Neurobiology Test #3 Study Guide Teacher's Version

2. Further, explain the major reward pathway and pleasure center.

Important brain areas in the DA pathway regulate the reward system: Once the DA neurons in the VTA are activated, the DA + signals travel to activate the... • Nucleus accumbens (NAc): mediates reward (pleasure) and motivation • Hippocampus (Hipp): encodes the memory of reward (pleasure) • Basolateral amygdala (BLA): is important for the motivation that is activated by drug-related environmental cues. Visual and auditory memory of drug-taking. • Prefrontal cortex (PFC): reward-associated thought and decision making.

Ketamine + DA levels

Ketamin blocks the NMDA receptor on the glutamate neuron that innervates the VTA GABA neuron.

Explain the changes in NE neuronal activity in anxiety, depression, and manic patients.

Lower NE: Anxiety and Depression Higher NE: Mania

What are the different types of Schizophrenia?

Major types of schizophrenia: 1. catatonia- movement disorder 2. paranoid- strange thoughts 3. disorganized- speech and behavior.

Atypical antipsychotics (Clozapine, Risperidone, Olanzapine) can have different effects than Typical antipsychotics...

More effective toward negative symptoms rather than positive with typical. - Clozapine blocks the 5-HT2 receptor and in turn the D2 receptors - As effective as typical antipsychotics on positive symptoms, atypical is more effective on negative symptoms. There are some side effects though: - Lower risk of tardive dyskinesia - Dystonia: involuntary muscle contraction - Hyperglycemia and diabetes - Weight gain

Explain neurogenesis in depression and the effect of antidepressant treatment on neurogenesis. Why can antidepressants improve neurogenesis?

Neurogenesis decreases in depression... Decreased neurogenesis and synaptic plasticity play a role in the etiology of depression. - Increased glucocorticoid (or cortisol) in the brain by stress inhibits neurogenesis by decreasing BDNF (Brain-derived neurotrophic factor protein) levels. - The decrease in neurogenesis (mainly synaptogenesis, or creating/strengthening of synapses) causes atrophy in the prefrontal cortex and hippocampus of depressed patients. - Antidepressants promote neurogenesis by INCREASING BDNF LEVELS. Chronic stress turns anxiety into depression...

Nicotine + DA levels

Nicotine increases DA release in the nucleus accumbens through: • Direct activation of VTA DA neurons by targeting nAChR (Nicotinic acetylcholine receptor) in DA neuron • Indirect activation of DA neuron by targeting nAChR in presynaptic glutamate neurons. - Prolonged nicotine exposure desensitizes nAChR, which results in dramatic decreases in DA release by smoking

Talk about the brain areas involved in bipolar disorder and pharmacological treatments.

Parts of the brain affected: - basal ganglia - amygdala - prefrontal cortex - dorsal raphe - striatum Treatments for bipolar disorder: - Lithium bicarbonate improves both manic and depression symptoms -Valproate only treats manic symptoms Lower whole-brain glucose metabolic activity was found in bipolar patients suffering from a depressed state than a manic state.

What are the different symptoms of schizophrenia: positive, negative, and cognitive?

Positive symptoms: are psychotic behaviors not generally seen in healthy people. • Hallucination: seeing or hearing (in more cases) things that don't exist. • Paranoia and Delusion: false beliefs that are not based on reality. • Disorganized speech: speech quickly jumps from one unrelated topic to another due to abnormal thoughts. • Catatonia: purposeless movements such as staying still, fast or strange movement, lack of speech. So things that are added from what would be considered "normal" functioning ~~~~~ Negative symptoms: disruption in normal emotions and behaviors, or taking away from what would be considered "normal" functioning. • "Flat affect" ((e.g., lack of facial expression, poor eye contact) • Reduced feelings of pleasure • Difficulty in starting and sustaining activities • Reduced speaking ~~~~~ Cognitive symptoms: changes in memory or other aspects of thinking/memory • Poor "executive functioning" (the ability to understand information and use it to make decisions) • Trouble focusing or paying attention • Problems with "working memory"

What are pyramidal and extrapyramidal systems in movement control? What causes the extrapyramidal side effect of typical antipsychotics?

Pyramidal system vs. Extrapyramidal system - Pyramidal system: corticospinal tract, corticobulbar tract, originate from the primary motor cortex and supply motor neurons of the spinal cord and brainstem by traveling through the pyramids of the medulla. - Extrapyramidal system: a neural network that is part of the motor system. They originate primarily from the following structure and regulate the pyramidal system of movement. • Basal ganglia: including caudate, putamen, globus pallidus, substantia nigra, subthalamic nucleus • Cerebellum • Red nucleus • Reticular formation • Vestibulospinal tract ~~~~~~ Extrapyramidal side effects: • Typical antipsychotics (that target a bunch of DA receptors in both D1 and D2) can cause serious extrapyramidal side effects by blocking DA receptors in basal ganglia of the extrapyramidal system. Side effects can include: - uncontrolled movements, in posture, the face, the legs, the eyes, etc.

Explain the mechanism of SSRI in treating depression and why the anti-depressive effect is delayed.

SSRIs that block the 5-HT transporters (so that 5-HT stays floating in synapses and has the chance to turn into Serotonin) relieve symptoms in 6-12 weeks after treatment: Decrease in presynaptic 5-HT autoreceptors with time following SSRI blockade of 5-HT transporter contributes to the delayed effect of antidepressants.

What is the history of Schizophrenia diagnosis and the definition?

Schizophrenia is a serious mental disorder that affects a person's ability to interpret reality including thinking (thought and cognition), feeling (emotion), and behavior (movement). ~~~~~~ Emil Kraepelin (1856-1926): German Psychiatrist - Schizophrenia was firstly named "dementia praecox" by him to describe the symptoms (paranoia, delusion, hallucination, abnormal emotion, bizarre thoughts). Eugen Bleuler (1857-1939): Swiss Psychiatrist He was the first to categorize the symptoms into positive and negative. He changed the term "dementia praecox" to Schizophrenia for the name of the disorder. The word "schizophrenia" comes from the Greek roots schizo (split) and phrene (mind) to describe the fragmented thinking of people with the disorder: Split mind

Explain the initial step in the therapy of drug addiction: detoxification

Step 1: Detoxification (get rid of drugs!!!) • Detoxification can be achieved naturally by ceasing intake of the drug, and the process can be aided with various medications for decreasing the negative effect of withdrawn - Maintaining abstinence after leaving the detoxification facility (stay away from drugs!!!)

What are the neurochemical and hormone imbalances in depression?

Step by Step Explaination The reward pathway: from the ventral tegmental area to the nucleus accumbens (NAc) NAc is involved in pleasure, motivation, and reinforcement. It is the interface of emotional and motor responses. This is why emotion leads to the behavioral response. ~~~~~~~~ In patients with depression, anhedonia (lack of pleasure) may be caused by low DA function in nucleus accumbens. Learned helplessness: subject fails to respond appropriately to environment. Possibly resulting from malfunction in NAc. When giving amphetamine to stimulate DA neurotransmission in reward pathway, subjects with depression experienced enhanced feelings of pleasure! ~~~~~~~~ Brain Stem •Both 5-HT and NE are produced by nuclei in the brainstem: 5-HT in the raphe nuclei, NE in the locus coeruleus (LC). •Both 5-HT and NE neurons project to the prefrontal cortex, limbic system, and reward system for the regulation of emotion and reward. -Suicide victims with major depression have increased levels of 5-HT transporters in 5-HT neurons of the brain stem, suggesting suppression of the 5-HT system in the brain stem. - NE activity in LC is also decreased in patients with depression. ~~~~~~~~ -5-HT imbalance: dysfunction of serotonergic (serotonin) neurotransmission in depression. The reduction of 5-HT production in dorsal raphe is hypothesized to the development of depression. Evidence supports 5-HT hypothesis: Drugs that increase serotonergic transmission alleviate symptoms of depression. Lower levels of 5-HIAA (5-hydroxyindoleacetic acid), a metabolic product of 5-HT in the CSF of depressed patients. Fewer 5-HTT (serotonin transporters) sites are found on the platelets of depressed patients before treatment.

Explain the structural and activity changes in the brain of depression, brain areas involved in neural circuits of depression (prefrontal cortex, hippocampus, amygdala, cingulate cortex, nucleus accumbens, brainstem, white matter), the role of white matter lesion by traumatic brain injury in the development of depression

Step by Step Explanation: Prefrontal cortex: PFC plays important role in the cognitive processing of emotion. It sends and receives connections to the hippocampus and amygdala for emotional control. Related evidence: Both postmortem and neuroimaging data support the involvement of the PFC in major depression. •Postmortem analyses show atrophy and cellular loss in PFC of patients with depression •Brain imaging shows blood flow and metabolism in DLPFC (Dorsolateral prefrontal cortex, part of PFC) are decreased in patients with depression. (Low activity of PFC) •BUT, it remains unclear how PFC plays the role in depression though we know its involvement. ~~~~~~~~ Limbic system: includes Hippocampus and Amygdala. Key brain regions for stress response and emotional expression •Decreased hippocampal volume in depressed patients, but not an immediate effect. It appears age-dependent. This is probably why patients with depression are hard to form new memory to replace the fear/anxiety-related memory. •Larger amygdala volume and increased amygdala activity in depressed patients. This is why the amygdala is easy to be activated for aversive emotional expression. Link with anxiety? ~~~~~~~~~ Anterior cingulate cortex: relays information between the limbic system and the PFC. •Subgenual anterior cingulate cortex (sgACC) is smaller in depressive patients. •Deceased volume and activity in the dorsal anterior cingulate was found in depressive patients. ~~~~~~~~~ White matter (myelinated axons) connects the prefrontal cortex to the subcortical areas including the limbic system. •Subjects with severe white matter lesions are more likely to have depression. •White matter lesions caused by trauma and stroke, may contribute to late-onset depression (occurring after the age of 40).

3. Talk about the brain areas that regulate the major reward pathway.

THE VTAAAAA (and DAAAAA) which will in turn regulateeeee... • Nucleus accumbens (NAc): mediates reward (pleasure) and motivation • Hippocampus (Hipp): encodes the memory of reward (pleasure) • Basolateral amygdala (BLA): is important for the motivation that is activated by drug-related environmental cues. Visual and auditory memory of drug-taking. • Prefrontal cortex (PFC): reward-associated thought and decision making.

What are the brain areas that project to the nucleus accumbens for the involvement in addiction?

The VTA mostly, but also PFC, hippocampus, and amygdala can do that as well because they can urge the brain (usually the NAc, the pleasure center) to take a certain action to increase addiction (fear, stress, physically getting a pill bottle, etc...)

Mesocortical DA Pathway

The mesocortical pathway is a dopaminergic (DA) pathway that connects the ventral tegmentum to the prefrontal cortex. It is one of the four major dopamine pathways in the brain. It is essential to the normal cognitive function of the dorsolateral prefrontal cortex (part of the frontal lobe), and is thought to be involved in cognitive control, motivation, and emotional response.

Mesolymbic DA pathway

The mesolimbic pathway is characterized by dopaminergic (DA) projections from the VTA to nucleus accumbens (NAcc) and olfactory tubercle and is involved in reward processing behavior.

What are the specific structural changes/differences in the brain of Schizophrenics?

They tend to have: - thicker corpus callosums - atrophy of the prefrontal cortex - enlarged lateral ventricles (like Alzheimer's) - shrinkage of the hippocampus - smaller basal ganglia and less cortical gray matter - disorganized hippocampal neurons with a smaller size

Tryptophan

Tryptophan is important to the functions of many organs in the body. When you consume tryptophan, your body absorbs it and changes it to eventually become a hormone called serotonin. Serotonin transmits signals between your nerve cells and also narrows (constricts) blood vessels. The amount of serotonin in the brain can affect mood. Eat Tryptophan----> turns into 5 HT ----> turns into Serotonin.

What are the ventral tegmental areas activated by expected and unexpected rewards?

VTA activity and reward: • The human VTA DA neuron is activated more by unexpected rewards, less by expected rewards, and is inhibited by lack of expected rewards. - VTA -NAc - Basolateral amygdala - Prefrontal cortex

Explain the neurochemistry of schizophrenia.

When experiencing a hallucination, chronic schizophrenic patients have been tested with an increased activity using fMRI in: - thalamus - auditory cortex - orbitofrontal cortex - cingulate cortex - striatum - hippocampus - Broca's area ~~~~~ - Enlarged lateral ventricle and reduced volume of cortical gray matter. • Thicker corpus callosum. ~~~~~ Dopamine hypothesis - Drugs that temporarily increase DA levels lead to schizophrenic-like symptoms • Both amphetamine (increases DA release), and cocaine (inhibits DA reuptake) can produce paranoia, delusion, and auditory hallucination. • The two drugs also exacerbate symptoms of schizophrenia • The effects can be blocked by D2 receptor antagonists such as chlorpromazine - Drugs that block DA can improve positive symptoms of Schizophrenia.

Addiction

a chronic brain disorder characterized by compulsive behavior engaged in rewarding stimuli (drug, substance, sex, gambling) despite adverse consequences.

Opioids + DA levels

activate opioid receptors in VTA GABA neurons. (similar to alcohol, GABA is inhibitory for DA, less DA, more inhibitory for people)

Dependence

an adaptive state associated with withdrawal symptoms upon cessation of repeated exposure to drug intake. - Physical dependence: dependence that involves persistent physical-somatic withdrawal symptoms (e.g., fatigue, vomiting, and delirium tremens). - Psychological dependence: dependence that involves emotional-motivational withdrawal symptoms (e.g., dysphoria and anhedonia).

Reinforcement

enhancement of behavior by increased motivation for getting a reward or ending a punishment. • Positive reinforcement: increased behavioral response to get a positive reward (food, sex, etc.). • Negative reinforcement: increased behavioral response to end punishment (pain, starvation).

Withdrawal symptoms

physical and psychological symptoms that the individuals experience after stopping or reducing drug intake.

Alcohol + DA levels

promotes the activation of GABA receptors in VTA GABA neurons (GABA is inhibitory for DA, less DA, that's why alcohol in more inhibitory for people)

Tolerance

the diminishing efficacy of a drug resulting from repeated drug intake at a given dose. The individual requires higher doses to obtain the initial effect of the drug

Drug Addiction

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Mood Disorders

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Schizophrenia

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Neurochemistry of schizophrenia: Acetylcholine Involvement

• About 80% of individuals diagnosed with schizophrenia reportedly smoke lots of cigarettes. • Smoking may promote the transient improvement of schizophrenic patients. • Acetylcholine receptor agonist nicotine may alleviate negative symptoms through increasing DA release in the brain pathways. ~~~~~ - Typical antipsychotics: - DA receptor antagonists: Block D2 receptors to mainly treat positive symptoms. Nonselective DA receptor antagonist: Chlorpromazine was the FIRST drug that was used to treat schizophrenia. - Selective D2 receptor antagonists: Haloperidol, Thioxanthene Discovery of chlorpromazine dramatically decreased hospitalization of schizophrenics and put an end to frontal lobotomy Ph

Talk about the roles of D1R and D2R in nucleus accumbens for reward.

• Both D1R-expressing and D2R-expressing neurons in nucleus accumbens are excited by VTA DA neuronsssss ~~~~~~ • The activation of the D1-expressing NAc neuron is associated with reward, whereas the activation of the D2 expressing NAc neuron is associated with aversion (avoidance). • DA (dopamine) activates D1-expressing neurons but inhibits D2 expressing neurons for reward. DA activation of D1-expressing neuron directly mediates reward, whereas DA inhibition of D2-expressing neuron opposes aversive responses (activates?).

What are the mechanism and the pharmacological target of ketamine treatment of depression?

• Ketamine: NMDAR blocker, binds to phencyclidine (PCP) binding site of NMDAR to block NMDAR ion channel. • Low-dose ketamine produces antidepressant effects within 2 hr.

Neurochemistry of schizophrenia: Serotonin

• The effect of atypical antipsychotics suggests that serotonin is also involved in the development of schizophrenia, but the etiology is more complex... - Activation of the 5-HT2 receptor by Lysergic acid diethylamide (LSD) or mescaline produces visual hallucinations. BUT schizophrenic hallucinations are mostly auditory.

Priming

(i.e., a single drink or intake off a drug that precipitates a binge): - The DA in the nucleus accumbens appears to play a critical role in priming. It is just like an appetizer before dinner. - Priming activates the VTA DA neuron to release DA in NAc: The reinitiated drug-seeking after the extinction is elicited by the administration of DA agonists. - Activation of D2 receptors in the NAc mediates drug-triggered priming for relapse: The priming effect of heroin, amphetamine, and cocaine is blocked by D2 receptor antagonists.

Neurochemistry of schizophrenia: Dopamine

- Drugs that temporarily increase DA levels lead to schizophrenic-like symptoms • Both amphetamine (increases DA release), and cocaine (inhibits DA reuptake) can produce paranoia, delusion, and auditory hallucination. • The two drugs also exacerbate symptoms of schizophrenia • The effects can be blocked by D2 receptor antagonists such as chlorpromazine ´Drugs that block DA can improve positive symptoms of Schizophrenia. ~~~~~~ Brain DA pathway and function: From the VTA (produces DA) outward to the amygdala, nucleus accumbens, frontal cortex, and prefrontal cortex for processing. The D1 receptor family (D1+D5) are excitatory receptors for DA release while the D2 receptor family (D2, D3, D4) are inhibitory receptors for DA non-release. ~~~~~~ HYPERACTIVE dopamine transmission in the nucleus accumbens of the mesolimbic DA pathway is associated with positive symptoms of schizophrenia such as hallucinations and delusions. - Increased D2 receptor level and D2 receptor activation in nucleus accumbens of schizophrenia (usually inhibitory, but when not working, excitatory) • HYPOACTIVE dopamine transmission in the PFC of the DA pathway is associated with negative symptoms of schizophrenia such as emotional dysregulation and impaired motivation. - Reduced D1 receptor activation in PFC leads to decreased activity of frontal cortex. (usually excitatory, but when not working, inhibitory to the Frontal Cortex) Decreased DA function in caudate nucleus may also contribute to symptoms like reduced speaking and immobility

What are the targets of typical and atypical antipsychotics, the discovery of the first antipsychotic changed the history of inpatient treatment of Schizophrenia?

- Targets of typical antipsychotics: mainly D2 receptors - Targets of atypical antipsychotics: both D2 receptors and 5-HT receptors ~~~~~ - Nonselective DA receptor antagonist (so targeted every DA receptor (D1+D2 fams)): Chlorpromazine was the FIRST drug that was used to treat schizophrenia. - Selective toward D2 receptor antagonists: Haloperidol, Thioxanthene, so helps with positive symptoms mostly, not exactly focused on negative symptoms.

What are the vulnerabilities of drug addiction?

- stress - genetic predisposition - age (teenagers are more vulnerable)

Explain the types of antidepressants: targets of the drugs (MAOIs, SSRIs, SNRIs, selective NE reuptake inhibitor, CRH blocker, Ketamine). Electroconvulsive therapy (ECT) and depression treatment (are most effective but cause memory and cognitive loss).

-Monoamine oxidase inhibitors (MAOIs)- blocks the MAO that metabolizes monoamine neurotransmitters (5-HT, DA, and NE) into inactive forms, so activates 5-HT, DA, and NE... •Unpopular due to side effects: elevation in blood pressure, headaches, nausea, and sweating... ~~~~~~~ - SSRIs: selectively block 5-HT transporters: Fluoxetine •SSRI not only blocks 5-HT reuptake but also decreases presynaptic autoreceptor levels with time. •New studies suggest SSRIs also promote neurogenesis by increasing BDNF levels. •side effects: sexual dysfunction (75% of patients with treatment). ~~~~~~~~~ Serotonin and norepinephrine reuptake inhibitors (SNRIs): such as venlafaxine and milnacipran ~~~~~~~~~ Selective NE reuptake inhibitor: Reboxetine •influences social functioning; no apparent sexual side effects •appears to help those not responding to SSRIs. •not approved for use in the USA ~~~~~~~~~~ Corticotropin-releasing hormone blocker: Antalarmin was recently tested to reduce stress response in rhesus macaques (part of the brain). •reduced anxiety and depression-like symptoms •increased exploration and sexual behavior ~~~~~~~~~ Dopamine transport blocker: Bupropion ~~~~~~~~~ Ketamine: newly approved antidepressant Ketamine: NMDAR blocker, binds to phencyclidine (PCP) binding site of NMDAR to block NMDAR ion channel. • Low-dose ketamine produces antidepressant effects within 2 hr. Target 1: - Ketamine inhibits presynaptic inhibition by blocking NMDA receptors in PFC GABA interneurons that innervate the presynaptic axons of PFC glutamate synapses. •It increases the function of PFC glutamate neurons that project to the limbic system and other brain areas for emotion control. •Increased BDNF release following Ca2+ influx promotes synaptogenesis. Target 2: lateral habenula (LHb) • Glutamate neurons in Lateral Habenula inhibit DA and 5-HT release based on neural circuit connections. (RMTg: rostromedially tegmental nuclei) • Ketamine INHIBITS glutamate neurons in LHb to INCREASE DA and 5-HT release. ~~~~~~~~ Electroconvulsive Therapy (ECT) •Oldest treatment for mental illness. It involves a brief electrical stimulation of the brain while the patient is under anesthesia. •Most effective somatic treatment for depression: 60-80% success rate. •Offered to individuals not responding to pharmacotherapy and individuals at highest risk for suicide (serious cases). •We don't know how it works, but it may increase regional cerebral blood flow and increase the number of 5-HT fibers through neurogenesis. •Does not cause brain damage, but induces memory loss. ~~~~~~~~ Repetitive transcranial magnetic stimulation • Involves magnetic stimulation of left prefrontal cortex • 50% improvement of symptoms over time • uncertain how it works, but it possibly: - activates the cingulate gyrus, amygdala, and other areas -decreases the sensitivity of 5-HT1A and 5-HT1B auto receptors ~~~~~~~~~~ Cognitive Behavioral Therapy (CBT) •CBT involves 1) educating the patient about how cognitioninfluencese emotion 2) discussing how patients can serve as cotherapists and change their behavior and cognition to improve depression 3) the patient and therapist work together to restructure the patients' cognition and behavior. •One advantage of CBT: is its long-term protection against the high relapse rate observed following pharmacotherapeutic approaches. ~~~~~~~~~ Deep brain stimulation •Surgical placement of electrodes into the subgenual anterior cingulate cortex .•DBS decreased symptoms in 4 of 6 patients. •This procedure is currently being assessed in larger-scale clinical trials in the US.

Dopamine depletion hypothesis of addiction and Sensitization hypothesis of addiction

1. Dopamine Depletion Hypothesis: decreased hedonic value for tolerance - Increased incentive value (anticipated pleasure) by a sensitized motivation system of the brain: T 2. Sensitization hypothesis of addiction: - behavioral sensitization for craving. - Increased incentive value (anticipated pleasure) by a sensitized motivation system of the brain: This hypothesis predicts that repeated drug use would "sensitize" the brain's motivation system to produce compulsive behaviors for craving. The motivation system is sensitively activated by both drug priming and drug-associated cues or context due to neuroplasticity in VTA, PFC, hippocampus, and amygdala.

Explain a dysfunction of dopamine pathway that leads to anhedonia in depression.

1. Dopamine imbalance: Decreased DA transmission in the mesolimbic DA pathway (reward pathway) leads to anhedonia in depression. •Mesolimbic dopamine pathway: dopaminergic projection from ventral tegmental area to nucleus accumbens, hippocampus, and amygdala.

What are other factors that can affect depression?

1. gender (women> men) 2. social isolation 3. genetic factors 4. anxiety and stress 5. tryptophan-containing food.

What triggers addiction?

1. priming- (i.e., a single drink or intake of drug that precipitates a binge): DA in nucleus accumbens appears to play a critical role in priming. It just like an appetizer before dinner. - Priming activates VTA DA neuron to release DA in NAc: The reinitiated drug seeking after the extinction is elicited by the administration of DA agonists. - Activation of D2 receptors in the NAc mediates drug-triggered priming for relapse: The priming effect of heroin, amphetamine, and cocaine is blocked by D2 receptor antagonists. 2. drug-associated cues and context- VTA-NAc pathway, amygdala, and PFC are all involved. Drug-associated context or cues induce a desire or wanting for drugs. 3. Stress- increases the risk of drug addiction in general because it is an outlet 4. Obsessive Thoughts- lead to compulsive reinforcement/behaviors

What is the initial onset of Schizophrenic symptom and diagnosis?

15 to about 35, so a 20 year window

Typical Antipsychotics

A class of older drugs to treat schizophrenia and related psychotic disorders primarily by reducing excess levels of dopamine in the brain. - DA receptor antagonists: Block D2 receptors to mainly treat positive symptoms. -Nonselective DA receptor antagonist: Chlorpromazine was the FIRST drug that was used to treat schizophrenia. - Selective D2 receptor antagonists: Haloperidol, Thioxanthene ~~~~~ Problems with typical antipsychotics: - Only improve positive symptoms - Serious side effects (especially extrapyramidal side effects) due to nonselective blockade of DA receptors in another brain pathway. - Tardive dyskinesia - Cramping - Tremors - Weight-gain

Amphetamines + DA levels

Amphetamine mainly increases DA level in the synaptic cleft by promoting DA release from presynaptic DA neuron terminals. So just increasing the release rather than keeping it floating there like coke.

1. Explain the brain areas involved in reward and addiction.

Brain areas involved in reward and motivation & addiction: • Nucleus accumbens: mediates both reward and motivation • Hippocampus: encodes the contextual memory of rewarding pleasure for motivation. • Basolateral amygdala: sensitive to environmental cues related to drug use from behavioral sensitization. • Prefrontal cortex: reward-associated thought and decision making to control motivated behavior. All these brain areas can be regulated by drug activation of VTA DA neurons!! (continued on next...)

Cocaine + DA levels

Cocaine increases DA levels in the synaptic cleft by blocking DA transporters (DAT) at presynaptic DA neuron terminals, so DA stays floating in there.

What are the current ideas about both mesolimbic and mesocortical DA pathways for the symptoms of Schizophrenia?

Current ideas about dopamine hypothesis (mesolimbic and mesocortical pathways): • HYPERACTIVE dopamine transmission in nucleus accumbens of mesolimbic DA pathway is associated with POSITIVE symptoms of schizophrenia such as hallucinations and delusions. - Increased D2 receptor level and D2 receptor activation in nucleus accumbens of schizophrenia. • HYPOACTIVE dopamine transmission in the PFC of mesocortical DA pathway is associated with NEGATIVE symptoms of schizophrenia such as emotional dysregulation and impaired motivation. - Reduced D1 receptor activation in PFC leads to decreased activity of the frontal cortex. • Decreased DA function in caudate nucleus may also contribute to symptoms like reduced speaking and immobility.

Neurochemistry of schizophrenia: Glutamate

Decreased glutamate transmission leads to reduced activity in the frontal cortex. Because glutamate is needed to open the channels (for Na+/K+ pump for signals) where PCP lies, blocking it. Evidence that supports the glutamate hypothesis includes: • Phencyclidine (PCP) produces symptoms of schizophrenia: - Auditory hallucination - Depersonalization -Delusion • Ketamine also produces schizophrenia-like symptoms. • However, why are glutamate agonists not clinically used to treat schizophrenia? -Nonselective effect of glutamate agonists produce seizures and excitotoxicity.

Explain the decrease in inhibitory control of the prefrontal cortex on motivation center and VTA-NAc pathway in addiction

Decreased inhibitory control on compulsive craving • Decreased inhibitory control of lateral OFC of NAc neurons in the VTA-NAc reward pathway due to repeated drug exposure leads to cravings and addiction.

Explain the neurochemistry involved in drug addiction (dopamine, serotonin, acetylcholine), and the neurotransmitter in the nucleus accumbens for aversion (acetylcholine).

Dopamine: • DA is released during drug self-administration. Most, if not all, abused drugs directly or indirectly activate the DA system. • It is believed that the reinforcing property of cocaine is diminished by the DA antagonist. The reinforcing property prompts the rats to work harder to receive any amount of reward. ~~~~~ Serotonin: • When knocking out the vesicle monoamine transporter 2 (VMAT2), these mice were less likely to develop a preference for amphetamine. However, DA transporter knockout mice still developed a place preference for cocaine and amphetamine. • This finding indicates that 5-HT (the serotonin receptor) may also play a role in addiction. ~~~~~ Acetylcholine (ACh): • ACh neurons in the nucleus accumbens may be involved in aversion (avoidance), the opposite function of the DA neuron. • Rats decrease consumption of water sweetened with saccharin as levels of ACh increase in the nucleus accumbens. ACh may stop the behavior triggered by the activation of the mesolimbic DA system and therefore, suppress addiction.

Talk about the close relationship between the rate of drugs entering the brain and the psychological high or euphoria.

Drugs are something that can be used as a reward. A reward is positive emotional effects (pleasure, euphoria) produced by rewarding stimuli such as drugs. Motivation is the desire or willingness to do something. • Drugs of abuse increase motivation due to drug rewards. Behavioral Reinforcement is the enhancement of behavior by increased motivation for getting a reward or ending a punishment. Reward ----> Increased motivation----> Behavioral reinforcement

Provide evidence for the 5-HT hypothesis in depression...

Evidence supports 5-HT hypothesis: - Drugs that increase serotonergic transmission alleviate symptoms of depression. - Lower levels of 5-HIAA (5-hydroxyindoleacetic acid), a metabolic product of 5-HT in the CSF of depressed patients. - Fewer 5-HTT (serotonin transporters) sites are found on the platelets of depressed patients before treatment.

Dopamine Hypothesis + Dopamine in the Brain of Schizophrenic people.

Evidence that supports DA hypothesis: - Drugs that temporarily increase DA levels lead to schizophrenic-like symptoms • Both amphetamine (increases DA release), and cocaine (inhibits DA reuptake) can produce paranoia, delusion, and auditory hallucination. • The two drugs also exacerbate symptoms of schizophrenia • The effects can be blocked by D2 receptor antagonists such as chlorpromazine ´Drugs that block DA can improve positive symptoms of Schizophrenia. ~~~~~~ Brain DA pathway and function: From the VTA (produces DA) outward to the amygdala, nucleus accumbens, frontal cortex, and prefrontal cortex for processing. The D1 receptor family (D1+D5) are excitatory receptors for DA release while the D2 receptor family (D2, D3, D4) are inhibitory receptors for DA non-release. ~~~~~~ HYPERACTIVE dopamine transmission in the nucleus accumbens of the mesolimbic DA pathway is associated with positive symptoms of schizophrenia such as hallucinations and delusions. - Increased D2 receptor level and D2 receptor activation in nucleus accumbens of schizophrenia (usually inhibitory, but when not working, excitatory) • HYPOACTIVE dopamine transmission in the PFC of the DA pathway is associated with negative symptoms of schizophrenia such as emotional dysregulation and impaired motivation. - Reduced D1 receptor activation in PFC leads to decreased activity of frontal cortex. (usually excitatory, but when not working, inhibitory to the Frontal Cortex) Decreased DA function in caudate nucleus may also contribute to symptoms like reduced speaking and immobility

Relapse

Going back to substance abuse because of prior priming and withdrawal symptoms.