Neuropharmacology (I) Lecture Notes PDF

Topic : Lecture 1 **Topic 6: Neuropharmacology (I)** **The neuron:** Early philosophers and scientists speculated about how animals and humans could change their behaviour in response to external stimuli, and they tried to understand the mechanisms behind these changes **Early \"Balloonist\" The...

Topic : Lecture 1 **Topic 6: Neuropharmacology (I)** **The neuron:** Early philosophers and scientists speculated about how animals and humans could change their behaviour in response to external stimuli, and they tried to understand the mechanisms behind these changes **Early \"Balloonist\" Theories:** **1)René Descartes (1596--1650):** Descartes proposed that the body operated like a machine and that behaviour was controlled by the movement of fluids within the body. He suggested that when external events caused changes in these fluids in the brain and spinal cord, these changes were transmitted to the muscles, resulting in movement. = René Descartes: expansion of fluids within the brain & spine were transduced into muscle movements. 2\) Galvani's Contribution to Neuroscience: He demonstrated that electrical energy plays a crucial role in transmitting information between the brain and muscles. Results: A\) Electrical Induction in Frogs' Legs:\ Galvani found that applying an electrical current to a frog's leg caused it to twitch, even when detached from the body. This indicated that muscle movement could be triggered by electrical energy, not fluid pressure as earlier theories suggested. B)Neural Pathways & Behaviour:\ Galvani proposed that when a frog sees a fly (sensory information detected by the eyes), this sensory input is transmitted through electrical signals along neurons to the brain. The brain processes the information and sends an electrical signal down motor neurons, causing the frog to jump (muscular activity) and catch the fly. C\) Communication Between Neurons:\ Galvani's work suggested that communication between sensory neurons (which detect stimuli) and motor neurons(which control muscles) occurs through electrical impulses running along a neural pathway. **3)Camillo Golgi** developed a groundbreaking technique that allowed scientists to see individual brain cells for the first time. This method revolutionized our understanding of the nervous system. Golgi discovered a way to stain neurons by depositing black silver chromate particles into their membranes. This made neurons stand out clearly under a microscope, appearing as stark black structures against a lighter background. Before Golgi's staining method, neurons were difficult to distinguish because the brain's dense tissue made it hard to see individual cells. Golgi's technique provided a clear, well-contrasted image of neurons, allowing scientists to observe their unique shapes and connections. This staining method eventually led to the acceptance of the 'neuron theory,' which states that the nervous system is made up of distinct, individual cells (neurons) that communicate with each other. GOLGI WAS THE FIRST ONE but Staining methods have evolved significantly and are now used to identify many different types of brain cells, each with specialized functions within the nervous system. There are: Retinal cells (involved in visual processing), cortical pyramidal cells, cerebellar Purkinje cells (very big and extensive dendrites) **The neuron** **USE THIS ACTIVITY https://moodle.telt.unsw.edu.au/mod/hvp/view.php?id=7366650** **Dendrites:** branch-like structures that receive information/signals from other neurons. **Cell body (soma):** control region which contains the machinery that keeps the neuron alive & functioning. **Axon hillock:** where the excitatory & inhibitory input from other cells are summated to determine whether the cell will "fire" (AKA action potential) or not. **Axon**: thin fibre extending from the soma which is involved in transmitting electrical signals to other neurons (via an action potential) **Myelin sheath:** is a fatty layer that covers portions of the axon which speeds up electrical conduction down the axon. **Nodes of Ranvier:** allows the electrical charge to jump to each node, speeding conduction. **Terminal buttons:** passes the electrical signal to the dendrite of a neighbouring cell (via neurotransmitter release) **The action potential:** The process by which an electrical signal is transmitted along an axon. Basis for how brain cells communicate with each other along neuron pathways. \- Andrew Huxley's: breakthrough in understanding the action potential using the giant squid axon. The squid's axon was chosen because it is much larger than those of other animals, making it easier to measure electrical signals. -Resting membrane potential: brain cells create a resting membrane potential by pumping positively charged sodium ions (Na+) out of the cell & potassium ions (K+) into the cell. -More positive ions outside compared to inside the cell creates a negative electrical charge inside the cell (-70mV) -Occurs when a neurotransmitter from another cell, or a drug, causes sodium channels to open which allows sodium ions to flood inside the cell, creates a brief positive charge ("fires") inside the cell before the sodium ions are pumped out again. This brief positive electrical charge within the cell causes neighbouring voltage- gated sodium ions channels on the axon to open, allowing the positive electrical signal to move down the length of the neuron like a Mexican wave. \- As action potential travels down axon, myelin sheath acts as an electrical insulator. It blocks the transit of ions across the cell membrane except at the Nodes of Ranvier. This enables the electrical signal to pump down the neuron at a much faster speed than without the myelin sheath. **Neurotransmission** \- The action potential may continue into the next cell through a process known as neurotransmission or synaptic communication. This is how cells communicate with each other \- Synaptic cleft (gap): space between the terminal button & the dendrite (spine) of the target (neighbouring) cell.\ -Changes in neurotransmission at the synaptic cleft are the basis for learning & behaviour, **and it is here that drugs act to create addiction**. -When action potential reaches terminal, stimulates the release of neurotransmitters molecules from sacs called vesicles, those cross synaptic cleft, binding in synapse site in neighbour/receiving neuron. This allows electrically charged atoms to enter the receiving neuron and excite or inhibit a new action potential. \- after releasing neurotransmitter from vesicles to synaptic cleft, the sending neuron reabsorbs excess neurotransmitter molecules= process called reuptake **Synaptic Potentials** -Excitatory neurotransmitter and inhibitory: 2 types of neurotransmitters **Excitatory neurotransmitter:** opens sodium (Na+) channels allowing sodium ions to enter the postsynaptic cell which creates a positive internal charge increasing the probability of an action potential= What we call: Excitatory Postsynaptic Potential (EPSP) **Inhibitory neurotransmitter**: opens potassium channels (K+) releasing potassium ions trapped within the postsynaptic cell which creates a negative internal charge decreasing the probability of an action potential. Which is = Inhibitory Postsynaptic Potential (IPSP) Excitatory & inhibitory inputs compete ( each neurons have many come out so they compete, cell summate input to determine whether the cell "fires" or not)\ [ Drugs act by modifying this process to change cell firing rates] Topic 6: Lecture 2 **[Topic 6: Neuropharmacology (II) ]** **Neurotransmitters**: there are hundreds of different neurotransmitters molecules, and they do differ things in the brain, they either excitatory or inhibitory post-synaptic neurons **Key Neurotransmitters in Addiction:** Important in addiction: 1. Dopamine -- Involved in the brain\'s reward system; addictive drugs often increase dopamine levels, leading to feelings of pleasure. 2. Serotonin -- Affects mood and emotion; imbalances can lead to mood disorders and contribute to addiction. 3. Endorphins -- Natural painkillers; opioid drugs mimic endorphins, leading to dependency. 4. Acetylcholine -- Linked to memory and attention; nicotine stimulates acetylcholine receptors, reinforcing smoking behaviour. 5. GABA -- An inhibitory neurotransmitter that calms brain activity; alcohol enhances GABA's effects, causing sedation. 6. Glutamate -- The brain's primary excitatory neurotransmitter, crucial for learning and memory; drug abuse can disrupt glutamate pathways. 7. Endocannabinoids -- Regulate mood, appetite, and memory; cannabis directly affects this system, leading to altered states of consciousness. -Addictive substances act on neurotransmitter systems, either by mimicking their action, enhancing their release, or blocking their reuptake. -Over time, repeated drug use changes neurotransmitter levels and receptor sensitivity, reinforcing addictive behaviours and making it harder to quit. \- primary site of action on a addictive drug or they form a crucial part of the downstream cascade that drives the formation of addictive behaviour. -Each drug acts on its primary target receptors, which sets in motion a cascade of "downstream" neural communication. \- The ability of drugs to release dopamine, either directly or indirectly, is crucial for addiction. \- Cocaine & amphetamines act primarily on the dopamine system. \- Unique properties of other drugs, arising from their target receptor specificity, makes them attractive for different reasons. Example: nicotine- enhancer enabled by Acetylcholine -MDM attractive as a mood enhancer through serotonin A table with text on it Description automatically generated -Opium produces intense euphoria through endorphin system -alcohol: relaxant through its target GABA -TCH has sedative properties through its action on endocannabinoid system **[AFFECT OF DRUGS ON NEUROTRANSMITTERS:]** **Agonists & Antagonists** \- Ion channels are opened or closed by neurotransmitters. Depending upon what ions these channels allow to flow in which direction, the neurotransmitters either excite or inhibit the cell. -Drugs modify cell activity by having a similar molecular shape to the shape of a neurotransmitter molecule. -Drugs are classified as agonistic if they fit a receptor perfectly & thus cause the linked channel to open or close. -Drugs are classified as antagonistic if they fit a receptor imperfectly & thus block the action of the neurotransmitter. -Drugs may be both agonists and antagonists at different receptors, creating complex effects in different parts of the brain.  **Dose-response curve** -Compares behaviour or experience against dose taken -Dose-response curves: plot the response to drugs, indexed by a measure of behaviour or experience (e.g. pain relief) against the dose of the drug administered. Usually, S shaped because neurons have limits on how much they can fire. If fire too much: it can be excitotoxic \- At low doses there is little response as the dose increases so does the response, until an upper limit is reached where further increases in dose produce no additional response. \- Effective Dose (Called (ED) 50: is the dose at which 50% of the maximum response is achieved. **Dopamine** -Neurotransmitter, -There are 3 main dopamine pathways in the brain: 1\) Mesocortical Pathway 2\) Nigrostriatal Pathway -- not spoken on tutorial both only the 3rd 1)[Mesolimbic pathway]: Also known as the **reward pathway.** Ventral tegmental area (VTA) to the nucleus accumbens When a person consumes an addictive substance, dopamine is released in the ventral striatum, particularly in the nucleus accumbens, creating feelings of pleasure and reinforcing the behaviour that led to the substance use. - key for learning about rewarding properties of drug -- key for drug reward learning - common path for drugs to produce their rewarding effects - **Relevance to addiction**: Addictive substances cause a surge of dopamine in this pathway, reinforcing drug-seeking behaviour. - **How do we know that dopamine is involved in reward**?: Olds & Milner (1954): early evidence for the role of dopamine in reward, they noticed that rats favoured the location of the box in which they had received electrical stimulation of the medial forebrain bundle (midpoint of the mesolimbic pathway -- MSB is the midpoint between VTA and nucleus accumbens). So stimulating this area would stimulate reward. **Dopamine agonists** -Cocaine & amphetamine are dopamine (DA) agonists- increase the amount of DA presence in the synaptic cleft (via different mechanisms). -Cocaine blocks DA reuptake -- so it does not go back to the presynaptic cell and this allows more dopamine to be sitting in the synaptic cleft for longer periods of time and so the more dopamine available in the synaptic cleft, the more dopamine is available to be taken up by the postsynaptic cell \- So Cocaine is dopamine agonist -Amphetamine causes dopamine to be released from the vesicles into terminal button and reverses direction of dopamine reuptake (Amphetamine causes DA to be released from synaptic vesicles into the terminal button and, reverses the direction of the DA reuptake transporter)- AGAIN: making supernormal increase of DA availability within the synaptic cleft -Wise (1996): found that electrical self-stimulation reward was mediated by the mesolimbic DA pathway. Did rat test using different frequencies of stimulation (higher frequencies were more rewarding & supported higher rates of lever pressing to obtain the stimulation) but when rats were given amphetamine making lower frequency stimulation more rewarding, while dopamine antagonist requires higher levels of stimulation to achieve the same level of reward in rats. -Indicates that behaviours which cause an increase in DA activity will increase to the extent that DA is released. -Addiction appears to form by virtue of drugs releasing dopamine **[Dopamine: drug reward ]** Drug self-administration procedure: Rats are given access to a lever which if pressed causes the infusion of a drug into the blood stream. The fact that rats acquire the self-administration response to obtain drugs indicate that drugs are rewarding. The mesolimbic dopamine (DA) pathway is important for drug reward because research shows that damaging the nucleus accumbens (a key part of this pathway) stops animals from taking cocaine or amphetamines on their own. This means that drugs need to activate dopamine in the nucleus accumbens to reinforce drug-taking behaviour and make users want to take the drug again. Without dopamine activation in this area, the motivation to keep using the drug disappears. **[Serotonin ]** -Cell bodies for neurons that express serotonin (5-HT) are located in the raphe nuclei of the brain stem -serotonin is also known as 5-HT \- These neurons project also axons extensively across the Brain -5-HT neurons in the raphe nuclei play an important role in maintaining conscious arousal level (wakefulness), these cells are inhibited during sleep. -Has multiple roles in synaptic communication: - it acts on different ION channels to produce excitatory & inhibitory transmission of action potentials - diffuses into the extracellular fluid to excite neighbouring neurons -- (called neuromodulation) - interacts with other neurotransmitter - systems including glutamate and GABA to influence learning & memory which is important for cognition Serotonin is best known for its role in positive mood: evidence is the antidepressant medication influencing serotonin transmission in some way to increase availability of serotonin in synaptic cleft increasing mood **[MDMA/Ecstasy]** -Serotonin agonist -MDMA blocks serotonin reuptake. This action prevents the reabsorption of serotonin into the presynaptic neuron, causing an increase in serotonin levels in the synaptic cleft. Similar to: SSRIs (Selective Serotonin Reuptake Inhibitors) are a class of antidepressants that work by blocking the serotonin transporter (SERT) -Also: Hallucinogens (psilocybin, mescaline, peyote, LSD) & Stimulants (cocaine, amphetamine) also block 5-HT reuptake, but MDMA more \- So for being serotonin agonists: suggests that positive mood may be a common element amongst these drugs which helps maintain their recreational use. -MDMA (& hallucinogens) also release dopamine in the nucleus accumbens \- the dopamine enhancing effect of the drug determines if is gonna be addictive or not (addictive potential) \- MDMA release of dopamine is lower than cocaine and amphetamine so less addictive (MDMA'S relatively lower affinity for releasing dopamine compared to amphetamine & cocaine may explain why these compounds are ranked as having a lower addiction potential than other drugs with higher dopamine affinity) **[Endorphins (Opioids): Pain & Pleasure ]** -Another time of neurotransmitter important in addiction: ENDORPHINS -Endorphin is a (neuropeptide) -play a key role in pain reduction (analgesia) & subjective pleasure (euphoria). -Endorphin receptor is called: opioid receptors because they respond to opioids/opiates -These receptors are located throughout spine and sensory motor pathways of the brain -Opioid receptors work by opening potassium K+ channels or close Na+ channels reducing the likelihood of action potentials carrying pain signals. -Endorphins are released by pituitary glands during a fight or flight response to reduce pain sensation -Endorphins are also located within the VTA of the mesolimbic dopamine pathway (reward pathway) by inhibiting inhibitory GABA neurons (those control activity of other neurons) causing an increase in dopamine release in the nucleus accumbens **[Heroin & Dopamine ]** -Heroin works primarily on endorphin system but its effects also strongly involve dopamine. -After binding to opioid receptors, heroin indirectly increases **dopamine** levels in the brain\'s reward system. This happens because the activation of opioid receptors inhibits neurons that normally suppress dopamine release. As a result, dopamine floods the synapses, contributing to heroin's powerful reinforcing and addictive effects. Zito et al. (1985): allowing rats to self-administer heroin (press a lever to get a dose) until their behaviour became stable---meaning the rats had developed a regular pattern of heroin use. They damaged (lesioned) the nucleus accumbens in some rats. This brain region is known to be involved in reward and dopamine release. Conclusion: The study shows that the nucleus accumbens and dopamine are essential for heroin's rewarding effects. Without a properly functioning nucleus accumbens, the rats didn't find heroin as rewarding, so they used it less. This highlights how dopamine in the nucleus accumbens drives addictive behaviour. **[Endorphins: Pain & Pleasure ]** study by **Berridge & Kringelbach (2008)** on the neural mechanisms of emotional reactions to opiates: **Hedonic reactions**: The researchers used a simple test to measure **emotional reactions in rats**. They squirted either a **sweet (pleasant)** or **bitter (unpleasant)** solution into the rats' mouths. They recorded the rats\' **facial reactions** with a close-up camera. When the rat tasted something sweet, it would show **pleasure**, and with bitter, it would show **displeasure**. The researchers then **injected opiates** (like heroin or morphine) into different **subregions** of the rats\' **nucleus accumbens**---a brain area involved in reward and pleasure. **What they found:** - **Larger region (purple)**: The opiate injections in this part of the nucleus accumbens made the rats **dislike bitter tastes less**---they didn't react as negatively to the bitter solution. - **Smaller region (red)**: The opiate injections in this part **increased the rats' liking for sweet tastes**---they reacted more positively to the sweet solution. - **Very small region (blue)**: In contrast, a very small part of the nucleus accumbens injected with opiates actually **decreased the rats\' liking for sweet tastes**---they didn't enjoy the sweet solution as much. **Conclusion:** This study showed that different **subregions within the nucleus accumbens** have specific effects on how rats **experience pleasure and displeasure**. The results suggest that the **nucleus accumbens is involved in the brain's reward system**, but specific areas within it can influence how much the rat enjoys or dislikes certain tastes, and **opiates can modulate** these emotional reactions. This is important because it highlights that **reward and pleasure are not controlled by just one part of the brain**, but by **different subregions** that can produce **different emotional responses** to stimuli like sweet or bitter tastes. **Topic 6: Neuropharmacology (III) -LECTURE 3** **[Acetylcholine ]** -Acetylcholine has a role in cognitive capacity: sensitivity to sensory events, memory, speed of responding etc. -Alzheimer's disease is marked by broad impairments in cognitive capacity & characterised by destruction of acetylcholine cell bodies -Some brain cells that use **acetylcholine (ACH)** send signals to many different parts of the brain. These cells help manage **higher-level brain functions**, like attention, focus, and reacting to things happening around us. (These cells project broadly across the cortex, they are believed to modulate higher cortical functions as a whole.) -It functions as a cognitive enhancer (Acetylcholine acts like a **brain booster)**, t helps us stay focused and improves our ability to respond to events in our environment, making us more alert and reactive (improving attention & reactivity to environmental events) -At the cellular level, acetylcholine (ACH) increases the signal to noise ratio in the firing rate response to stimulation: **Signal-to-noise ratio**:\ Brain cells normally have a steady, **background firing rate** (like a quiet hum). When something important happens, they **increase** their firing rate to respond (this is called \"tuning\" because the cells are \"tuned\" to react to specific events). - The **signal** is the increase in firing rate that happens when something important occurs. - The **noise** is the constant, background firing rate that isn\'t related to anything specific. Acetylcholine helps **increase the difference** between the signal (important stuff) and the noise (background activity). This makes it easier for the brain to detect important events and respond to them quickly. -All cells have a background firing rate & increase this rate in response to appropriate stimulation (called 'tuning' because cells are tuned to certain event) and the difference between the signal & the noise (background) is crucial for detection & responding to environmental events. **Sillito & Kemp (1983): Study**: Visual cortex in cats: The researchers studied cells in the visual cortex of cats, which is the part of the brain responsible for processing visual information. The cats were anesthetised, meaning they were in a sleep-like state and couldn\'t move. They tested how these cells responded to bars of light moving across the visual field in different directions (either left or right). Each cell in the visual cortex is \"tuned\" to respond to certain visual stimuli. In this case, the cells preferred bars of light moving in a particular direction. However, in the control (anesthetised) state, the cells\' responses were not very specific---they weren\'t strongly reacting to one direction over the other. When acetylcholine (ACH) was applied to the visual cortex: The selectivity of the cells increased. In other words, the cells became much more focused on reacting to the light bars moving in their preferred direction (either left or right). This shows that acetylcholine makes the cells more attuned to specific visual stimuli, improving their response to things they are \"tuned\" for. **Acetylcholine: Nicotine** -Nicotine is an acetylcholine agonist, binds to acetylcholine receptors in postsynaptic cell. These receptors are coupled to Na+ channels, which open in response to nicotine binding exciting the cell & thus increasing the probability of an action potential. -Also binds to pre-synaptic ACH receptors located on the terminal button of cells which express endorphins -Cells in the VTA increase firing rate in response to tobacco smoke (TS, bottom right figure) so then this activation in the VTA is essential for nicotine to maintain self-administration behaviour -Nicotine works on several neurotransmitters systems= contributes to its high addictive potential, it increases cognitive function by activating the ACH system, increases pleasure, well-being or pain/stress relief by activating the endorphin system and increases reward of self-administration behaviour by activating the DA system(dopamine system). This study explores cognitive effects of nicotine: Foulds et al. (1996) study: abstinent smokers & never smokers completed a RVIP task(visual task) before & after nicotine or placebo. - Placebo injection: being an ex smoker or not it does not improve in task, after injection both groups showed improvement (so enhancement when acetylcholine is activated) and abstinent smokers were slower than never smokers and this could be because of: withdrawal or tolerance effect of nicotine or neurocognitive damage from smoking. **GABA: Inhibition** -GABA is the chief inhibitory neurotransmitter regulating neural activity throughout the nervous system. -The release of GABA onto receptors causes a shift in ion channels which causes the cell to hyperpolarize (negative charge in cells decreasing probability of action potential on neighbouring cells) -GABA cells often play the role of inhibitory "interneurons", which is cells that connect different groups of neurons, by holding other cell groups inhibited (unless they themselves are inhibited by another cell) meaning GABA cells help to **hold other groups of cells \"inhibited\"** or **\"quiet\"**, meaning they prevent these cells from firing too much or too quickly. -GABA cells usually **inhibit** (or reduce the activity of) other neurons. This helps to keep the brain\'s activity **balanced** by preventing any one group of neurons from becoming overactive. -I**nfluence by other cells**: However, GABA cells themselves can be **inhibited** by other cells. When other neurons inhibit GABA cells, this **removes the brakes** on the cells GABA is controlling, allowing them to become more active. -they provide "negative feedback" in the sense that excitatory cell firing rates cannot exceed an upper limit -- protecting effect to avoid excitotoxic death, produced by overstimulation. -GABA: Inhibition: The explanation of GABA\'s role in inhibition and how it relates to epilepsy: **GABA** is the brain\'s primary **inhibitory neurotransmitter**. Its main job is to **reduce neural activity** by binding to specific receptors (GABA receptors) on neurons, making it harder for these neurons to fire action potentials (electrical impulses). This inhibitory function is essential for balancing the brain\'s overall excitability. When GABA is active, it helps maintain a **healthy level of neural activity** by preventing excessive firing of neurons. -Epilepsy is a condition marked by **abnormal, excessive neural firing**, which leads to **seizures**. The hallmark of seizures is a transition from normal to **supernormal levels of action potentials** (overactivity) in the brain. An **EEG (electroencephalogram)** can record this abnormal electrical activity, showing the patterns of rapid, synchronized firing typical of seizures. -To control or stop seizures, **anticonvulsant drugs** act on the brain\'s neurons to restore balance by increasing inhibition and reducing excessive activity -Increase GABA availability (agonists): GABA agonists are substances that increase the availability or effectiveness of GABA in the brain, enhancing its ability to inhibit neural activity. This helps prevent excessive firing of neurons, reducing the likelihood of seizures. Block voltage-gated sodium channels: -These drugs **block sodium channels** on neurons. Sodium channels are essential for the generation of action potentials. By blocking these channels, the drugs **reduce the ability of neurons to fire action potentials**, which helps **control seizures**. Antagonize the actions of glutamate: Glutamate is the primary excitatory neurotransmitter in the brain. It promotes the firing of neurons. Anticonvulsant drugs can block or reduce the activity of glutamate, decreasing neural excitation and reducing the risk of seizures. **Summary:** anticonvulsant drugs work by enhancing inhibitory signals (like GABA), reducing excitatory signals (like glutamate), and blocking the propagation of action potentials (by blocking sodium channels) to prevent the abnormal neural firing that leads to seizures. **Glutamate: Learning** -Glutamate (Glu) is another neurotransmitter, is the most abundant neurotransmitter in the brain \- Is present in over 50% of CNS tissue. -plays a crucial role in learning & memory, is involved in change of synaptic connections between neurons= basis of changing behaviour -Heavily involved in neuroplasticity: the process by which pathways & synapses in the brain are changed as a result of experience. Plastic changes can occur with experiences in environment, behaviour, learning, drugs... Two functions performed by Glu receptors: 1)AMPA & Kainate receptors: respond to Glu release by opening Na+ channels thus initiating an action potential within the receiving cell. So theses areionotropic receptors =they directly control ion channels when activated by glutamate AMPA and Kainate receptors arespecific types of glutamate receptors When glutamate is released from neuron, binds to these receptors (AMPA and kainite) causing Na+ channels to open in receiving neuron Influx of Na+ generates=depolarization of the cell, which is the first step for creating action potential. This is a fast excitatory responses meaning it increases changes that receiving neuron will fire action potential In summary, AMPA and Kainate receptors help transmit signals quickly by opening sodium channels when glutamate binds to them, leading to neuron activation (action potential). 2\) NMDA Receptors: NMDA receptors are another type of glutamate (Glu) receptor, but they are distinct from AMPA and Kainate receptors. When glutamate binds to NMDA receptors, it causes the calcium (Ca²⁺) channels to open in the receiving neuron. Unlike AMPA and Kainate, it allows Calcium ca2+ into neuron, this entry activates a second messenger system inside the cell which are intracellular signalling pathways that help trigger various cellular responses. One effect of this process: Long-Term Potentiation (LTP), which is a form of synaptic plasticity, a change in the strength of synaptic connection and it occurs when the strength of the connection between the 2 neurons increases over time so is more efficient at transmitting signals and this is tough to be the cellular basis for learning and memory \* **Long-Term Potentiation (LTP)** occurs as a result of the activation of the **second messenger system**, which is triggered by the influx of **calcium ions (Ca²⁺)** through **NMDA receptors**. \- The second messenger system also leads= **Increase in AMPA Receptors** on the postsynaptic neuron. More AMPA receptors mean that the synapse can respond more strongly to glutamate, increasing the efficiency of communication between neurons. **Alcohol** -Alcohol antagonises post-synaptic glutamate receptors and reduces release of glutamate -Because it reduces activity of glutamate, it impairs memory and learning (reason why blackout when drinking occur) -Alcohol works as GABA agonist: so it further reduces excitation levels, and this affect on GABA that is responsible for sedative effects, anxiety reduction & motor incoordination. \- Alcohol also reacts endorphins producing the euphoric & analgesic effect -Alcohol is also dopamine agonist: increases dopamine activity in Nucleus Accumbens (It receives dopamine signals, which make us feel **rewarded** and **motivated** to repeat the behaviour that led to the reward) this increase activation is responsible for rewarding pleasant effect of alcohol and rewarding self-administration (When **dopamine** is released in the **nucleus accumbens** in response to a behaviour (like drinking alcohol), it reinforces that behaviour. The brain **learns** that this behaviour is rewarding and **motivates the individual to repeat it**) -Opiate release partially responsible for alcohol reward because alcohol self-administration can be reduced by opiate antagonists (e.g. naltrexone). Meaning the statement highlights the role of **endorphins** (the body\'s natural opioids) in alcohol\'s **rewarding effects** and explains why **opiate antagonists** like **naltrexone** can reduce alcohol consumption. So, alcohol stimulates the release of endorphin, endorphins is responsible for pleasure feelings and associates with alcohol consumption so the process makes alcohol reinforcing. \- **Naltrexone** is an **opiate antagonist**, which means it **blocks the action of endorphins** at their receptors in the brain. it **prevents endorphins** from binding to their receptors, thereby **reducing the euphoric and rewarding effects** of alcohol. This makes drinking alcohol less pleasurable and less reinforcing. **Cannabinoid receptors- Retrograde inhibition** \- **Anandamide** is a **neurotransmitter** classified as an **endocannabinoid**.  \- Endocannabinoids are naturally occurring chemicals in the brain that bind to **cannabinoid receptors** to regulate various physiological and cognitive processes. \- **CB1 receptors** are one of the main types of receptors that **anandamide** binds to, they are primarily located on the **pre-synaptic terminal button** of neurons \- When **anandamide** binds to **CB1 receptors**, it has an **inhibitory effect** on the release ((meaning release of these neurotransmitters is reduced) of various neurotransmitters Including: - **Acetylcholine (ACh)** - **Dopamine (DA)** - **Gamma-Aminobutyric Acid (GABA)** - **Glutamate (Glu)** -The action of **anandamide** on **CB1 receptors** leads to **modulation** of overall **neural activity**. And depending on which neurotransmitter that was affected by inhibition the outcome could be increase or decrease in different brain regions, so for instance if is decrease of GLUTAMATE or GABA this might affect neural excitation or inhibition affecting mood, memory and motor control. -**Endocannabinoids** (like **anandamide**) are not stored in synaptic vesicles like other neurotransmitters. Instead, they are **manufactured on demand** by **post-synaptic cells**. So, when neurotransmitters from the **pre-synaptic cell** bind to their receptors on the **post-synaptic cell**, this triggers the **synthesis of endocannabinoids** in the post-synaptic neuron. -Endocannabinoids act as a **retrograde messenger**, meaning they **travel backward across the synapse**: **from the post-synaptic** neuron to the **pre-synaptic** neuron. This retrograde signalling sends information **back to the pre-synaptic cell**, where it **binds to CB1 receptors** and provides feedback. This **feedback inhibition** helps to regulate and fine-tune synaptic transmission, ensuring that the neurotransmitter release is not excessive and that the communication between neurons is properly balanced. **Cannabinoid & THC** -**THC (Tetrahydrocannabinol)**, the main psychoactive compound in cannabis, acts as a **CB1 receptor agonist**, meaning it **binds to** and **activates** CB1 receptors in the brain. -CB1 receptors are part of the **endocannabinoid system** and are widely distributed across various brain regions -When THC binds to these receptors, it can influence different psychological and physiological processes. -The **CB1 receptor** is found in many areas of the brain, including regions involved in **memory, pleasure, movement, thinking, concentration, and coordination**. -Psychological Effects of Cannabis: THC binds to CB1 receptors, can activate areas associated with reward, pleasure in nucleus accumbens, if in hippocampus can lead to difficulties in memory formation, can have altered perception, in cerebellum can cause motor incoordination. -THC also works on dopamine system, When **THC** (Tetrahydrocannabinol) is administered to rats, it has been shown to **increase the firing rate of dopamine-producing cells** in the **Ventral Tegmental Area (VTA)**. This increase in dopamine firing can contribute to the **euphoric effects** of cannabis use, as dopamine is commonly associated with **pleasure** and **motivation**. And the same can be seen in humans. **Cannabinoid: retrograde inhibition** - **THC** (the active compound in cannabis) binds to **CB1 receptors** located on **GABA interneurons** within the **Ventral Tegmental Area (VTA)**. This process is known as **retrograde inhibition**, as it involves feedback from the postsynaptic cell (the DA cell) to the presynaptic cell (the GABA interneuron). **Mechanism:** - **GABA interneurons** normally play a role in inhibiting **dopamine (DA) cells** in the VTA. These GABA interneurons help regulate the firing of dopamine neurons. - When THC binds to the **CB1 receptors** on the **GABA interneurons**, it **inhibits** these neurons. - This **inhibition** of GABA interneurons leads to **disinhibition** of the **dopamine neurons**. - In other words, the inhibition normally provided by the GABA interneurons is removed, so the **dopamine cells** can **fire more**. The increased **dopamine activity** in the **mesolimbic pathway** results in **rewarding sensations**, reinforcing the behaviour and potentially contributing to **addiction**. This mechanism plays a key role in how cannabis use can lead to **addictive patterns of behaviour**.  QUIZ: 1)The neurotransmitter \_\_\_\_\_\_\_\_\_\_\_\_\_ is best known for its role in positive mood. **a. Serotonin** b. Glutamate c. GABA d. Dopamine 2\) Which part of the neuron allows the ions to cross the cell membrane via the ion channels? a. soma **b. Nodes of Ranvier** c. myelin sheath d. axon The **Nodes of Ranvier** are small gaps in the myelin sheath along the axon where ion channels are concentrated 3\) \_\_\_\_\_\_\_\_\_\_\_\_\_\_ open potassium (K+) channels releasing potassium ions trapped within the postsynaptic cell which creates a negative internal charge decreasing the probability of an action potential. a. Excitatory neurotransmitters **b. Inhibitory neurotransmitters** c. Inhibitory postsynaptic potential d. Excitatory postsynaptic potential 4\) The rewarding effects of THC is thought to be mediated by a complex interplay of which neurotransmitter systems? a. GABA & Dopamine b. Cannabinoid & Dopamine c. Canabinoid & GABA **d. Cannabinoid, GABA & Dopamine** 5\) Lesions to the \_\_\_\_\_\_\_\_\_\_\_\_ abolish cocaine and amphetamine self-administration suggesting that this area plays a key role in the reinforcing effects of drug-self administration. **a. Striatum** b. Substantia nigra c. Nucleus accumbens d. Ventral tegmental area 6)Alcohol is a relaxant through its targeting of \_\_\_\_\_\_\_\_\_\_\_\_\_\_ receptor/s. a. Opioid b. GABA  c. Glutamate **d. GABA & glutamate** **Alcohol acts as a relaxant by targeting both GABA and glutamate receptors. It enhances the inhibitory effects of GABA, which leads to sedative and anxiolytic effects. At the same time, it inhibits glutamate, an excitatory neurotransmitter, which further contributes to the depressant effects of alcohol on the central nervous system. This combination results in the calming and relaxing effects of alcohol.** 7\) The functions of which neurotransmitter's receptors are vitally important for long term potentiation? a. Dopamine b. GABA **c. Glutamate** d. Serotonin 8\) Changes in neurotransmission at the \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ are the basis for learning and behaviour, and it is here that drugs act to create addiction. **a. synaptic cleft** b. dendrite c. neurotransmitter d. terminal button 9\) True or False: Drugs are classified as antagonistic if they fit a receptor imperfectly and thus block the action of the neurotransmitter. a. False **b. True** 10\) Following electrical induction of muscle movements in frogs\' legs, who put forth the notion that electrical energy mediated the transduction of sensory information into muscular activity? a. Descartes b. Golgi c. Huxley **d. Galvani**