Final Exam Flashcards
comprehensive, including lecture 21-22
what is ibogaine?
ibogaine is a psychoactive indole alkaloid derived from the root bark of the African shrub, ingestion can lead to intense visions with closed eyes like a waking dream, accompanied by a vivid recall of autobiographical visual memories, has a potential for therapeutic use but is cardiotoxic and cause hallucinations that can last more than 24 hours
what is the therapeutic effect of ibogaine?
can alter addiction-related circuitry by promoting neural plasticity, TBG (a drug that is structurally similar to ibogaine) reduced the hallucinogenic effects of LSD (as measured by head twitch response)
why is ketamine better than PCP?
shorter duration of action, reduced mind-altering effects, maintenance of protective airway reflexes, provided both analgesia and anesthesia, strong safety profile with respiratory stability
what is the mechanism of ketamine?
anesthesia effects: acts as a non-competetive NMDAR antagonist, interferes with pain signal transmission in the spinal cord and inhibitis nitric oxide synthase (an enzyme that produces nitric oxide) which is important for pain signaling and consciousness
ion channels: ketamine can also block voltage-sensitive calcium channels which reduces the release of pain signaling NTs, ketamine blocks sodium channels which hyperpolarizes nerve cells
what are the antidepressent effects of ketamine?
inhibits the reuptake of NE and serotonin, has been found that a single dose of intravenous ketamine produced rapid antidepressant effects in patients with MDD
how does racemic vs R and S configuration ketamine differ?
racemic: equal quantities of R and S enantiomers are marketed as an anesthetic agent for diagnostic and surgical procedure
S: has higher affinity for NMDAR compared to equivalent doses of R and racemic ketamine, also has lower side effects, effective for 50% of patients with treatment resistant depression
R: lower NMDAR affinity and is not used as a clinical drug
how does ketamine work on NMDAR?
NMDAR is tetrameric ion channel composed of four subunits that form a pore permeable to calcium, sodium, and potassium, when the membrane is depolarized the magnesium block in removed and calcium can enter the cell, ketamine binds inside the NMDAR when it is open which blocks further calcium influx, S ketamine works in the same way but does it more frequently
how do ketamine and esketamine exert their antidepressent effects?
the initial action begins with NMDAR antagonism on GABAergic inhibitory interneurons which results in enhanced glutamate release into the synaptic cleft leading to BDNF release and more synaptic spine growth
what does GluN2A knockout result in?
NR2A knockout mice showed reduced anxiety-like behaviors across multiple tests, the NR2A knockout mice displayed antidepressant-like behaviors
where is the brain does ketamine exert antidepressant effects?
mPFC: ketamine acts on NMDAR on GABA interneurons which disinhibits pyramidal cells, enhanced synaptic connectivity and dendritic spine growth in mPFC
hippocampus: ketamine increases BDNF levels in this region, enhanced plasticity and structural changes (restores stress-induced synaptic deficits)
lateral habenula: ketamine blocks abnormal bursting activity in this anti-reward center, reduced activity here helps normalize downstream monoamine signaling
brainstem monoamine centers: ketamines effects on DR (serotonin) and VTA (dopamine) restores normal monoamine signaling
how does ketamine alter brain connectivity?
MDD patients showed reduced connectivity in PFC compared to healthy controls, ketamine increases connectivity in the PFC and the number of brain regions with abnormal connectivity decreased dramatically (connectivity increased specifically in the lateral PFC, caudate and insula)
how does ketamine alter the lateral habenula?
ketamine blocks NMDAR-dependent burst firing in the LH, this disinhibits downstream monoaminergic reward centers, reversing depression-like behaviors in animal models, LH bursts were shown to drive depression-like behavior, which ketamine reversed
what is the circumplex model of emotions?
valence (positive or negative) and arousal (high or low) are used to measure emotions with opposite emotions being on opposite poles for valence and activation
what was Charles Darwins theory of emotion?
he believed that animal emotions are homologs for human emotions and that there are a set of basic emotions that present across species
what is the James-Lange theory of emotion?
emotions occur as a response to a specific physiological reaction (i feel afraid because my heart is pounding, i feel sad because i cry)
what is the Cannon-Bard theory of emotion?
they observed that despite severing connections between emotional responses and physiological responses animals still had normal emotional responses, from this they concluded that emotions and physiological responses occur simultaneously (my heart pounds and i feel afraid)
what is the Schachter-Singer theory of emotion?
we must label the physiological response in order to generate an emotion, individual perception and thoughts about a stimulus can influence the type of emotion (my pounding heart means i’m afraid because i interpret the situation as dangerous)
what theory of emotion is most supported by scientific evidence?
James-Lange theory is most closely supported, Antonio Damasio proved that each basic emotion produces a distinct pattern of neuronal reponse and physiological changes that occur before they are interpreted as an emotion
what is the Yerkes-Dodson law?
the optimal amount of arousal for performance is an inverted U-shaped curve where too little arousal leads to poor performance (boredom, lack of motivation) but too much arousal leads to poor performance as well (stress, anxiety)
what is the ‘feeling’ stream/downstream path of the Papez circuit?
represents the rapid generation of emotional states and responses
thalamus -> hypothalamus -> anterior thalamus -> cingulate cortex
what is the ‘thinking’ stream /upstream path of the Papez circuit?
represents the analysis of sensory information and formation of thought and memories
thalamus -> sensory cortex -> cingulate cortex -> hippocampus -> hypothalamus
what makes up the limbic system and what does it do?
limbic system regulates emotions and social behaviors as well as memory formation and stress response and is made up of the hippocampal formation, thalamus, hypothalamus, cingulate cortex, amygdala and prefrontal cortex
what are the sub-areas of the amygdala and what do they contain?
basolateral amygdala (BLA): cortex-like structure, 80% glutamatergic, 20% GABAergic interneurons, recieves input from sensory systems and allows them to pass through
central amygdala (CEA): striatum-like structure, mostly GABAergic neurons that project to other areas of the brain to mediate defensive behaviors, output region for the expression of innate emotional responses and their physiological processes
how does the infralimbic and prelimbic cortexes respond to fear and drug-seeking?
IL: decreases fear and drug seeking (increases extinction of fear by inhibiting reconsolidation of memories)
PL: increases fear and drug seeking
who is patient SM?
she has Urbach-Wiethe disease, a
rare genetic disorder that caused
bilateral calcification and atrophy of
her amygdala, which resulted in exclusive and complete bilateral amygdala destruction since late childhood, as a result she has trouble recognizing fearful expressions, identifying how intense they are, and drawing fearful faces from memory
what role do the amygdala and hypothalamus play in anger?
lesioning of the amygdala or stimulation has been used to treat severe, refractory aggression in some patients, stimulation of the hypothalamus has been shown to induce sham rage
how do the lateral and anterior hypothalamus alter the rage response?
anterior: stimulation of anterior hypothalamus produces sham rage
lateral: stimulation of the lateral hypothalamus produces true rage
what role does dopamine play in social isolation/sadness?
optogenetic activation of DA neurons in a social context promotes social interaction while activating these neurons in the absence of a social conspecific is aversive, DR DA neurons projecting to the CeA
promote sociality, while those projecting to the posterior BLA regulate negative affective state
what four brain regions play a role in fear learning?
amygdala: the amygdala processes and stores emotional aspects of traumatic memories
prefrontal cortex: the prefrontal cortex regulates emotional responses and can modulate fear memories in the amygdala
hippocampus: the hippocampus encodes contextual information and supports memory consolidation and retrieval
infralimbic prefrontal cortex: plays a role in extinction learning by inhibiting reconsolidation of memories
what is the monoamine hypothesis of depression?
the monoamine systems of serotonin, noradrenaline, and dopamine are involved, low activity of at least one of these neurotransmitters is responsible for depression
what are the major pathways of the dopaminergic system?
mesolimbic: VTA to nucleus accumbens
nigrostriatal: substantia nigra to dorsal striatum/basal ganglia
mesocortical: VTA to PFC
where do serotonin neurons project and what behaviors do they regulate?
5HT neurons are in the raphe nucleus and project to the basal ganglia to control movement, obsessions, and compulsions while projections to the limbic area are involved in regulating anxiety and panic and projections to the hypothalamus regulate appetite and eating behavior
where do norepinephrine neurons project and what behaviors do they regulate?
NE cell bodies are located in the locus coeruleus, in patients with depression low noradrenaline activity is associated with decreased alertness, low energy,
inattention, loss of interest, concentration difficulties, and cognitive deficits
how do monoamine oxidase inhibitors work?
MAOI bind to and inhibit MAOA in synapses from degrading 5HT and NE
MAOI bind to and inhibit MAOB in synapses from degrading dopamine
what are the 5 actions of tricyclic antidepressants (TCAs)?
SRI: block the reuptake of 5HT by blocking SERT
NRI: block the reuptake of NE by blocking NET
alpha: block a1 adrenergic receptors
H1: block histamine receptors
M1: block muscarinic cholinergic receptors
how do selective serotonin reuptake inhibitors (SSRIs) work?
blocks SERT so that it cannot reuptake serotonin from the synapse, selective because they only block reuptake pumps for serotonin
how do norepinephrine and dopamine reuptake blockers (NDRIs) work?
blocks DAT or NET so that dopamine and NE are stuck in the synapse
how do noradrenergic and specific serotonergic antidepressants (NaSSAs) work?
acts as an antagonists to the alpha 2 receptors as well as blocking three kinds of serotonin receptors and histamine receptors, prevents the negative feedback effect of synaptic NE on 5HT (alpha receptors are autoreceptors on the presynaptic cell, by blocking NE from binding to the alpha receptors it stops them from inhibiting the release of 5HT and NE from the presynapse)
what does inescapable shock do to the brain?
inescapable shock induces a strong activation of the DR serotonin neurons which leads to an acute release of 5HT in the amygdala, dorsal PAG, and nucleus accumbens, also induces a long-lasting desensitization of 5HT autoreceptors in the DR
what is general adaptation syndrome (GAS)?
a foundational theory that describes how the body responds to prolonged exposure to stressors, contains an alarm stage, resistance stage, and exhaustion stage, where the bodies ability to withstand the effects of stress increase during alarm, are maintained throughout resistance, and then decreased throughout exhaustion
what role does the HPA axis play in stress?
hypothalamus: modulates pituitary gland
anterior pituitary: associated with hormones, adrenocorticotropic hormone (ACTH)
posterior pituitary: release oxytocin and vasopressin
adrenal: cortisol (a glucocorticoid) binds to membrane-bound glucocorticoid receptors (GRs) located on CRH neurons in the PVN of the hypothalamus, this triggers endocannabinoids production which inhibits glutamatergic activation of CRH neurons which reduces CRH and the stress response
how does chronic stress affect the BLA?
stress-induced structural changes in the BLA correlate with the development of anxiety-like behavior, increased plasticity in the BLA cause enhanced anxiety behavior and maladaptive behavioral changes (and PTSD)
how does chronic stress affect the PFC?
stress leads to decreased dendritic length and complexity in certain populations of the PFC neurons which means the PFC cannot regulate the rest of the brain as effectively
what effect does stress have on memory?
stress long before forming new memories impairs memory formation
stress shortly before or after new information enhances subsequent memory performance
stress before memory retrieval impairs recall of previously learned information
stress effects on knowledge updating impairs integration of new information into existing knowledge structures
what brain regions are altered in bipolar disorder?
smaller volumes in bipolar patients: hippocampus, thalamus, amygdala
larger volumes in bipolar patients:
lateral ventricles
ventricular volume increases correlated with decreases in subcortical volumes
how does lithium effect the brain?
neuroanatomical effects: increased grey matter volume and density in specific brain regions: amygdala (involved in
emotion processing) hippocampus (important for memory and emotion regulation) prefrontal cortex (critical for executive functions and mood regulation)
cellular and molecular mechanisms: affects second messenger systems, promotes cellular viability and neuroprotection, affects neurotransmitter systems
what is the mechanism of action of lithium?
dopamine and glutamate are elevated during mania is bipolar patients, lithium inhibits excitatory neurotransmission by decreasing pre-synaptic dopamine activity and modulating post-synaptic G-proteins, it also modulates glutamatergic neurotransmission
by initially stimulating and then chronically downregulating the NMDA receptor, and inhibiting
the myo-inositol (mI) second messenger system, which is involved in maintaining signaling efficiency, additonally lithium promotes inhibitory neurotransmission by facilitating the release of GABA
and upregulating the GABA-B receptor
what is the mechanism of action of valproic acid?
VPA improves manic-like symptoms but not depressive symptoms by: acetylation promotes a more open chromatin structure and increased transcriptional activity, deacetylation leads to a more condensed chromatin structure and gene repression, HDAC inhibitors like valproic acid (VPA) shift the balance toward increased acetylation, this results in a more relaxed chromatin conformation and upregulation of gene transcription
how can you assess the validity of an animal model for mental disorders?
face validity: how well a model mimics symptoms of a disorder
construct validity: assesses whether the underlying mechanisms in the animal model are similar to those thought to be involved in the human disorder
predictive validity: the ability of the model to mimic treatments for the disorder
what are some experiments with optogenetics done on the amygdala?
used optogenetics to selectively activate or inhibit BLA terminals in the CEA in mice, found that activating BLA terminals in CEA reduced anxiety behaviors and inhibiting the BLA terminals in the CEA increased anxiety behaviors
what role does the bed nucleus of the stria terminalis (BNST) play in anxiety disorders?
BNST is considered part of the extended amygdala, BNST lesions reduced anxiety like behaviors, spider phobics showed increased activation in the BNST during spider vs mushroom anticipation compared to controls, when ovBNST activity is inhibited, it leads to reduced anxiety in rodents, adBNST to lateral hypothalamus
(LH): Stimulating this pathway
decreases anxiety-related behaviors
how do benzodiazepines effect GABA transmission?
GABA A: ionotropic (ligand-gated ion channels), primary target for benzodiazepines
GABA B: metabotropic (G-protein coupled receptors), pentameric
GABA binding its receptor allows Cl- to enter the neuron which hyperpolarizes the cells and reduces AP, benzodiazapines act as positive allosteric modulators of GABA A receptors (enhance the effect of GABA at the receptor, increasing frequency of Cl- channels opening which inhibits neurotransmission), anxiolytics effects mediated by alpha 2 subunit and sedative effects are mediated by alpha 1 GABA A receptors
overall BDZs cause more frequent openings of the GABAA channel, hyperpolarization, and increased receptor affinity for GABA and act mostly in the amygdala
how do barbiturates effect GABA transmission?
barbs enhance GABA A receptor function but they bind to a different site, at low doses, they increase the duration of chloride channel opening, at higher doses they can directly activate the channel in the absence of GABA
what is the incentive-sensitization theory of addiction?
liking (hedonic impact): drug gives a pleasurable experience
wanting (incentive salience): motivational aspect of a reward
across time the liking decreases and wanting increases, wanting persists long after drug use stops, making people vulnerable to relapse especially when exposed to drug-related cues or contexts
what is the homeostatic theory of addiciton?
views addiction as a disorder of disrupted homeostasis in brain reward and stress symptoms, as addiction cycle goes on mood drops further and further below the homeostatic set point following drug use, this means individuals will need to use drug to even reach their normal homeostatic set point, this leads to a allosteric negative emotion state/down regulation of the reward system (less dopamine release), transition from positive reinforcement (drug use for pleasure) to negative reinforcement (drug use to alleviate negative withdrawal
states)
how were the pleasure centers in the brain discovered?
intracranial self-stimulation (ICSS) of the medial forebrain bundle (which contain ascending dopamine fibers from the VTA to the nucleus accumbens) are part of the reward and motivation pathway with the lateral hypothalamus, VTA and prefrontal cortex are also effective sites, found that animals will work hard to get ICSS suggesting its rewarding properties
what are some characteristics of the substantia nigra (SN) dopaminergic system?
SN plays crucial role in movement control and contains dopamine neurons that project to the striatum (nigrostriatal pathway), this pathway is critical for motor learning and execution
what are some characteristics of the ventral tegmental area (VTA) dopaminergic system?
VTA plays a key role in the mesocorticolimbic dopamine system, it’s involved in both “wanting (incentive salience) and “liking” (hedonic impact) aspects of reward, the VTA is crucial for positive reinforcement and reward prediction error
what does the nucleus accumbens (NA) do and what type of dopamine receptors reside there?
the NA is a key brain region involved in regulating reward, motivation, and pleasure-related behaviors with dopamine release being intensity dependent
D1 receptor-expressing medium spiny neurons promote reward-related and drug-seeking behaviors
D2 receptor-expressing MSNs tend to inhibit these behaviors
what are the pain areas of the brain?
sensory processing area: primary somatosensory cortex (S1) and the secondary somatosensory cortex (S2)
emotional/limbic areas: anterior cingulate cortex (ACC) and insula (higher ACC activation correlates with perception of more unpleasantness and ACC to NA is necessary for social transfer of pain)
cognitive/associative areas: prefrontal cortex (PFC)
subcortical areas: thalamus and cerebellum
how does attention and emotion alter pain?
attention affects the sensory-discriminative aspects (how intense it feels), emotions affects emotional-affective aspects (how unpleasant it feels)
what are the emotion and attention circuits of pain modulation?
the emotional component of pain primarily works through ACC to PFC and (PAG) when our emotional state affects how unpleasant pain feels, this circuit becomes active, when distracted from pain activation decreased in the rostral ACC, which processes emotional pain responses
the attention-related circuit involves the superior parietal lobe (SPL) to both the primary somatosensory cortex (S1) and the insula, when distracted from pain activation increased in the dorsal ACC
how does the placebo effect reduce pain?
when someone perceives a placebo but believes it will reduce their pain, their brain activates a specific pain-control network involving the ACC, PFC, and PAG, when naloxone was used as an opioid antagonist the placebo effect disappeared suggesting that the opioid system plays a role in placebo pain relief
