NEUR201 Neuropharmacology - Stimulants

Neuropharmacology: Stimulants

Neuropharmacology Block Overview

• Neuropharmacology is the study of drugs acting on the nervous system.

• It includes drugs that affect the brain and nerves regulating muscle and organ function.

• Key areas of focus include GPCRs (G protein-coupled receptors) and various drug types like PNS (Peripheral Nervous System) pharmacology, SNS (Sympathetic Nervous System) pharmacology, stimulants, depressants, and opioids.

Objectives

• Describe drug properties contributing to drug dependence.

• Describe two different ways drug tolerance can develop.

• Explain how tonic and phasic dopamine firing affects dopamine receptor activation.

• Explain how dopamine receptor affinity affects the feeling of euphoria and drug dependence risk.

Drugs of Abuse

• Drugs of abuse tend to increase dopamine release into the nucleus accumbens.

• Common examples include stimulants, opioids, alcohol, benzodiazepines, psychedelics, and cannabis.

• Some drugs are more likely to cause substance use disorder.

• Stimulants increase locomotion, wakefulness, and cognition.

• Stimulants significantly increase dopamine release in the nucleus accumbens.

• The strongest stimulants are dopamine releasing agents followed by NDRIs (Norepinephrine-Dopamine Reuptake Inhibitors).

New Zealand and US Drug Abuse Statistics

• NZ Drug Overdose Death Stats:

  • 2019: 124

  • 2020: 150

  • 2021: 171

  • 2022: 163 (0.032 per 1000 people)

• US Overdose Deaths:

  • 2023: 103,000 (0.31 deaths per 1000 people)

  • 8th leading cause of death in 2023 (number 1 cause of death in people aged 18-44).

Drug Harm in New Zealand

• Alcohol causes the most harm in New Zealand.

• 76% of Kiwis drank alcohol in the past year (lowest rate in over 10 years).

• 14% used cannabis in the past year, compared to 7.6% in the UK, 24% in California, and 25% in Canada

What is Drug Harm?

• Drug-related mortality.

• Dependence.

• Loss of income, housing, and employment.

• Injury.

• The extent to which drug use increases the chance of injuries to others, both directly and indirectly, including violence, traffic accidents, and fetal harm.

• Intergenerational impacts: the extent to which drug use directly or indirectly impacts future generations (e.g., family mana, transmission of addictive behaviors).

• Community impacts: the extent to which drug use creates a decline in social cohesion and well-being of the community.

What is Drug Dependence?

• Drug dependence occurs with one or more of the following:

  • Drug taking becomes compulsive, taking precedence over other needs.

  • Loss of control over the amount of drug taken.

  • Physical dependence: typically marked by withdrawal symptoms if drug use stops.

  • Drug tolerance: a decrease in the effect of a drug with repeated use, often correlated with drug dependence, but not always.

  • Psychological dependence: the urge to take drugs long after physical dependence has worn off.

• Drugs are not the only things that can be addictive: food, sex, gambling, social media, etc.

• Substance Use Disorder (SUD) is the clinical term for problematic drug use.

DSM V Diagnostic Criteria: Substance Use Disorder

• Severity:

  • 2-3 criteria: mild.

  • 4-5 criteria: moderate.

  • 6 or more criteria: severe.

• Examples of criteria:

  • Cravings and urges to use the substance.

  • Failure to manage responsibilities at home, work, or school due to substance use.

  • Continued use despite causing problems in relationships.

  • Recurrent use even when it puts the user in danger.

Substance Use Disorder (SUD)

• Severe SUD (6 or more criteria) is the clinical term for addiction.

• 13% of adults have mild to moderate SUD (2-5 criteria).

• Most societal drug harm occurs from this group (drunk driving, domestic violence, etc.).

• 4-5% of adults meet 6 or more criteria.

Tolerance

• Tolerance is a decrease in the potency of a drug after repeated use, requiring more drug for the same response.

• Causes of tolerance:

  • Change in receptor function (e.g., NACh desensitization).

  • Internalization of receptors.

  • Internalization of transporters.

  • Exhaustion of mediators.

  • Increased drug metabolism.

Mechanisms of Tolerance

• Change in receptor expression:

  • μ-opioid receptor expression is downregulated with chronic use (fewer receptors are present on neurons).

  • Dopamine transporters and receptors can be downregulated in methamphetamine abusers.

• Internalization of receptors:

  • Prolonged exposure to agonists will cause receptors to be internalized into the cell.

How Tolerance Impacts Neurotransmission

• Receptor downregulation:

  • Fewer receptors are available on postsynaptic neurons.

  • Neurotransmitter release results in less receptor activation.

  • Decreased intracellular signaling.

  • If fewer D1GPCRs are present, less cAMP will be produced inside the cell.

Receptors Involved in Drugs of Abuse

• Dopamine

• Alpha (noradrenaline)

• Serotonin

• NMDA (glutamate)

• Opioid

• GABA

• Cannabinoid

• Nicotinic (acetylcholine)

Dopaminergic Pathways in the Brain

• Dopamine is believed to be involved in several behavioral addictions (gambling, food, sex).

• The ventral tegmental area (VTA) releases dopamine.

• Dopamine receptors are found in the nucleus accumbens.

Dopamine in the Reward Pathway

• VTA activity increases (dopamine release into the nucleus accumbens) with the presence of an unexpected reward.

The Role of Dopamine in Drug Dependence

• Most, but not all, drugs that cause dependence increase dopamine levels in the brain.

• Phasic or “burst” firing of dopamine receptors is more likely to cause drug dependence.

Methamphetamine

• Methamphetamine and amphetamine enter vesicles and push dopamine and noradrenaline out into the synapse.

• Once in the synapse, these high levels of neurotransmitters will bind to dopamine and noradrenaline receptors.

• Methamphetamine enters the brain more rapidly than amphetamine.

• Methamphetamine exhibits increased dependence risk compared to amphetamine.

Serotonin Releasing Agents (SRAs)

• MDMA releases neurotransmitters similarly to methamphetamine.

• MDMA primarily releases serotonin rather than dopamine.

• MDMA is much less likely to cause dependence than methamphetamine.

Are Amphetamines Bad?

• Many drugs can be abused.

• It all depends on the dose and delivery method.

• Paracelsus: “The dose makes the poison.”

• A 1979 study found methamphetamine improved memory.

• Medicinal doses are much smaller than abused doses (>100 mg).

Cocaine

• Cocaine is an NDRI (Norepinephrine-Dopamine Reuptake Inhibitor).

• NET (Norepinephrine transporter) and DAT (Dopamine transporter) recycle dopamine/noradrenaline by removing them from the synapse.

  • increases noradrenaline binding to α2 receptors

  • increases dopamine binding to D1 receptors in the nucleus accumbens.

• Effects are not long-lasting, contributing to addictive potential.

• Smoking cocaine (crack) is much more addictive than intranasal cocaine.

Speed of Administration

• Routes like smoking or injecting drugs (vs. snorting or swallowing) lead to:

  • More frequent drug use.

  • Greater spending on drugs.

  • Greater loss of control over drug taking.

  • Higher likelihood of overdose.

Speed of Drug Absorption and Use

• The speed of drug delivery with NDRIs/NDRAs is more likely to imitate the phasic release of dopamine.

• The speed of drug delivery results in rats self-administering higher total doses of drug.

• Mouse studies show dopamine receptor downregulation differences between rapid and slow delivery of cocaine.

• The speed of drug delivery alters some gene expression pathways in neurons.

Why Does the Speed of Speed Administration Matter?

• D1 receptors are responsible for the dopamine “high.”

• D1 receptors are lower affinity receptors than D2 receptors.

• Affinity describes how tightly a drug or neurotransmitter binds to a receptor.

• Phasic (burst) firing of dopamine is required to activate D1 receptors.

• Rapid drug delivery increases D1 receptor activation.

• D2 receptors are occupied first before D1 receptors.

• High concentrations of dopamine are needed in the synapse to activate remaining D1 receptors.

Speed of Administration (Example)

• IV (intravenous) vs. oral delivery of methylphenidate leads to different activation of brain regions in humans.

• There is a significant correlation between subjective high rating and dACC (dorsal anterior cingulate cortex) functional connectivity with the striatum (composed of the caudate nucleus and the nucleus accumbens).

Review Questions

• Assuming an equal number of D1 and D2 receptors in a brain region, phasic dopamine release will activate more D2 receptors than D1 receptors BECAUSE dopamine has a higher affinity for D2 receptors than D1 receptors.

Dependence to Stimulants

• Not everyone who uses stimulants becomes dependent.

• Twin studies suggest a 50% genetic component of dependence.

• Amphetamines exhibit rapid tolerance.

• Dependence to amphetamine can be strong.

• Withdrawal effects can occur due to depletion of noradrenaline and dopamine.

• It is estimated that 10-15% of users develop dependence.

• Cocaine may exhibit stronger psychological dependence than physical dependence.

• Withdrawal symptoms are not nearly as severe as with opioids, alcohol, or benzodiazepines.

• Often used in binges after a withdrawal period rather than continuous use.

Drug Harm Based on Neurotransmitter Pathway

• Overview of neurotransmitter pathways affected by various drugs, including GABA, opioid receptors, dopamine, acetylcholine, serotonin, cannabinoid, and glutamate.

Subjective Effects That May Lead to Dependence

• Ego-Dissolution and Ego-Inflation in the context of Psychedelics shown with Ego-Dissolution Inventory (EDI).

• The connection between dose and feelings.

Summary

• Strong stimulants are NDRIs and NDRAs, increasing dopamine levels in the brain.

• The drug dependence risk is higher with the phasic release of dopamine from the VTA to the nucleus accumbens.

• Drugs that increase dopamine neurotransmission generally have a high risk of drug dependence.

• The route of drug delivery is very important in the development of dependence.

• The speed of drug delivery also plays a role in drug dependence.

• Phasic dopamine release and activation of lower affinity D1 receptors are primary drivers of stimulant dependence.

Additionally, repeated exposure to stimulants can lead to neuroadaptive changes in the brain's reward pathways, reinforcing the cycle of addiction.

Dopamine Pathways:

• Methamphetamine & Amphetamine:

  • Mechanism: These drugs enter vesicles and force dopamine and noradrenaline into the synapse.

  • Result: Increased levels of these neurotransmitters bind to dopamine and noradrenaline receptors.

• Cocaine:

  • Mechanism: Cocaine acts as a Norepinephrine-Dopamine Reuptake Inhibitor (NDRI).

  • Result: This action increases noradrenaline binding to α2 receptors and increases dopamine binding to D1 receptors in the nucleus accumbens.

Serotonin Pathways:

• MDMA:

  • Mechanism: Primarily releases serotonin rather than dopamine.

  • Dependence: Less likely to cause dependence than methamphetamine.

General Neurotransmitter Involvement:

Drugs of abuse can involve various neurotransmitter systems:

• Receptors: Dopamine, alpha (noradrenaline), serotonin, NMDA (glutamate), opioid, GABA, cannabinoid