Neurotransmitters and Drugs PDF

Neurotransmitters and Drugs Learning objectives Drug Types Drugs exert their effects at synapses 1. Agonist - drug that turns up a function in a specific neurotransmitter system (increasing) 2. Antagonist - drug that turns down a function in a specific neurotransmitter system (decreasing)...

Neurotransmitters and Drugs Learning objectives Drug Types Drugs exert their effects at synapses 1. Agonist - drug that turns up a function in a specific neurotransmitter system (increasing) 2. Antagonist - drug that turns down a function in a specific neurotransmitter system (decreasing) But it doesn't mean turning up/down brain activity! 3. Other More than 100 identified neurotransmitters Neurons named for their neurotransmitters Small molecule neurotransmitters ○ 1. Amino acids, 2. Amines, 3. Others (acetylcholine, gas, unconventional neurotransmitters) Large-molecule neurotransmitters ○ 1. Neuropeptides, opioid peptides Co-occurence in the norm (most neurons will release several molecules/neurotransmitters) Psychoactive drugs act on neurotransmitter systems Amino Acid Glutamate: primary excitatory neurotransmitter; used throughout the brain ○ Most commonly used Ionotropic receptors ○ AMPAR ○ NMDAR ○ Kainate receptor Metabotropic receptors - more recently discovered ○ mGluR 1-8 Glutamate system is not usually targeted for therapy, mental health, drugs ○ You can’t localize your effects - if you change glutamate function, you will alter activity across the whole brain (thus, not a great therapeutic target) Glutamate (all antagonists) ○ Barbiturates ○ Nitrous oxide (“laughing gas”) ○ Ketamine - sedating and dissociative effects ○ Ethanol - drinking alcohol - Decreasing brain activity → sedation → until no activity at all = death (higher and higher doses) Agonists ○ High doses of glutamate agonists can lead to seizures, intense anxiety Spontaneous activity Link with epilepsy GABA (gamma-Aminobutyric acid) Primary inhibitory neurotransmitter (less ubiquitous than glutamate) Used throughout the brain Ionotropic (GABA A) and metabotropic (GABA B) receptors Agonists - increasing inhibition (brain is less active) ○ Benzodiazepines (Xanax, Ativan) - used recreationally; known for pleasing effects; anti-anxiety ○ Ethanol (alcohol) ○ Chloroform ○ Ether - gas anesthetic (no longer used) ○ All above drugs are sedating, dampening brain activity Antagonists - blocking inhibition in the brain (unpleasant effects) Amines Dopamine ○ Originates from two nuclei in the tegmentum Substantia nigra pars compacta Ventral tegmental area ○ Projects to some brain areas, but not everywhere ○ Dopamine is also made in the hypothalamus, where it is a hormone ○ Precursor from diet: tyrosine and phenylalanine Converted into dopamine, via enzymes ○ Overlaps with norepinephrine Both catecholamines ○ Five dopamine receptors (D1 → D5) All are metabotropic ○ Not just the pleasure/reward molecule! ○ Motivation for Brain Stimulation: Olds & Milner, 1954 Dopamine axons project from the Ventral Tegmental Area (VTA), to the nucleus accumbens (NAcc) Based on rat behavior, continuously pressing button to receive dopamine, leads researchers in 1954 to conclude that dopamine is related to pleasure Drugs of addiction and dopamine ○ All addictive drugs directly or indirectly increase dopamine transmission ○ Amphetamine, vaccine, heroin, nicotine, oxycodone, ethanol, cannabinoids, etc… directly increase dopamine transmission Dopamine and Parkinson’s Disease ○ Great decrease in voluntary movements; motor disorder ○ Caused by the loss of the substantia nigra, and those dopamine neurons ○ L-DOPA is a gold standard Parkinson’s Disease treatment → very effective treatment ○ Relationship between PD, L-DOPA and pleasure Do not see an increase in baseline levels of pleasure, but rather in voluntary movement/motor control ○ Side effects: hypersexuality, impulse control disorders  ○ No higher level of pleasure ○ Even with normal, healthy people → no change in pleasure upon administering L-DOPA Dopamine and schizophrenia ○ Schizophrenia medications are dopamine antagonists ○ The more the drug blocks dopamine, the more the symptoms of schizophrenia are relieved ○ Reduce positive symptoms of schizophrenia = hallucinations, delusions, disorganized speech/thoughts (perhaps schizophrenia has to do with high dopamine) Reducing dopamine reduces frequency of these symptoms Psychostimulants and dopamine ○ Psychostimulants act on the monoamine systems; monoamine agonists (i.e. cocaine, crack cocaine, methamphetamine, amphetamine, cathinones) ○ Drugs cause a wide variety of effects (including euphoria) ○ In high doses, they can also cause temporary psychosis ○ Not easily distinguished from positive symptoms of schizophrenia Separating pleasure from motivation Salamone (1990s) - T-maze task ○ Dopamine antagonist: can be systemically or directly injected into Ventral Tegmental Area (VTA) or Nucleus Accumbens ○ Low effort, low reward vs high effort, high reward experiment tasks with rats 1. Train rats to know the options: 1 path with little resistance and 2 sugars; 1 path with high resistance and 4 sugars 2. Give rats free choice baseline (allowing them to decide which pathway to choose) 3. They choose the high effort most of the time, in order to get the 4 sugars (high reward) 4. Administer dopamine antagonist drug to rats (blocking dopamine receptors) and we see that the rats switch their preference over to the low effort, low reward option 5. Allow rats to choose again, with the dopamine antagonist, and remove the high effort obstacle, and the rats switch back to choosing the high reward option (4 sugars) a. Probably because the obstacle was removed (= the high effort task) b. When you remove the work, the animals switch back to preferring the high reward option, but with the dopamine antagonist, they are no longer motivated to put in the effort to obtain the high reward Function of dopamine in 2024: relationship between reward and motivation; dopamine is related to manifesting the motivation to obtain the reward Dopamine antagonists ○ Decrease motivation, but not pleasure Dopamine and reward prediction error (operant conditioning experiment) - Schultz et al., 1990s.  ○ Primates are given a reward of grape juice and dopamine neurons fire ○ Associative learning: the light shines and then primates receive a drink of grape juice Dopamine neurons no longer fire for the grape juice Instead, they fire when the light turns on No longer firing for the reward, but rather the indication that the reward is coming ○ Then, present the light but no grape juice When the light shines, dopamine levels go up, but when no drink is presented, the dopamine goes down ○ Dopamine: the expectation of the reward; reward expectancy ○ Dopamine neurons shift what they fire for, based on our expectations (increase in dopamine when the reward is just what we expected, but goes down when it is not what we expected) Summary of study: ○ Dopamine neurons fire at first for unexpected reward ○ Then, they shift their firing to stimuli that predict reward ○ Then, they go silent when the predicted reward is not delivered ○ Can be chained forward in time Functions of dopamine 1. Important for movement 2. Important for motivation 3. Important for learning, related to movement and motivation 4. Important for levels of arousal, attention, executive function 5. NOT the pleasure molecule Epinephrine (adrenaline) Norepinephrine (noradrenaline) ○ Both a hormone (in the blood), and a neurotransmitter (between synapses) ○ It originates in the brain stem region called the locus coeruleus ○ Norepinephrine projects all over the brain ○ Two main receptor types (alpha and beta) with subtypes and sub-subtypes All metabotropic ○ NE and epinephrine act similarly, on the same receptors ○ Causes heterosynaptic facilitation ○ Baseline levels in wakefulness and arousal High levels of arousal, stress, etc = lots of norepinephrine activity in the brain ○ Enhancement of memory by stress and emotion ○ Evolutionarily useful Post-traumatic stress disorder (and norepinephrine) - Extremely high level of norepinephrine release, creating really strong memories - Propranolol (beta blocker; norepinephrine receptor antagonist) - for the heart; reduces heart rate by blocking beta receptors - Target beta receptors to interfere with PTSD  - Potential PTSD treatment via reconsolidation - Consolidation: process by which memories go from working into long-term memory - Reconsolidation: long-term memory back into working memory (memory recall) - It is possible to distort memories during recall - Still remembering traumatic events, but experiencing less of an intense, visceral response in reaction to remembering, using Propranolol - Experimented with Propranolol in experiences with heartbreak Histamine Serotonin ○ Originates from the raphe nuclei (reticular formation nuclei) - brain stem ○ Projects all over the brain, especially the cortex, the thalamus, the cerebellum ○ 15 receptor types, almost all metabotropic ○ Precursor: tryptophan (amino acid in the diet; including in turkey, tofu) And carbs are required to get tryptophan across the blood-brain barrier ○ Serotonin depletion effects/studies Bring people into lab to live there, eating provided food Control condition: eating normal diet Manipulation: chemically-altered food without tryptophan Serotonin levels deplete in manipulation condition Effects: cognitive flexibility Performing far worse on cognitive flexibility tasks Higher levels of aggression in lab (punishing others more severely) No decrease in mood Lower mood with participants with family history of depression No effects with participants with no family history of depression Selective Serotonin Reuptake Inhibitors (i.e. Prozac) ○ Prescribed for depression, anxiety, etc ○ Chemical imbalance theory of depression History of monoamines implicated in mood disorders, suggesting an imbalance ○ Block serotonin from being removed from the synapse Bind to the serotonin transporters and prevent them from taking it back into the axon; resulting in more serotonin function in the synapse ○ The effects of SSRIs are quick, but improvement is slow Affect transporters within the hour, but up to 1 month before you actually see benefits SSRI efficacy ○ Major problem with SSRI: not all data was published ○ 75% of all original SSRI data was not published → limiting our ability to make sense of the efficacy of the drug  ○ Original meta-analysis: SSRIs are no better than placebo for mild to moderate depression They may help with major depression Effect size is relatively small ○ More modern meta analyses are more favorable Effect size (how effective is it): very small Reduces depression symptoms, but not significantly ○ Side effects: changes in sleeping/wake, eating/appetite, sexuality Hallucinogens ○ Psychedelic drugs (LSD, DMT, ayahuasca, psilocybin) are serotonin receptor agonists ○ Radical changes to our conscious perception and thoughts, minimal effects on mood Effects on mood are very minimal (you experience the mood you brought into the experience: good mood before = ‘good trip’) ○ Recent reexamination of psychedelics’ therapeutic value in end of life care, PTSD, addiction, etc ○ Not addictive ○ Hallucinations: activity in the cortex, perhaps Acetylcholine (other small neurotransmitter) ○ The first discovered neurotransmitter ○ The neuromuscular junction ○ Basal forebrain - subcortical structures Wakefulness, attention, etc Overall levels of stimulation and wakefulness ○ Nicotine: acetylcholine receptor agonist Endocannabinoids (other small neurotransmitters) ○ Recently discovered neurotransmitter system ○ 2 neurotransmitters, 2 receptors, G-protein ○ Travel from the dendrite to the axon (retrograde transmission) - opposite travel ○ Very able to cross membrane, slip through membrane very well ○ Weakens the connection between 2 cells at a synapse ○ THC (in cannabis) is a cannabinoid receptor agonist (while CBD is less clear) Adenosine (other small neurotransmitters) ○ Adenosine triphosphate (ATP) is cellular energy Adenosine is an ATP byproduct Adenosine receptors all over brain Adenosine receptors (metabotropic receptors) are largely inhibitory Inhibition builds up throughout the day Adenosine: buildup and accumulation of daytime sleepiness (directly correlated) Feeling of becoming sleepy during the day ○ caffeine/theophylline  Caffeine: antagonist - blocks activity at adenosine receptors (prevents adenosine buildup, which then leads to blocking daytime sleepiness) Endogenous opioids (large molecule neurotransmitters) - relief of pain ○ Also known as: endorphins Endogenous morphine = portmanteau ○ Giant peptide neurotransmitters ○ Receptors are all metabotropic: G-protein coupled receptors ○ Largely inhibitory ○ Many neurotransmitters and types/subtypes ○ The neurotransmitter system that exogenous opioids (i.e. heroin) mimic Artificial Agonists ○ Pain relief = analgesia ○ Highly addictive - causing intense euphoria ○ Fentanyl (opioid crisis) ○ Receptors found in spinal cord, periaqueductal gray (PAG), nucleus accumbens, etc ○ Counteract effects by giving an opioid antagonist: naloxone Almost all metabotropic - plays a modulatory role