies the normal role of endocannabinoids in reward, feeding, and memory.

cannabis is not addictive. T or F?

fALSE

-Treatments are mainly psychosocial: CBT, relapse prevention

cannabinoid hyperemesis Syndrome

- occurs years after regular use

- causes cyclic vomiting/nausea

does long-term marijuana use affect the lungs?

not a lot

- mj does not cause lung cancer or dec pulmonary function

reduced cognitive function?

Some impairments to decision making/planning

- even after 3+ weeks of abstinence

mj leads to significantly reduced...

gray matter in areas of orbitofrontal cortex

- IQ

after rats were exposed to CB agonist as adolescents, as adults they showed:

- Reduced cognitive (memory) function

- Reduced dendritic complexity in prefrontal cortex (dendrite number and length

___ receptors are important in neurodevelopmental changes during adolescence.

CB1

Studies have found an increased incidence of ______ among cannabis users.

psychosis

- smoking mj puts you at higher risk for psychosis than schizophrenia

Greatest predictors of psychosis risk are... (2)

- daily use

- high-potency cannabis

Psychosis risk increases even more during early....

abstinence/withdrawal

- cannabis withdrawal associated with triggering and exacerbating first-episode psychosis

Cannabis-induced psychosis dramatically enhances the risk of transitioning to ____ ______ within 3 years, particularly for young males.

chronic psychosis (schizophrenia)

2017 report on cannabis

comprehensive review of recent research or health effects of rec/therapeutic use

- cannabis users in US inc from 2002-2015

therapeutic effects of cannabis

- reduced pain

- reduced nausea/vomiting

risks of therapeutic mj

immediate:

- inc risk of car accidents

- impaired learning, memory, attention

Repeated use:

- no inc risk of cancer (newer reports >> brain/neck, chronic bronchitis)

- inc risk of developing schizophrenia or psychosis

- inc risk of social anxiety, suicidal thoughts

**both have conclusive evidence

glutamate -- synaptic transmission

- packaged by?

- following release?

- packaged by VGLUT1, 2, 3

- inactivation by reuptake transporters: EAAT 1-5 (excitatory AA transporters)

functional roles of glutamate

synaptic plasticity, learning and memory

which receptors play a role in synaptic plasticity?

AMPA, NMDA

- long-term potentiation (LTP)

ketamine is rewarding in humans. T or F?

true

ketamine reward mechs

- ketamine self-admin by animals

- DA release in NAcc

- no synaptic plasticity after ketamine >> lower addiction liability

salvinorian A

selective KOR agonist (other KOR agonists are aversive and not hallucinogenic

- rewarding (CPP) and reinforcing (self-admin) in animals

Salvinorian A self-admin blocked by

- KOR antagonist

- CB1 antagonist

Salvinorian A dec activity in ____ in humans (like psychadelics)

Default Mode Network (DMN)