Lecture 4

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.

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.