diff --git a/2016-11-25-lecture18.md b/2016-11-25-lecture18.md index 84eed2c..28e6d2a 100644 --- a/2016-11-25-lecture18.md +++ b/2016-11-25-lecture18.md @@ -29,9 +29,8 @@ Visceral ## Autonomic motor system -Neuroscience 5e Fig. 21.1 -
+
Neuroscience 5e Fig. 21.1
Note: @@ -41,86 +40,53 @@ blood vessels in skin and gut contract, rerouting blood to muscles hairs stand on end, piloerection making us look more fearsome, bronchi dilate for incr oxygenation, heart rate accelerates. Sympathetic activity also stimulates adrenal medulla to relesase adrenaline and noradrenaline into the bloodstream to mobilize glucagon release from pancreas. - - - - Parasympathetic: Preganglionic is in the brainstem, Peripheral ganglia in DRG - - - ---- - -## Autonomic motor system - -
- -Note: - - - --- ## Facial expression of emotion * Duchenne de Boulogne -* Facial muscle stimulation can create a variety of expressions recognizable as emotion. +* Facial muscle stimulation can create a variety of expressions recognizable as emotion -
- -
+
+
Note: +TODO: img src unknown + Emotions can trigger facial muscles that can’t be done on purpose. --- ## Facial expression of emotion -* Two pathways to get to facial muscles that display emotion– voluntary and emotional pathways are separable +Two pathways to get to facial muscles that display emotion– voluntary and emotional pathways are separable. -Neuroscience 5e Box 29A +
Neuroscience 5e Box 29A
+
Neuroscience 5e Box 29A
- -
- -
- Note: extrapyramidal system: is a neural network that is part of the motor system causing involuntary movements - - pyramidal pathways (corticospinal and some corticobulbar tracts) may directly innervate motor neurons of the spinal cord or brainstem - - extrapyramidal system centers on the modulation and regulation (indirect control) - - - - Extrapyramidal tracts are chiefly found in the reticular formation of the pons and medulla, and target neurons in the spinal cord involved in reflexes, locomotion, complex movements, and postural control - - paresis: muscle weakness - - - --- ## Expression of emotion -
+
Note: @@ -130,73 +96,40 @@ animals express emotion as well— ## Hypothalamus as a coordinator of emotional behavior +
+
+ * Phillip Bard / Walter Hess -* Hypothalamus as a critical center for coordination of both the autonomic and somatic components of emotional behavior. -* Removed huge areas of the forebrain and noticed two basic types of behaviors. -* One class exhibited as if they were enraged. Angry behavior occurred spontaneously and included the usual autonomic correlates of anger. Increased blood pressure and heart rate, dilation of pupil, hair raising. Also contained somatic motor components such as arching the back and tail. Called Sham rage. -* Sham rage found to require the hypothalamus. -* Stimulation of discreet parts of hypothalamus could elicit different behaviors associated with anger. +* Hypothalamus as a critical center for coordination of both the autonomic and somatic components of emotional behavior +* Removed huge areas of the forebrain and noticed two basic types of behaviors +* One class exhibited as if they were enraged. Angry behavior occurred spontaneously and included the usual autonomic correlates of anger. Increased blood pressure and heart rate, dilation of pupil, hair raising. Also contained somatic motor components such as arching the back and tail. Called Sham rage +* Sham rage found to require the hypothalamus +* Stimulation of discreet parts of hypothalamus could elicit different behaviors associated with anger + +
Note: - --- ## Hypothalamus as a coordinator of emotional behavior * Phillip Bard / Walter Hess, early 1900s. Conducted seminal studies that determined the hypothalamus is a critical center for coordination of both the autonomic and somatic components of emotional behavior. +* [http://www.youtube.com/watch?v=TtU77nHL-p4](http://www.youtube.com/watch?v=TtU77nHL-p4) -[http://www.youtube.com/watch?v=TtU77nHL-p4](http://www.youtube.com/watch?v=TtU77nHL-p4) - -Neuroscience 5e Fig. 29.1 - - - -
+
Neuroscience 5e Fig. 29.1
Note: started by removing cerebral hemispheres of cats, when anesthesia wears off they acted as if enraged. Involved all the autonomic components of the sympathetic nervous system. Called sham rage because no obvious target. - - Sham rage: Angry behavior occurred spontaneously included autonomic correlates of anger. Increased blood pressure and heart rate, dilation of pupil, hair raising. Also contained somatic motor components such as arching the back and tail. - - Connection from ventral hypothalamus to midbrain needs to be present to elicit sham rage. - - Bard suggested that emotional behaviors are often directed towards self-preservation (point also made by Charles Darwin). ---- - -## - -
- -Note: - - - ---- - -## Affective attack expression - -* Sham Rage -* An affective attack expression -* Evoked by radio stimulation of medial hypothalamus - -“Because the cat does not direct its attack toward any target, we regard this as just a fragment of a normal attack” (Delgado, 1981) - -
- -Note: - - - --- ## Affective attack expression @@ -205,241 +138,146 @@ Note: * An affective attack expression * Stimulation of medial hypothalamus -Note: +
+Note: --- ## General connectivity of emotions -* Both a volitional (with deliberate action) and a non-volitional component. Are in separate pathways. Both pathways ultimately lead to motor pools that activate muscle contraction or smooth muscle/gland secretions. -* Lateral projections control specific movements or emotional behaviors, medial projections provide support for these behaviors. +* Both a volitional (with deliberate action) and a non-volitional component. Are in separate pathways. Both pathways ultimately lead to motor pools that activate muscle contraction or smooth muscle/gland secretions +* Lateral projections control specific movements or emotional behaviors, medial projections provide support for these behaviors Note: - --- ## Descending systems that control somatic and visceral motor pathways in the expression of emotion -Neuroscience 5e Fig. 29.2 +
Neuroscience 5e Fig. 29.2
- -
- Note: - --- ## How does your brain impinge on emotions? -* Anatomists had shown that there was a subregion of the brain that formed a rim around the corpus callosum and the medial aspects of the cerebral hemispheres. -* Contains the hippocampus and cingulate gyrus. -* These areas found to form a circuit with other areas, including hypothalamus–amygdala, and parts of the thalamus. Together these areas make up the limbic system. +* Anatomists had shown that there was a subregion of the brain that formed a rim around the corpus callosum and the medial aspects of the cerebral hemispheres +* Contains the hippocampus and cingulate gyrus +* These areas found to form a circuit with other areas, including hypothalamus–amygdala, and parts of the thalamus. Together these areas make up the limbic system Note: - --- -## The limbic system +## Limbic system -Neuroscience 5e Fig. 29.4 - - - -
+
Neuroscience 5e Fig. 29.4
Note: The limbic system. - - Green is modern view of limbic system critical for processing emotion. Blue includes other areas of the traditional limbic system such as the hippocampus and mammillary bodies that are not considered critical to circuits for emotional processing. +--- +## Limbic system +
Limbic system
+
Basal ganglia
+Note: + +TODO: img src unknown --- ## Limbic system -Limbic system - -Basal ganglia - -
- -
+
Neuroscience 5e Fig. 29.4
Note: - - ---- - -## Limbic system - -Neuroscience 5e Fig. 29.4 - - - -
- -Note: - - - - - amgydala—> ventral basal ganglia —> mediodorsal nucleus of thalamus —> orbital and medial prefrontal cortex —> amygdala +amgydala, Latin for ‘almond’ + --- ## Crude lesion studies -* John Downer (London in 1950’s) removed the temporal lobes of monkeys and witnessed weird emotional behaviors. -* Unable to recognize objects, although not blind. (why?) +* John Downer (London in 1950’s) removed the temporal lobes of monkeys and witnessed weird emotional behaviors +* Unable to recognize objects, although not blind (why?) * Bizarre oral behaviors -* Hyperactivity and hypersexuality, making physical contact with virtually anything. -* No longer showed fear. Neither to humans or to snakes. -* Eventually the fear behaviors was narrowed down to a region called the amygdala. +* Hyperactivity and hypersexuality, making physical contact with virtually anything +* No longer showed fear. Neither to humans or to snakes +* Eventually the fear behaviors was narrowed down to a region called the amygdala * [Kluver-Bucy syndrome– a disease due to damage of temporal lobe and limbic system https://www.youtube.com/watch?v=7RDFRASiq4M](https://www.youtube.com/watch?v=7RDFRASiq4M) Note: - ---- - -## Amygdala - -* Latin for ‘almond’ - -
- -
- -
- -Note: - - - --- ## Selective lesion studies -* Cut out only 1 amygdala (remember there is one on each side of brain) at the same time as transecting the optic chiasm, corpus callosum and anterior commissure. -* Optic chiasm cut blocks contralateral retinal axons thus now each eye’s information goes to same-side visual cortex. -* Creates an animal with a single amygdala that had access only to visual inputs from the eye on the same side of the head. -* If shut eye that goes to intact amygdala animals showed no fear responses. If open eye that maps to intact amygdala then animal shows normal fear behaviors. Therefore the amygdala is required for fear behaviors. +* Cut out only 1 amygdala (remember there is one on each side of brain) at the same time as transecting the optic chiasm, corpus callosum and anterior commissure +* Optic chiasm cut blocks contralateral retinal axons thus now each eye’s information goes to same-side visual cortex +* Creates an animal with a single amygdala that had access only to visual inputs from the eye on the same side of the head +* If shut eye that goes to intact amygdala animals showed no fear responses. If open eye that maps to intact amygdala then animal shows normal fear behaviors. Therefore the amygdala is required for fear behaviors Note: - - ---- - -## Visual field deficits resulting from damage along the primary visual pathway - -Black means blind - -Blue means see - -Neuroscience 5e Fig. 12.6 - -Blindness in R eye - -Bitemporal hemianopsia - -L homonymous hemianopsia - -Upper quadrant hemianopsia - -Homonymous hemianopsia with macular sparing - -
- -Note: - - - --- ## Insights on the role of the amygdala in appraising emotions from patient S.M. -S. M. - -Neuroscience 5e Box 29d - - - -
+
Amygdala damage in patient S.M
Neuroscience 5e Box 29d
Note: patient SM has rare autosomal recessive condition called Urbach-Wiethe disease. Disorder of bilateral calcification an atrophy of anterior-medial temporal lobes. Both amygdalas are extensively damaged. Little to no injury of the hippocampus. - - She has no motor or sensory or intelligence or memory or language impairment. However she can’t recognize the emotion of fear in photographs. Furthermore, she exhibits little fear herself (to dangerous animals, scary houses, films, etc). - - --- ## Insights on the role of the amygdala in appraising emotions from patient S.M. -Adolphs et al. 1995 +
Adolphs et al. 1995
+
Adolphs et al. 1995
- -
- -
- -Note: - - - ---- - -## Adolphs et al., 1995 - -* Subject with bilateral amygdala lesions was asked to draw facial expressions of emotions. - -
- Note: +Adolphs et al., 1995. Subject with bilateral amygdala lesions was asked to draw facial expressions of emotions. +
--- ## Amygdala: aggression -* Among 603 operations for control of untreatable aggressiveness— -* there were 481 cases with bilateral amygdalotomies and 122 cases with mostly secondary posteromedian hypothalamotomies have been performed. Initially excellent or moderate improvement was achieved in 76%. After a follow-up of more than three years this figure only slightly decreased to 70%. The group of patients who did not positively respond (30%) needs further study to discover the reasons for failure. +* Among 603 operations for control of untreatable aggressiveness... + * ...there were 481 cases with bilateral amygdalotomies and 122 cases with mostly secondary posteromedian hypothalamotomies that have been performed + * Initially excellent or moderate improvement was achieved in 76%. After a follow-up of more than three years this figure only slightly decreased to 70%. The group of patients who did not positively respond (30%) needs further study to discover the reasons for failure Note: - --- ## Fear conditioning -* Pair a normally neutral stimulus with an inherently aversive one. Over time the animal will show behaviors to the neutral stimulus similar to that when given the aversive one. The animal learns to attach new meaning to a stimulus. -* Can use this assay to determine what areas of the brain are required for the learned behavior. +* Pair a normally neutral stimulus with an inherently aversive one. Over time the animal will show behaviors to the neutral stimulus similar to that when given the aversive one. The animal learns to attach new meaning to a stimulus +* Can use this assay to determine what areas of the brain are required for the learned behavior Note: @@ -451,28 +289,21 @@ Note: A white rat presented to an infant does not innately elicit fear, but pairing the rat with an aversive noise, produces crying and attempts to crawl away, even when the rat was presented without the noise. -
+
Note: Classic experiments from Watson and Rayner demonstrating fear conditioning in an infant - - As early as the 1920s, fear conditioning was demonstrated in infants. A white rat presented to an infant does not innately elicit fear, but pairing the rat with an aversive noise, produces crying and attempts to crawl away, even when the rat was presented without the noise. - - --- ## Fear conditioning in rats -Principals of Neural Science, Kandel, Schwarz, Jessel Fig. 50.07 +
Principals of Neural Science, Kandel, Schwarz, Jessel Fig. 50.07
- -
- Note: @@ -481,15 +312,17 @@ Note: ## Pathways involved in fear conditioning -Neuroscience 5e Fig. 29.5 +
Neuroscience 5e Fig. 29.5
- -
- Note: + --- @@ -501,9 +334,8 @@ Motor output Sensory input -
+
-
Note: @@ -527,82 +359,40 @@ PVN– paraventricular nucleus of hypothalamus. Contains groups of neurons activ ## Long term potentiation (LTP) in the amygdala -Synapse strengthened +
Neuroscience 5e Fig. 8.9
-Synapse strengthened - -Synapse strengthened - -Synapse not strengthened - -Neuroscience 5e Fig. 8.9 - - - -
- -Note: - - - ---- - -## NMDA receptor opening leads to strengthening of synapses - -
Note: +TODO: review this figure legend +NMDA receptor opening leads to strengthening of synapses --- ## Insertion of more AMPA receptors in synapse -Neuroscience 5e Fig. 8.13 - - - -
+
Neuroscience 5e Fig. 8.13
Note: - --- ## Spine growth, more synapses between neurons -Neuroscience 5e Fig. 8.15 - - - -
+
Neuroscience 5e Fig. 8.15
Note: - ---- - -## Physiological pathways for amygdala mediated fear conditioning - -
- -Note: - - - --- ## Model for associative learning in the amygdala -Neuroscience 5e Fig. 29.6 +
Neuroscience 5e Fig. 29.6
- -
- Note: @@ -611,12 +401,9 @@ Note: ## Model for the awareness of emotional feelings -Neuroscience 5e Fig. 29.7 +
Neuroscience 5e Fig. 29.7
- -
- Note: @@ -638,11 +425,11 @@ Note: ## Mood disorders– depression -* Can be unipolar or bipolar. -* Unipolar depression affects 5% of world’s population. 8 million Americans at any given time. -* Average age of onset 28 years. More common in women than men. -* Bipolar disorders– have a manic phase. 1% of people have it at some point during lifetime. Affects men and women equally. -* Account for a large fraction of suicides. +* Can be unipolar or bipolar +* Unipolar depression affects 5% of world’s population. 8 million Americans at any given time +* Average age of onset 28 years. More common in women than men +* Bipolar disorders– have a manic phase. 1% of people have it at some point during lifetime. Affects men and women equally +* Account for a large fraction of suicides Note: @@ -652,32 +439,21 @@ Note: ## Treatments for depression -* Iproniazid- inhibits monoamine oxidase, increases monoamine concentration in synaptic terminals. +* Iproniazid- inhibits monoamine oxidase, increases monoamine concentration in synaptic terminals * Imiprmine and fluoxetine (Prozac), inhibit monoamine transporters. Prozac selectively inhibits serotonin reuptake, selective serotonin reuptake inhibitors) Note: - ---- - -## In vivo assay for inhibition of reuptake - -
- -Note: - - - --- ## Anxiety disorders -* Most common types of psychiatric disorders, include anxiety, phobias, panic disorders, obsessive-compulsive disorder. -* Often associated with fatigue, muscle tension, and sleep disturbance. 5% of people report some type of general anxiety disorder. -* Barbiturates– reduce anxiety but also are potent sedatives. Overdose is lethal. -* Benzodiazepines– reduce anxiety without as much sedation. Harder to overdose on benzodiazepines. -* Both drugs bind to the ionotropic GABA receptors and enhance GABA transmission. +* Most common types of psychiatric disorders, include anxiety, phobias, panic disorders, obsessive-compulsive disorder +* Often associated with fatigue, muscle tension, and sleep disturbance. 5% of people report some type of general anxiety disorder +* Barbiturates– reduce anxiety but also are potent sedatives. Overdose is lethal +* Benzodiazepines– reduce anxiety without as much sedation. Harder to overdose on benzodiazepines +* Both drugs bind to the ionotropic GABA receptors and enhance GABA transmission Note: @@ -690,24 +466,25 @@ Note: * Benzodiazepines increase the affinity of the receptor for GABA * Barbituates can activate the GABA receptor independent of GABA -
+
Note: +TODO: img src unknown + Act at the level at the interface of the alpha and gamma subunits. Different neurons express different gamma subunits. Six different genes for the alpha subunit. Benzodiazepines only can interact with the a1,a2, and a5 subunits, have a conserved histidine. --- ## Drug abuse and addiction -* Emotional processing in the limbic system signals the presence or prospect for reward and punishment, and activates programs to procure rewards and avoid punishment. -* Most known drugs (heroin, cocaine, ethanol, opiates, marijuana, nicotine, amphetamines) act on the limbic circuitry. -* Most act by altering dopamine circuits that go through the basal ganglia. +* Emotional processing in the limbic system signals the presence or prospect for reward and punishment, and activates programs to procure rewards and avoid punishment +* Most known drugs (heroin, cocaine, ethanol, opiates, marijuana, nicotine, amphetamines) act on the limbic circuitry +* Most act by altering dopamine circuits that go through the basal ganglia Note: - --- ## Functional and anatomical organization of the limbic loop through the basal ganglia @@ -715,304 +492,37 @@ Note: * Nucleus accumbens– contains MSNs * Ventral tegmental area (VTA)– releases dopamine -Nucleus accumbens +
Neuroscience 5e Fig. 29.10
-Neuroscience 5e Fig. 29.10 - - - - - -
Note: Much like the direct pathway. Inputs from different parts of cortex, including amygdala. - - to MSNs in ventral striatum the nucleus accumbens. These gabaergic projections then inhibit inhibitory projections in the in the ventral globus pallidus called the ventral pallidum. So there is a disinhibitory effect, much as we discussed before for other basal ganglia loops. - - - ---- - -## - -* - -Dopamine Pathways - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -Functions - -reward (motivation) - -pleasure,euphoria - -motor function - - (fine tuning) - -compulsion - -perserveration - -decision making - -Serotonin Pathways - -Functions - -mood - -memory - - processing - -sleep - -cognition - - - - - -nucleus - -accumbens - -hippocampus - -striatum - -frontal - -cortex - -substantia - -nigra/VTA - -raphe - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
- -Note: - - - ---- - -## Title Text - -[http://courses.pbsci.ucsc.edu/mcdb/bio125/Animation06-03NeurotransmitterPathwaysDopamine.mov](http://courses.pbsci.ucsc.edu/mcdb/bio125/Animation06-03NeurotransmitterPathwaysDopamine.mov) - -
- -Note: - - +serotonin pathways +* mood +* memory processing +* sleep +* cognition + +dopamine pathways +* reward (motivation) +* pleasure, euphoria +* motor function (fine tuning) +* compulsion +* perserverance +* decision making --- ## Changes in the activity of dopamine neurons in the VTA during stimulus–reward learning -Neuroscience 5e Fig. 29.12 +
Neuroscience 5e Fig. 29.12
- -
- Note: The VTA signals the occurrence of a reward relative to its prediction @@ -1021,13 +531,16 @@ The VTA signals the occurrence of a reward relative to its prediction ## Stimulation of reward pathway is incredibly powerful +
+
+ * Self stimulation experiments have demonstrated that rats will bar press for stimulation of the VTA or NAc -* Olds & Milner, 1954, J Comp Physiol Psychol, 47 -* This behavior can be blocked by cutting the pathway from the VTA or by administering dopamine antagonists. +* Olds and Milner, 1954, J Comp Physiol Psychol, 47 +* This behavior can be blocked by cutting the pathway from the VTA or by administering dopamine antagonists -[http://www.youtube.com/watch?v=aNXhyPj-RsM](http://www.youtube.com/watch?v=aNXhyPj-RsM) +
-
+
Rat self reward stimulation
Note: @@ -1035,33 +548,24 @@ Note: --- -## +## Key components of reward circuits -* +
+
-* 1) Mesolimbic (dopamine pathway) -* - Neurons from ventral tegmental area (VTA) to nucleus accumbens (major neurotransmitter: dopamine) -* - A critical pathway for drug addiction -* +1. Mesolimbic (dopamine pathway): + - Neurons from ventral tegmental area (VTA) to nucleus accumbens (major neurotransmitter is dopamine) + - Critical pathway for drug addiction +5. VTA– nucleus accumbens pathway + - Acts as a rheostat of reward. Tells other brain centers how rewarding an activity is. The more rewarding an activity is deemed, the more likely the organism is to remember it well and repeat it +2. Amygdala: + - Helps assess whether an experience is pleasurable or aversive and whether it should be repeated or avoided to forge connections between an experience and other cues +3. Hippocampus: + - Recording the memories of an experience +4. Frontal regions: + - Coordinates and processes all this information and determines ultimate behavior of the individual -* 2) Amygdala: -* - help to assess whether an experience is pleasurable or aversive -* - and whether it should be repeated or avoided to forge connections between an experience and other cues -* - -* 3) Hippocampus: -* - recording the memories of an experience -* -* 4) Frontal regions: -* - coordinate and process all this information and determine the ultimate -* behavior of the individual. -* - -* 5) VTA– nucleus accumbens pathway -* - acts as a rheostat of reward: it tells the other brain centers how rewarding an -* activity is. The more rewarding an activity is deemed, the more likely the organism is to remember it well and repeat it - -Key components of reward circuits +
Note: @@ -1071,10 +575,10 @@ Note: ## Addictive drugs hijack the brain’s reward system by enhancing the action of VTA dopamine neurons -* Drug addiction: compulsive drug use despite long-term negative consequences. -* All drugs of abuse increase dopamine concentration at the output targets of the ventral tegmental area. -* Nucleus accumbens– processes reward information. -* Prefrontal cortex– goal selection and decision making. +* Drug addiction: compulsive drug use despite long-term negative consequences +* All drugs of abuse increase dopamine concentration at the output targets of the ventral tegmental area +* Nucleus accumbens– processes reward information +* Prefrontal cortex– goal selection and decision making Note: @@ -1089,30 +593,36 @@ Note: * Ethanol boosts dopamine concentrations– mechanism unknown * Cocaine blocks dopamine reuptake via the plasma membrane dopamine transporter (DAT) * Ecstasy causes dopamine release in vesicle independent manner, inhibits -* Dopamine degradation and increases dopamine biosynthesis. +* Dopamine degradation and increases dopamine biosynthesis Note: Specifically, studies in primates and rodents have shown that many VTA dopamine neurons encode reward prediction errors. This error signal is hypothesized to direct synaptic plasticity in target neurons in the nucleus accumbens and prefrontal cortex for reinforcement-based learning. If VTA dopamine neurons signal a reward, the action or behavior that immediately preceded the reward is reinforced through dopamine modulation of downstream circuits (see Figure 10–44). Drugs of abuse bypass natural signals that activate these dopamine neurons, thus dissociating the reward system from its natural stimuli. Specifically, by increasing dopamine concentration at dopamine neurons’ presynaptic terminals, drug consumption mimics dopamine neuron activation; this reinforces the preceding actions, include drug consumption itself. Thus, addictive drugs hijack the brain’s reward system and exploit mechanisms that otherwise regulate learning and motivational + + --- ## Drugs of abuse act on endogenous neurotransmitter receptors and transporters -Inhibits 5-HT transporters and VMAT. Increased +
+
+Drug | Endogenous ligands | Mechanism of action +-------------- | ---------------------------- | ------------------------------------------------- +Nicotine | acetylcholine | Agonist of ligand gated channels (nAChR) +THC | anandamide, 2AG | Agonist of cannabinoid receptors (GPCRs) +Opioids | enkephalin, ß-endorphin, Dynorphin | Agonist of opioid GPCRs (µ,∂,k) +Cocaine | | Inhibits 5-HT transporters, DAT, NET. Increased DA, NA, 5-HT in synaptic cleft. +Amphetamine | | Inhibits MAO, NET, and VMAT. Increased DA and NA in synaptic cleft. +MDMA (ecstasy) | | Inhibits 5-HT transporters and VMAT. Increased DA, 5-HT, NA in synaptic cleft. - -DA, 5-HT, NA in synaptic cleft. +
Note: - - Cocaine - - DAT: dopamine transporter, extracellular NET: NA transporter, extracellular @@ -1130,53 +640,20 @@ VMAT2: vesicular monoamine transporter, intracellular : transports monoamines—particularly neurotransmitters such as dopamine, norepinephrine, serotonin, and histamine from cytosol into synaptic vesicles - - -MDMA enters monoamine neurons by acting as a monoamine transporter substrate (i.e., a substrate for DAT, NET, and SERT) - - ---- - -## Circuits involved in drugs of abuse - -* Nicotine enhances input onto VTA by presynaptic excitation -* Opioids, benzodiazepines, and cannabinoids act by hyperpolarizing GABAergic neurons -* Ethanol boosts dopamine concentrations– mechanism unknown -* Cocaine blocks dopamine reuptake via the plasma membrane dopamine transporter (DAT) -* Ecstasy causes dopamine release in vesicle independent manner, inhibits -* Dopamine degradation and increases dopamine biosynthesis. - -
- -Note: - -Specifically, studies in primates and rodents have shown that many VTA dopamine neurons encode reward prediction errors. This error signal is hypothesized to direct synaptic plasticity in target neurons in the nucleus accumbens and prefrontal cortex for reinforcement-based learning. If VTA dopamine neurons signal a reward, the action or behavior that immediately preceded the reward is reinforced through dopamine modulation of downstream circuits (see Figure 10–44). Drugs of abuse bypass natural signals that activate these dopamine neurons, thus dissociating the reward system from its natural stimuli. Specifically, by increasing dopamine concentration at dopamine neurons’ presynaptic terminals, drug consumption mimics dopamine neuron activation; this reinforces the preceding actions, include drug consumption itself. Thus, addictive drugs hijack the brain’s reward system and exploit mechanisms that otherwise regulate learning and motivational - --- ## Drugs of abuse affect dopamine projections from the VTA to the nucleus accumbens -
+
Synaptic locations of action for psychoactive drugs of abuse
Neuroscience 5e Fig. 29.11
+
Functional changes at VTA projections in addicted individuals
Neuroscience 5e Fig. 29.11
+ Note: - - - - Exposure to drugs of abuse causes long-lasting enhancement of excitatory input to VTA dopamine neurons, increasing AMPA/NMDA receptor ratio at these synapses. ---- - -## Exposure to drugs of abuse causes long-lasting enhancement of excitatory input to VTA dopamine neurons - -
- -Note: - - - --- ## Long-term changes in the brain as a result of abuse @@ -1185,32 +662,21 @@ Note: * Decreases in metabolism in orbito frontal cortex (OFC) * Decreases in dopamine D2 receptor binding -Volkow et al. - -Synapse 14 (2), 1993, pp. 169-177. - -Striatum: caudate, putamen - -nucleus accumbens - - - -
+
Striatum (caudate, putamen), nucleus accumbens
Volkow et al., Synapse 14 (2), 1993, pp. 169-177
Note: - --- ## Schizophrenia * 1% of general population * Onset during adolescence– hallucinations, delusions, and paranoia. Positive symptoms -* Social withdrawal, lack of motivation, cognitive impairment- Negative symptoms. -* Chlorpromazine and reserpine are drugs that alleviate positive symptoms, with side effects. -* Reserpine interferes with metabolism of all three monoamine neurotransmitters– dopamine, norepinephrine and serotonin by inhibiting a vesicular monoamine transporter (VMAT) effectively depletes the levels of these neurotransmitters. -* Chlorpromazine blocks D2 dopamine receptors. +* Social withdrawal, lack of motivation, cognitive impairment- Negative symptoms +* Chlorpromazine and reserpine are drugs that alleviate positive symptoms, with side effects +* Reserpine interferes with metabolism of all three monoamine neurotransmitters– dopamine, norepinephrine and serotonin by inhibiting a vesicular monoamine transporter (VMAT) effectively depletes the levels of these neurotransmitters +* Chlorpromazine blocks D2 dopamine receptors Note: @@ -1220,7 +686,7 @@ Note: ## VMAT is a target of anti-psychotics -
+
Note: @@ -1231,18 +697,13 @@ Note: ## Candidate genes associated with psychiatric disorders * Schizophrenia and bipolar disorder are heritable (80%) -* Depression and anxiety disorders is lower (30%). -* No simple Mendelian inheritance pattern has been shown but many genes have been implicated to be risk factors. +* Depression and anxiety disorders is lower (30%) +* No simple Mendelian inheritance pattern has been shown but many genes have been implicated to be risk factors -
+
Note: Table 11-2 Selected candidate genes associated with psychiatric disorders. - - --- - ---- -