EB - Psychoactive Drugs III Flashcards
What was amphetamine first synthesized from?
Ephedrine, a naturally occurring compound
What are the actions of amphetamine? (4)
- Appetite suppressant
- Euphoria
- Raised blood pressure
- Can cause psychosis
What are some clinical uses of amphetamine? (3)
- Weight control
- Narcolepsy
- Attention deficit disorder
Is methamphetamine used clinically?
No, methamphetamine is not used clinically.
It is a street drug, more addictive than cocaine
What is the mechanism of action of amphetamine (and methamphetamine)? (3)
- Prevents reuptake of dopamine into the presynaptic terminal.
- Reverse transport: Amphetamine is taken up into the nerve terminal instead of catecholamines, increasing catecholamine levels in the synaptic space.
- Results in higher dopamine levels in the synaptic space.
How do addictive and aversive drugs affect dopamine? (2)
- Addictive drugs like opiates, ethanol, nicotine, amphetamine, and cocaine increase the release of dopamine in the nucleus accumbens.
- Aversive drugs do not have this effect.
What are the pathways involved in addiction? (2)
- Evidence for common involvement of the limbic system.
- Dopamine signalling is especially involved, including the VTA projection to the nucleus accumbens.
How does dopamine affect the nucleus accumbens and cortex? (3)
- Dopamine has an inhibitory effect on neurons in the nucleus accumbens, which project to the cortex.
- These neurons are typically inhibitory, meaning they normally reduce activity in the cortex.
- Increased dopamine activity suppresses these inhibitory neurons, leading to disinhibition of the cortex (i.e., the cortex becomes more active).
What are the addiction stages?
Impulsive stage:
- Substance use - pleasurable effects (e.g. euphoria)
- Heavy use - craving the reward (positive reinforcement)
Compulsive stage:
- Early dependence
- Late dependence - withdrawal effects occur (negative reinforcement)
What are the long-term changes associated with addiction in terms of D receptors? (2)
- D1 receptor activation (more available) causes an upregulation of adenylyl cyclase, converting ATP to cAMP.
- PKA translocates to the nucleus, phosphorylating CREB, leading to gene expression changes.
What is epigenetics?
Changes in gene expression that aren’t caused by underlying changes to the DNA sequence
Mediate effects of lifetime exposures
How are epigenetic changes related to addiction? (2)
- Epigenetic changes, like histone acetylation, alter chromatin structure and gene expression, contributing to addiction.
- Cocaine can induce histone acetylation in the nucleus accumbens
How does the loss of CBP affect cocaine-induced behaviors? (2)
- CBP (CREB-binding protein) is a histone acetyltransferase in the NAc.
- Loss of CBP in the NAc prevents cocaine-induced locomotion and conditioned place preference (CPP), suggesting CBP is necessary for cocaine’s effects on behavior.
What is the role of the Cre-LoxP system?
- The Cre-LoxP system allows gene manipulation at specific times.
- Cre recombinase interacts with LoxP sites to cut out DNA between them.
- This system is used to create knockouts or activate genes by removing stop codons.
What are the site-specific epigenetic changes after stimulant exposure? (5)
- Acute stimulant exposure rapidly induces genes like c-fos.
- Loss of CBP in NAc neurons decreases histone acetylation and alters c-fos expression in response to stimulants.
- After chronic stimulant exposure, these changes become desensitized.
- ΔFosB is induced by chronic stimulant use and binds to the c-fos gene.
- Chronic exposure leads to the loss of H3K9me2 at the Fosb gene, altering gene expression.
How is the orbitofrontal cortex (OFC) involved in addiction? (5)
- Addiction is associated with decreased OFC activity.
- Cocaine-addicted subjects show compromised reward systems and decreased OFC glucose metabolism.
- Downregulation of dopamine D2
- Deficit could be implicated in relapse
- Reversal by optogenetic activation restored normal behaviour
What is the role of the amygdala in chronic addiction? (4)
- Strong evidence links the amygdala to alcohol use disorder.
- Unlike cocaine, rats do not self-administer alcohol unless genetically predisposed (e.g., msP rats).
- Innate or acquired hyperactivity of extrahypothalamic CRF systems is associated with high alcohol preference
- Corticotropin-releasing factor receptor 1 (CRF1) antagonist, blocks stress-induced relapse-like behaviour
What are some potential targets for treating stimulant use disorders? (5)
- stimulants’ ability to block catecholamine reuptake out of the synaptic cleft.
- Targeting the molecular chaperone σ1R.
- Opioid system
- GABA transmission
- psychedelics like psilocybin.
What is the sigma-1 receptor (σ1R) and its role in addiction? (4)
- The sigma-1 receptor (σ1R) is an endoplasmic reticulum chaperone protein.
- It is widely expressed throughout the brain, including the midbrain and striatum.
- σ1R interacts with methamphetamine and cocaine at relevant concentrations.
- Exposure to these drugs increases σ1R levels in dopamine transporter (DAT)-expressing brain regions.
How does blocking σ1R affect cocaine’s effects? (3)
- Blocking σ1R prevents cocaine-induced conditioned place preference (CPP).
- It also inhibits cocaine-stimulated locomotion.
- σ1R siRNA prevents cocaine’s effect in enhancing D1R agonist-induced cAMP production.
What is the effect of σ1R activation on methamphetamine? (2)
- σ1R activation decreases methamphetamine-stimulated dopamine efflux without affecting basal dopamine neurotransmission.
- It reduces methamphetamine-induced locomotion, motivated behavior, and the enhancement of brain reward function.
This makes σ1R a potential target for therapies in addiction treatment.
What is psilocybin and its significance in addiction treatment? (3)
- Psilocybin is a non-addictive, serotonergic psychedelic with neuroplasticity-inducing properties.
- It shows promise in clinical trials for methamphetamine and cocaine-use disorders.
- For alcohol use disorders, psilocybin has a strong effect in decreasing the number of heavy drinking days.
