Lecture 4&5: Cocaine and Weed

Dopamine transporter targeted psychostimulants

• cocaine

• methamphetamine

• D-Amphetamine

• methylphenidate

What is the role of psychomotor stimulants

to act directly at dopamine terminals to increase synaptic dopamine

Cocaine

• competitive dopamine transporter antagonist

• blocks reuptake of dopamine, norepinephrine, and serotonin

• also targets sodium channels, sigma receptors and kappa receptors

Cocaine increasing extracellular dopamine

requires presynaptic excitation

Amphetamine increasing extracellular dopamine

DOES NOT REQUIRE presynaptic excitation

THC

main psychoactive cannabinoid in cannabis

Cannabidiol (CBD)

• Not psychoactive but may be medicinally relevant

• Anti-anxiety, anti-psychotic, anti-inflammatory, & anti-nausea effects

Cannabinol (CBN)

• Primary degradation (breakdown) product of THC

• Low in fresh cannabis but increased as stored due to exposure to oxygen and light

• Minimal psychoactive activity

Cannabinoid Receptors in the Brain

• amygdala

• basal ganglia

• cerebellum

• hippocampus

• neocortex

• nucleus accumbens

• spinal cord

Effects of Cannabis

• bloodshot eyes

• dry mouth

• intense hunger (hypothalamus)

• increased heart rate

• muscle relaxation (cerebellum)

• drowsiness

• euphoria (NAc)

• increased appreciation of humor

• impaired reaction time (basal ganglia)

• alterations of perception

Cannabis Withdrawal Effects

• craving for cannabis

• irritability

• anxiety

• depression

• restlessness

• sleep disturbances

• decreased appetite

• cognitive impairment

Cannabinoid Receptor 1 (CB1R)

• g-protein coupled receptor

• decreased usage in cannabis users

• down-regulation is reversible after at least 4 weeks of abstinence

CB1

• endocannabinoid receptor

• mainly in inhibitory neurons of the brain

• g-protein coupled receptor (metabotropic)

• functional selectivity for Gi/o

CB2

immune system, glia

Anandamide (AEA)

• endogenous cannabinoid (fatty acid neurotransmitter)

• mostly binds to CB1

• weak agonist, doesn’t produce maximal signal

• similar to THC

2-AG

• high-affinity ligand for both the CB1 receptor (central nervous system) and CB2 receptor (immune system).

• Mechanism: It acts as a full agonist at the CB1 receptor, initiating inhibitory G-protein signaling that reduces neurotransmitter release.

• stronger agonist, larger response than AEA

Endocannabinoids synthesis

• on demand synthesis: synthesized in postsynaptic neurons from cell membrane phospholipids, not stored in vesicles

• cleaved from lipid precursors in cell membrane on an “as needed basis

• trigger by post-synaptic mGluR activation or an increase in intracellular calcium

Effect of Endocannabinoids on VTA-NAc function

• retrograde signaling of 2-AG from VTA dopamine neurons (post-synaptic) to presynaptic GABA terminals tunes GABA, modulating VTA dopamine neuron activity and NAc release

• THC binding to CB1R on pre-synaptic GABA terminals decreases GABA, disinhibiting VTA dopamine neuron

Effect of THC on NAc function

THC binding to CB1R on pre-synaptic Glu terminals projecting from PFC to NAc blunts Glu release, reducing LTD in d1

Endocannabinoids and Reward

• maladaptive reward seeking is linked with dysregulated endocannabinoid signaling

• may be due to genetic factors (mutation in FAAH) or previous drug use

• affects dopamine increase in response to cocaine and alcohol

  • makes alcohol and THC a very common combination