Test 1 Part 4 Flashcards
How do Wise and Koob differ in their characterization of “compulsive” drug taking (2 points)?
Wise’s characterization of “compulsive” drug taking: Compulsive drug taking is characterized by the steady, regular and predictable consumption of drugs by an animal, until the drug is withdrawn. ( or to the point of exhaustion/overdose). Compulsive druf intake can emerge BEFORE the development of physiological dependence. Neither dependence nor tolerance are necessary conditions for the compulsive self administration.
Koobs characterization of “compulsive” drug taking: His idea is that the combination of a decreased reward system function, and the recruitment of an “anti-reward” system provides a powerful source of negative reinforcement that defines compulsive drug seeking behavior.
- Compulsive drug taking results from opponent processes: excessive activation of an A process (REWARD SYSTEM) results in the strengthening of the aversive emotional state (B PROCESS) which drive negative reinforcement, so drug-taking becomes about removing the unpleasant withdrawal symptoms.
Describe one point of agreement (2 points) and disagreement (2 points) between Koob and Wise with respect to their respective conceptualizations of drug addiction.
Agreement; Wise and Koob both agree that that the starting point for addiction is the positive reinforcement, or hedonia/euphoria/pleasure that is felt when the drug is taken. This positive reinforcement GUIDES the initial repeated drug taking, and drug taking eventually becomes compulsive and habitual.
Disagreement: “we differ in semantics?”
- Koob believes that addiction involves long-term persistent dysregulation of the activity of the brain reward systems and stress/antireward systems.
o The main perpetrator of addiction is the excessive activation of the reward circuitry that will trigger neuroadaptive changes, producing withdrawal/negative affects.
o He believes that addiction arises once neuroadaptive changes have been made to compensate for the chronic drug taking.
- Wise does not think that “dependence” = “addiction”
o Addiction should be used in relation to the EARLY SIGNS OF COMPULSIVE DRUG TAKING AND THE CRAVINGS ASSOCIATED WITH IT”
♣ Not in relation to the subsequent bodily consequences that develop only after a long history of drug self-administration
o Addiction arises in the early stages of compulsive drug taking, whereas dependence results after the substance has already become a problem.
4 broad functions of glial cells
1) production of toll like receptor protein generates sequences so that immune cells can recognize healthy cells vs pathogen
2) also releases growth/tropic factors
3) metabolic factors: converts glc–> lactate
4) secretes NTs aka glial transmitters. Messing with glial cells can affect transmission in surrounding neutrons.
How do glial cells modulate synaptic activity?
they release glial transmitters in a general area, affecting multiple neurons’ firing rate. In can influence basal firing rate in an AREA because each astrocyte has its own territory, many do not overlap.
QUESTION: Describe the functions of two forms that microglia may take in the central nervous system
M1: Reactive form. Pro inflammatory. Gets activated in response to a pathogen.
- Releases cytokines at an UNCONTROLLED RATE to mitigate the immediate threat/pathogen.
- Can attack neurons by releasing neurotoxic factors like TNFALPHA and ROS.
- Drugs like etOH cold push microglia into their reactive forms.
M2: Trophic form. Considered to be anti-inflammatory. Provides nutritional support and growth factors to promote neuron survival.
- When activated, they can release cytokines AT A CONTROLLED RATE
- balances between neurogenesis and neuronal death by phagocytosis of apoptotic cells and cellular debris.
o Plays a role in synaptic pruning.
QUESTION: 1. Briefly, how does immune pathology lead to neuronal damage (2 points)?
1) self propelling neurotoxicity.
- M1 cells that were turned on by a stressor/pathogen/inflammatory trigger can cause neuronal damage. This damaged neuron will recruit more microglia to “fix the problem” by releasing laminin, which results in even more microglia being activated - reactive microgliosis. This signal continues to get amplified.
2) 2) glia and glutamate. The presence of reactive microglia inhibits GLAST transporters on astrocytes, preventing glutamate transport out of the synapse. This means that there is more Glu signaling that can occur in the area of the astrocytes and microglia.
- Glu can bind to AMPA receptors in NEURONS, resulting in enough depolarization to activate the NMDA receptors (remove magnesium ion). When Glu binds to NMDA, it causes a huge increase in calcium.
- Influx of Ca2+ results in apoptosis in Neurons in the area of the glia. Ca2+ induces apoptosis through a variety of pathways, such as the caspase pathway. ROS are also produced. There is also a disproportionate death of GABAergic neurons since these neurons have more glutamate receptors and are easily affected by too much glutamate.
explain the relationship between glia dysregulation and schizophrenia
symptom severity is dependent on M1 presence, and inversely dependent on M2 presence.
M1 affects neurotransmission in such a way that it manifests the positive symptoms of schizophrenia
explain the relationship between glitchesa dysregulation and parkinsons
Lewy bodies made of alpha synuclein is present in individuals with parkinson’s. This triggers a signalling cascade (astrocyte –> cytokines -_> M1 activation –> neuronal injury), specifically in the substantial nigra.
The BBB is also affected; T cells enter the brain, which provokes reactions with microglia as well, promoting an excessive M1 immune response, resulting in NUERONAL INJURY.
Because alpha synucleinis persistently expressed, T cells will continue to be secreted.
explain how reactive microgliosis occurs
M1 cells that were turned on by a stressor/pathogen/inflammatory trigger can cause neuronal damage. This damaged neuron will recruit more microglia to “fix the problem” by releasing laminin, which results in even more microglia being activated - reactive microgliosis. This signal continues to get amplified.
how does hedonic dysregulation = glial dysregulation
recall: glial cells secrete toll like receptor protein as part of an immune response.
EtOH stimulates dysregulation cascade. Modifies immune responses via the SAME LINKING HUB NFKB/AP1, which stimulates inflammatory factors.
therefore, increased stress, increased alcohol, or infection pushes the astrocytes, and excites microglia, results in increased ROS, NO, TR, TNF, Its etc. There is a generation of immune response that ends up in excitotoxicity.
