Source: A Brain-Mind Odyssey, UC Berkeley
Tags: psychoactive drugs, caffeine, nicotine, alcohol, opioids, cocaine, amphetamines, psychedelics, cannabis, endocannabinoids, neuroplasticity, neurogenesis, neural development, synaptogenesis, apoptosis
Chapter 9 surveys the major classes of psychoactive drugs, from sedative-hypnotics (alcohol, barbiturates, benzodiazepines) through opioids, stimulants, psychedelics, and cannabis, with emphasis on the receptor systems each one targets. Chapter 10 covers how the nervous system is built, from embryonic stem cells and the neural tube through axon guidance, synaptogenesis, pruning, and lifelong neuroplasticity, plus the discovery that adult neurogenesis occurs in the hippocampus and olfactory system.
Caffeine
Adenosine receptor antagonist. Found in coffee (Coffea arabica, northeast Africa), tea (Camellia sinensis, East Asia), cacao (Theobroma cacao, Central/South America), kola, guarana, and yerba mate.
Nicotine
Agonist at nicotinic acetylcholine receptors. Derived from Nicotiana tabacum. Named after Jean Nicot.
Ethanol (alcohol)
Produced by yeast fermentation. Acts as a sedative-hypnotic: facilitates GABA, increasing Cl⁻ flow into cells (anxiolytic). Was the first general anaesthetic used in medicine.
Sedative-hypnotic
A class of drugs that amplify the inhibitory effect of GABA at its receptor, keeping Cl⁻ channels open longer. Includes alcohol, barbiturates, benzodiazepines, and inhalation general anaesthetics (e.g. sevoflurane).
Barbiturates
Synthetic sedative-hypnotic drugs with a low therapeutic index (TI), meaning the gap between a therapeutic dose and a lethal dose is small. More dangerous in overdose than benzodiazepines.
Therapeutic index (TI)
The ratio of the lethal dose to the therapeutic dose. A low TI means a higher risk of fatal overdose.
Benzodiazepines
Sedative-hypnotic pharmaceuticals such as Valium and Xanax. Also act on GABA receptors but with a higher therapeutic index than barbiturates.
Opium
Derived from the seed pod of the opium poppy (Papaver somniferum). Used for thousands of years as a pain reliever, cough suppressant, and treatment for diarrhoea.
Morphine
An opioid produced by crystallising opium. Discovered and named by Friedrich Wilhelm Sertürner in 1803, after the Greek god Morpheus. Gave rise to the modern understanding that plants contain specific chemical constituents with medicinal properties.
Opioids
A class of drugs that act on opioid receptors (which are GPCRs) in the CNS. Brand-name examples include Vicodin, OxyContin, and Percocet.
Heroin (diacetylmorphine)
A semi-synthetic opioid first marketed by Bayer in 1898 as an analgesic and cough medicine. Less hydrophilic than morphine (fewer OH groups), so it crosses the blood-brain barrier faster.
Endorphins
Endogenous morphines: polypeptides produced in the brain that act as agonists at opioid receptors. The discovery of opioid receptors (GPCRs) prompted the search for these natural ligands.
Fentanyl
A synthetic opioid roughly 10,000 times more potent than morphine.
Opioid toxicity
Depression of respiratory control, risk of overdose and death from respiratory depression, high addictive potential.
Cocaine
Derived from the coca plant (South America). Blocks reuptake of norepinephrine and dopamine at the synapse, producing CNS effects (wakefulness, decreased fatigue, positive mood, decreased appetite) and autonomic effects (increased heart rate, pupil dilation, sympathomimetic). Highly addictive; affects frontal lobe and limbic system. Can produce stimulant psychosis.
Amphetamine (and related molecules)
Includes Adderall and Ritalin. Causes vesicles to become "leaky," spilling norepinephrine and dopamine into the synaptic cleft. Results in extra stimulation, increased arousal, stamina, attention, focus, and sympathomimetic effects. Takes longer to be excreted than cocaine.
Psychedelics / hallucinogens
Drugs that alter perception, thoughts, and sensory phenomena. All interact with serotonin in the raphe nuclei. Strongly affected by "set and setting" (one's expectations and the physical environment).
LSD (lysergic acid diethylamide)
One of the most potent psychoactive substances known. Derived from ergot fungus. Discovered by Albert Hofmann in 1943. Hofmann's work also contributed to the recognition of serotonin as a neurotransmitter, a turning point in neurobiology.
Maria Sabina
Mazatec curandera who introduced the Western world to the ritual ethnobotanical use of psilocybin mushrooms in her culture.
Psilocybin
Primary psychoactive component of psychedelic mushrooms. Also isolated by Albert Hofmann in 1958.
DMT (dimethyltryptamine)
Occurs widely in nature, particularly in Amazonian plants used in shamanic rituals. Also found endogenously in the brain.
Mescaline
The most powerful psychoactive compound in the peyote cactus. Associated with intensification of thoughts, feelings, and perceptions. Used in Mexican rituals.
Schedule I controlled substance
A drug classified as having no currently accepted medical use, high potential for abuse, and a lack of accepted safety under medical supervision. Illegal to manufacture or possess except for limited research. Psychedelic drugs fall into this category.
Cannabis / THC / cannabinoids
Cannabis has long been valued for its fibre (hemp). THC (delta-9-tetrahydrocannabinol) is the major psychoactive constituent, one of around 60 cannabinoids. THC is very hydrophobic and crosses cell membranes easily.
Cannabinoid receptors (CB receptors)
GPCRs found virtually everywhere in the brain. The most abundant of all GPCRs.
Anandamide / endocannabinoids
Endogenous agonists at cannabinoid receptors. Anandamide was the first endocannabinoid discovered.
Retrograde signalling
Endocannabinoids travel backwards across the synaptic cleft, from the postsynaptic dendrite to CB receptors on the presynaptic axon terminal. This tunes the strength of synapses.
Dopamine hypothesis of psychosis
Proposes that psychosis results from excess activity in particular dopamine pathways. Antipsychotic drugs are dopamine receptor antagonists. Cocaine and amphetamine activate dopamine pathways and can produce psychosis.
THC vs. CBD
THC is psychotomimetic (can mimic psychosis). CBD is antipsychotic.
Depression (neurochemical basis)
Depressed mood is associated with underactivity (hypofunction) in certain monoamine neurotransmitter systems, especially serotonin. Current prevalence roughly 5%; lifetime prevalence roughly 17%.
Alcohol, barbiturates, benzodiazepines, and general anaesthetics all amplify the effect of GABA at its receptor
They keep Cl⁻ channels open longer, producing a stronger inhibitory effect
The key clinical difference among them is the therapeutic index: barbiturates have a low TI (dangerous in overdose), while benzodiazepines are safer
Opium is the raw plant product; morphine is its crystallised active compound
Semi-synthetic opioids (e.g. heroin) are chemical modifications that cross the BBB faster
Opioid receptors are GPCRs; the endogenous ligands are endorphins
Fentanyl is roughly 10,000 times more potent than morphine
Chief toxicity risk: respiratory depression
Cocaine blocks reuptake of dopamine and norepinephrine
Amphetamines cause vesicles to leak dopamine and norepinephrine into the cleft
Both produce similar downstream effects (increased arousal, sympathomimetic) but differ in mechanism and duration
All classical psychedelics (LSD, psilocybin, DMT, mescaline) interact with serotonin in the raphe nuclei
Effects are heavily influenced by set (mindset/expectations) and setting (environment)
All are Schedule I in the US
CB receptors are GPCRs, the most abundant GPCRs in the brain
Endocannabinoids (e.g. anandamide) are retrograde signals: they travel from dendrite to axon terminal and modulate synaptic strength
THC is psychotomimetic; CBD has antipsychotic properties
Human genome
46 chromosomes (23 pairs, one set from each parent). Approximately 3 billion nucleotide base pairs. Only about 2% codes for functional protein; most of the remaining 98% is transcribed into various RNAs.
Embryonic stem cells
Cells capable of continued division and differentiation into any cell type in the body. Influenced by soluble contact factors and growth factors.
Neural progenitor cells
Cells that are on the path to becoming neurons or glia, but not yet fully differentiated.
Cell differentiation
Governed by transcription factor proteins and RNA regulation.
Transcription factors
Proteins that bind to DNA and regulate gene expression. They travel along DNA, reading the code and producing matching mRNA.
Neurogenesis
The formation of new neurons from neural progenitor cells.
Gliogenesis
The formation of new glial cells from neural progenitor cells.
Neural tube
A structure formed within three weeks of conception. The entire CNS develops from this tissue as it grows and differentiates.
Growth cone
The flared-out structure at the growing tip of an axon. First described by Santiago Ramón y Cajal. Contains finger-like extensions called filopodia.
Cytoskeleton
Internal protein scaffolding that drives the extension of axons and dendrites. Made of microfilaments (polymers of actin, 7 nm) and microtubules (polymers of tubulin, 25 nm).
Roger Sperry
Worked with frogs and salamanders in the 1930s–40s. Showed that if you cut a frog's optic nerve and rotate the eyeball 180°, the nerve regrows its original connections and the frog sees the world upside down and backwards. Formulated the chemo-affinity hypothesis. Nobel Prize winner.
Chemo-affinity hypothesis
Nerve cells use specific chemical signals to guide their wiring during development and neural regeneration.
Neurotrophins / nerve growth factors
Proteins that promote the growth or survival of neurons. The first to be discovered was NGF (nerve growth factor), by Rita Levi-Montalcini and Stanley Cohen. Others include BDNF (brain-derived neurotrophic factor).
Nerve guidance factors
Molecules involved in directing axon and dendrite growth. Include ephrins, netrins, neuropilins, plexins. Work through contact factors (physically touch the axon) or soluble factors (diffuse through the surrounding fluid). Can attract or repel the growing axon.
Synaptogenesis
The formation of synaptic connections between neurons. Vast numbers of synapses form through the cerebral cortex in the year following birth.
Apoptosis
Programmed cell death. After overproduction of neurons during development, 50% or more of neurons in some brain regions are selectively eliminated.
Synaptic pruning
The elimination of unused synapses. Activity-dependent: the more a synapse is used, the more stabilised it becomes.
Neuroplasticity
The capacity of neural circuitry to alter its properties. Occurs throughout one's entire life. Includes both presynaptic and postsynaptic mechanisms.
Presynaptic neuroplasticity mechanism (example)
Prolonging depolarisation in the axon terminal so voltage-gated Ca²⁺ channels stay open longer, fusing more vesicles and increasing NT release. Result: stronger synapse.
Postsynaptic neuroplasticity mechanism (example)
Altering transcription/translation of genes coding for reuptake transporters. More reuptake transporter proteins means NTs are removed faster from the cleft. Result: weaker synapse.
Adult neurogenesis
Most neurons are produced between 5 weeks and 5 months of embryonic development, but stem cells have been found in the adult brain in two main regions.
Dentate gyrus (hippocampus)
A major region for producing new neurons in the adult brain. Likely important for learning and memory.
Subventricular zone (SVZ)
Located near the lateral ventricle. New neurons born here migrate to the olfactory bulb, probably to maintain olfactory function.
Olfactory epithelium regeneration
Adult neurogenesis in the peripheral nervous system. New neurons here allow us to maintain our sense of smell throughout life.
The human genome has roughly 3 billion base pairs coding for about 21,000 proteins
Only about 2% of the genome codes for protein; most of the rest is transcribed into RNA
Embryonic stem cells differentiate into neural progenitor cells, which become specific neuron or glia types
Differentiation is controlled by transcription factors
The neural tube forms within 3 weeks of conception; the entire CNS develops from it
Axons extend via growth cones, driven by the cytoskeleton (actin microfilaments + tubulin microtubules)
Growth cones are guided by chemical signals: contact factors (direct touch) and soluble factors (diffusing gradients), each either attractive or repulsive
Cut the frog's optic nerve and rotated the eyeball 180°
The nerve regrew in its original pattern, and the frog continued to see upside down and backwards
This demonstrated that axons use specific chemical signals to find their targets (chemo-affinity hypothesis)
NGF was the first neurotrophin discovered (Rita Levi-Montalcini and Stanley Cohen)
Guidance factors (ephrins, netrins, etc.) direct axon growth via attraction or repulsion
Ephrin–ephrin receptor interactions can mediate either attraction or repulsion
The brain overproduces neurons, then eliminates 50%+ via apoptosis
Unused synapses are pruned; active synapses are stabilised
Neuroplasticity operates through both presynaptic mechanisms (e.g. increased NT release) and postsynaptic mechanisms (e.g. altered reuptake transporter expression)
Occurs primarily in the dentate gyrus of the hippocampus (likely for learning/memory) and the subventricular zone (new neurons migrate to the olfactory bulb)
Olfactory receptor neurons in the peripheral nervous system also regenerate throughout life
⚠️ Know the mechanism of action for each drug class: which receptor or transporter it targets and whether it is an agonist, antagonist, or reuptake blocker.
⚠️ Therapeutic index (TI) is a favourite exam concept. Low TI = more dangerous in overdose. Barbiturates have a low TI; benzodiazepines are safer.
⚠️ Cocaine blocks reuptake; amphetamines cause vesicular leakage. Do not confuse the two mechanisms.
⚠️ Retrograde signalling by endocannabinoids (dendrite to axon) is a distinctive feature. Know the direction.
⚠️ THC is psychotomimetic; CBD is antipsychotic. Easy to mix up.
⚠️ Distinguish neurogenesis (new neurons) from synaptogenesis (new synapses) from gliogenesis (new glia).
⚠️ Sperry's frog experiment is a classic. Know the result (frog sees upside down), the conclusion (chemo-affinity hypothesis), and the implication (axons use chemical signals to find targets).
⚠️ Presynaptic vs. postsynaptic plasticity mechanisms: be able to give one example of each and state whether it strengthens or weakens the synapse.
⚠️ Adult neurogenesis sites: dentate gyrus (hippocampus) and subventricular zone. Know what each is thought to support.
Q: What is the mechanism of action of cocaine at the synapse?
A: Cocaine blocks the reuptake of norepinephrine and dopamine, increasing their concentration in the synaptic cleft and prolonging their stimulatory effects.
Q: How do amphetamines differ from cocaine in their synaptic mechanism?
A: Amphetamines cause neurotransmitter vesicles to become leaky, spilling dopamine and norepinephrine directly into the synaptic cleft, rather than blocking reuptake.
Q: What is the therapeutic index, and why are barbiturates considered more dangerous than benzodiazepines?
A: The therapeutic index is the ratio of the lethal dose to the therapeutic dose. Barbiturates have a low TI, meaning the effective dose is close to the lethal dose, making overdose more likely.
Q: What did Roger Sperry's frog experiment demonstrate?
A: When the optic nerve was cut and the eye rotated 180°, the nerve regrew its original connections, causing the frog to see the world upside down and backwards. This demonstrated the chemo-affinity hypothesis: nerve cells use specific chemical signals to guide their wiring.
Q: Describe one presynaptic mechanism of neuroplasticity that strengthens a synapse.
A: Prolonging depolarisation in the axon terminal keeps voltage-gated Ca²⁺ channels open longer, causing more vesicle fusion and greater neurotransmitter release, which strengthens the synapse.
Q: Where does adult neurogenesis occur, and what is each site thought to support?
A: Primarily in the dentate gyrus of the hippocampus (thought to support learning and memory) and the subventricular zone near the lateral ventricle (new neurons migrate to the olfactory bulb, likely maintaining olfactory function).
Q: What is retrograde signalling in the endocannabinoid system?
A: Endocannabinoids are released from the postsynaptic dendrite and travel backwards across the synaptic cleft to bind CB receptors on the presynaptic axon terminal, tuning synaptic strength.
Q: What is apoptosis, and why is it important in neural development?
A: Apoptosis is programmed cell death. The developing brain overproduces neurons, then eliminates 50% or more via apoptosis. This selective culling, combined with synaptic pruning, refines neural circuitry.
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