Lecture 4

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Questions and Answers

What is the role of Corticotropin-releasing factor receptor 1 (CRF1) antagonist in addiction treatment?

Promotes caffeine metabolism

Stimulates opioid receptor sensitivity

Blocks stress-induced relapse-like behavior (correct)

Enhances dopamine production

Which of the following is a target of stimulant use disorder treatments?

Blocking the reuptake of catecholamine (correct)

Increasing endorphin levels

Activating adrenergic receptors

Inhibition of serotonin receptors

What is the function of the σ1R chaperone protein in the context of chronic addiction?

Enhances GABAergic transmission

Blocks opioid signaling pathways

Regulates dopamine signaling and binds to DAT (correct)

Facilitates serotonin reuptake

Following methamphetamine or cocaine exposure, how does σ1R expression change?

Increases in DAT-expressing brain regions Signup and view all the answers

Which system does the research suggest is involved alongside the σ1R in addiction therapies?

GABA transmission modulation Signup and view all the answers

What effect does addiction have on D2 receptors in humans?

Downregulate their number Signup and view all the answers

What is a primary action of amphetamine?

It serves as an appetite suppressant Signup and view all the answers

Which neurotransmitter is primarily involved in the action of cocaine?

Dopamine Signup and view all the answers

Which drugs have been documented to increase dopamine release in the nucleus accumbens?

Opiates, ethanol, nicotine, amphetamine, cocaine Signup and view all the answers

What is the reverse transport phenomenon associated with amphetamine?

Amphetamine is taken back into the nerve terminal instead of catecholamine Signup and view all the answers

Which part of the brain is commonly involved in the reward pathways linked to addiction?

Nucleus accumbens Signup and view all the answers

Which of the following is NOT a use of amphetamine?

Anxiety management Signup and view all the answers

Which mechanism do addictive drugs share when affecting the brain?

They increase the release of dopamine Signup and view all the answers

What impact does blocking σ1R have on cocaine's effects?

It prevents cocaine-induced conditioned place preference (CPP). Signup and view all the answers

Which receptor is affected by cocaine in the presence of σ1R siRNA?

D1R Signup and view all the answers

How does σ1R activation impact methamphetamine-stimulated dopamine efflux?

It decreases dopamine efflux significantly. Signup and view all the answers

What effect do psychotomimetic drugs have on the limbic circuitry of the brain?

They cause neuroadaptive responses. Signup and view all the answers

Which psychedelic is known for its non-addictive properties and serotonergic action?

Psilocybin Signup and view all the answers

What is the role of epigenetic-based therapies in addiction treatment?

To control gene expression at the pre-transcriptional level. Signup and view all the answers

What underlying change is suggested to support the phenomena of drug addiction?

Altered signaling in the reward circuitry. Signup and view all the answers

What is a noted impact of psilocybin in relation to substance use disorders?

It is being studied as a treatment for methamphetamine and cocaine-use disorders. Signup and view all the answers

What is one of the primary long-term changes associated with addiction?

Changes in chromatin structure Signup and view all the answers

Which of the following epigenetic changes occurs due to exposure to cocaine?

Loss of H3K9me2 at the Fosb gene Signup and view all the answers

How does cocaine affect histone acetylation in the nucleus accumbens?

Induces histone acetylation Signup and view all the answers

Which statement best describes the role of the orbitofrontal cortex (OFC) in addiction?

May contribute to relapse due to decreased glucose metabolism Signup and view all the answers

What is the involvement of ΔFosB in response to chronic stimulant exposure?

It binds to c-fos to regulate expression Signup and view all the answers

What aspect of addiction is associated with the amygdala according to the provided content?

Hyperactivity of extrahypothalamic CRF systems Signup and view all the answers

Which of the following best describes a behavioral effect linked to histone modifications in addiction?

Altered learning and memory Signup and view all the answers

What method was found to reverse behavioral deficits in cocaine-addicted subjects?

Optogenetic activation of the OFC Signup and view all the answers

During which phase does the loss of CBP in the NAc notably affect c-fos expression?

During acute stimulant exposure Signup and view all the answers

What does increased histone acetylation typically indicate in the context of addiction?

Activation of genes associated with reward processing Signup and view all the answers

Study Notes

Neuropharmacology of CNS Disorders - Psychoactive Drugs

Psychoactive drugs act through distinct molecular effectors.
Subclasses of psychoactive drugs with addictive potential share a common ability to affect the brain's limbic circuitry and cause neuroadaptive responses.
Altered signaling in the brain's reward circuitry, particularly the dopaminergic pathway from the VTA to the nucleus accumbens, is central to the phenomenon of drug addiction.
Addiction is more complex than just dopamine and reward.

Addiction and Dopamine in Humans

PET imaging with 11C-raclopride is used to label D2 receptors in the brain.
Dopamine D2 receptors are downregulated in individuals with substance use disorders.
The reward system is compromised in individuals with addiction to multiple drugs.

Amphetamine

Amphetamine is a sympathomimetic amine, first synthesized from ephedrine.
Amphetamine acts as an appetite suppressant, causes euphoria, and raises blood pressure.
A side-effect of amphetamine use can result in psychosis.
Amphetamine is used for weight control, narcolepsy, and attention deficit disorder.
Amphetamine alters dopamine through reverse transport, increasing catecholamine levels in the synaptic cleft.

Common Mechanisms for Reinforcement/Addiction

Addictive drugs increase dopamine release in the nucleus accumbens (opiates, ethanol, nicotine, amphetamine, cocaine).
Aversive drugs do not increase dopamine release in the Nucleus accumbens.
Evidence supports a common role of the limbic system in addiction.
Dopamine signaling, especially the VTA projection to the nucleus accumbens, is crucial in addiction.
Dopamine is central to the action of cocaine.

Long-Term Changes Associated with Addiction

Chronic drug use causes long-term changes that impact dopamine receptors (D2, D3, D4).
Long-term changes can affect gene expression, particularly increasing CREB expression.
Dopamine, GABA, and other neurotransmitters are impacted in long-term changes/regulation.

Epigenetic Changes Associated with Addiction

Changes in chromatin structure are associated with alterations in gene expression.
Cocaine directly and indirectly alters gene expression.
These altered expressions contribute to aberrant cellular function.
Epigenetic changes can mediate the effects of lifetime exposures.
Historical cocaine use can alter chromatin structure, affecting gene expression.

Histone Acetylation Changes Associated with Addiction

Cocaine usage causes histone acetylation changes in the nucleus accumbens.
The loss of CBP in the NAc prevents cocaine-induced locomotion and conditioned place preference (CPP) — the development of a preference for drug-associated environmental cues, in animal models.
Locus-specific changes in histone modifications occur.

Site-Specific Epigenetic Changes After Stimulant Exposure

Acute stimulant exposure rapidly induces genes, including c-fos.
Loss of CBP in NAc neurons leads to decreased histone acetylation and altered c-fos expression, affecting stimulant-induced responses.
Chronic stimulant usage creates site-specific epigenetic changes.
AFosB is also induced after chronic stimulant exposure in the NAc.

Rescuing Epigenetic Changes to Affect Addiction

Single types of histone modifications may alter gene expression in a single brain region.
Downstream behavioral effects might be produced.
Epigenetic changes may be reversible.

Addiction Associated with Decreased OFC Activity

Cocaine-addicted subjects exhibit compromised reward systems and decreased OFC glucose metabolism.
OFC is involved in both insight and relapse in addiction.
Optogenetic activation may restore normal behavior.

Amygdala in Chronic Addiction

Innate or acquired extrahypothalamic CRF systems' hyperactivity correlates with high alcohol preference.
Corticotropin releasing factor, receptor one (CRF₁) antagonist can block stress-induced relapse like behavior in the amygdala.

Treating Stimulant Use Disorder

Stimulants block catecholamine reuptake.
Molecular chaperone sigma 1 receptor (σ₁R) binds to DAT, regulating dopamine signaling.
Interventions targeting sigma-1 receptors (σ₁) may prevent cocaine-induced CPP or locomotion and potentiating of the dopamine receptor's effect.
The opioid system and GABA transmission are also important in treating stimulant use disorder.
Psychedelics are also being investigated as potential treatments.

Targeting the Sigma-1 Receptor

The σ₁R protein is an endoplasmic reticulum chaperone that is widely expressed in the midbrain and striatum.
It interacts with methamphetamines and cocaine at relevant concentrations.
Levels of σ₁R increase in dopamine expressing brain regions after meth/cocaine exposure.
Blocking σ₁R prevents both cocaine-induced CPP and cocaine-stimulated locomotion.
σ₁R siRNA prevents the effect of cocaine in potentiating D₁R agonist-induced cAMP.

Psilocybin

Psilocybin is a non-addictive, serotonergic psychedelic with neuroplasticity inducing properties.
Trials for psilocybin use in methamphetamine and cocaine use disorders are also under investigation.

Psilocybin as Treatment for Alcohol Use Disorders

Psilocybin-assisted treatment for adults with alcohol use disorder, randomly assigned,showed reduced heavy drinking days compared to a placebo.

Drugging the Epigenome

Epigenetic-based therapies aim to directly control gene expression at pre-transcriptional levels.
Early epigenomic therapies have nonspecific effects across the genome and side effects.
Precision epigenomic therapies target specific genes or epigenetic states and may avoid side effects.

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Description

Explore the complexities of psychoactive drugs and their effects on the central nervous system. This quiz examines the molecular mechanisms of addiction, dopamine's role in reward circuitry, and the implications for substance use disorders. Dive into specific substances like amphetamine and their impact on brain function.