Drug Dependence Test 2

How does an MRI work?

H atoms in our tissues spin around an axis, generating a magnetic field that “precesses” like a top. once a person is put inside an external magnetic field, precessions rotate about the magnetic field’s axis then get knocked askew by radio frequency pulses into a uniform orientation of precession at a 90 degree angle to the Bo. When protons “relax” to conform to the Bo field, they give off RF that is read by the receiver coil.

What is T-1 Relaxation?

recovery of longitudinal orientation of M along the main axis. T1 time refers to interval for 63% of longitudinal magnetization. relaxation time of protons varies as a function of local tissue type (fatty vs aqueous)

What is T-2 dephasing?

loss of transverse magnetization. T2 time refers to time interval for 37% loss of original transverse magnetization.

What is a structural MRI

earliest research use of MRI. segments the brain to grey matter, white matter, and cerebrospinal fluid. compares volumes between clinical groups.

what is VMB

voxel-based morphometry investigates gray matter abnormalities in mental illness. VBM spatially aligns every brain to a template, which gets rid of most of the large differences in brain anatomy and overall size among people. brain images are smoothed so that each voxel represents a weighted average of itself and its neighbors. image volume is compared across brains at every voxel.

What type of games activate the insula ?

simon says

What type of action activates the dACC ( dorsal anterior cingulate cortex)?

active when processing conflict or monitoring our behavior

What is a diffusion MRI

a MRI that looks at what water tells us about the brain. the more gray matter, the more willing a person is to wait for a delayed reward

What is fractional anisotropy

a scalar value from 0 to 1 that describes the preponderance of diffusion. FA=0 means diffusion is unrestricted(equally restricted) in all directions. FA=1 means diffusion occurs only along one axis and is fully restricted along all other directions

what are the features of sMRI

high resolution, single static volume, no absolute units, volumetric analysis

what are the features of fMRI

change over time, low spatial resolution, no absolute units, compare one brain state to another, reconcile signal with some modeled idealized expected signal

What does the blood oxygen level dependent (BOLD) fMRI do?

detects brief, localized excess flow of oxygen-rich hemoglobin. tell software when certain types of events occurred. software then reveals where signal correlates with idealized HRF responses.

what are block and event related fMRI designs

block design is more statistically powerful, less time required, lack of resolution and trial events. event-related design requires many trials, requires irregular timing, and enables separable detection of activation by specific trial events.

how does impulsivity in addiction guided

impulsivity in addiction guided by the brain calculating benefits relative to risk. different brain regions may contribute to decisions to take or refrain from risks.

how is alcoholics notifications of rewards and losses different

alcoholics showed greater reactivity of emotional brain circuitry to notifications of rewards and losses.

what are the two main analytic approaches to assessing inter-regional function connectivity with fMRI

seed based analysis and independent component analysis.

What is seed based analysis

hypothesis driven approach, how do well-implicated structures coactivate with other regions

What is independent component analysis

data-driven, how does the brain’s intrins activity assort itself into functional networks

What is a perfusion MRI

using MRI to quantify rate of blood flow to the brain. this method can assess blood flow, blood volume, and mean transit time

what is perfusion

capillary blood flow delivered to the tissue

how might differences in brain perfusion between smoking and non-smoking individuals affect fMRI experiments on addicted populations?

longitudinal arterial spin labeling (ASL) MRI study of persons with alcohol use disorder (AUD) shows recovery of cortical gray matter perfusion with abstinence in non-smokers but no perfusion recovery in persons who smoke

What is positron emission tomography (PET)?

create neutron-deficient, positron-generating atoms by blasting a standard atom with a proton beam. label biological molecules with the positron generating atom. neutron-deficient isotopes in the biological molecule will stabilize(decay) by emitting positrons that turn the proton into a neutron. positron collision with nearby electron annihilates both to yield gamma rays

what does 18F-deoxyglucose do?

the workhorse. structural analog of glucose. incorporated by cells and processes akin to regular glucose; not readily metabolized. a measure of local energy utilization.

What are advantages of fMRI

usually no contrast medium, decent spatial resolution, improved temporal resolution

What are disadvantages of fMRI

blood/vascular signal, no molecular information, very sensitive to head motion, no (ferrous) metal in body

What are advantages of PET

molecular information, energy utilization information, no metal contraindications

what are disadvantages of PET

use of radioactive contrast medium, requires long time scales, cost

what are important points MRI studies have shown?

-reduced gray matter volume in alcoholism and other addictions

-disrupted white matter fiber bundles in addiction

-altered activation in addiction by cognitive tasks

-increased activation of motivational neurocircuity by drug cues and nondrug reward deliveries across studies

-blunted activation of frontocortical circuits by demands to inhibit or monitor behavior

-enhanced connectivity between attentional control networks and other brain regions appears protective against drug relapse

-decrements in gray matter volume or task-elicited recruitment may not be so specific to addiction, especially in salience network, but may reflect common deficit in regulating responses to environmental challenges

What have PET studies shown?

reduced glucose metabolism in frontal cortex in addiction, reduced levels of DA D2 binding in addiction, the “high” from drugs correlates with dynamic DA displacement in ventral striatum

What is the preclinical abuse liability assessment?

in vitro receptor binding and efficacy. in vivo physiological and behavioral effects

What is the discriminative stimulus in drug self-administration

image that tells you something that’ll tell you something happened to you. some behavior with a stimulus produces a consequence/reward.

What is the response in drug self-administration

interaction with the stimulus

what is the reinforcing stimulus in drug-self administration

deliberate act to the subject based on its behavior

what is the 3-term contingency

Sd→R→Sr. drug taking is an operant behavior. drug addiction is a learned operant behavior.

When is a drug considered to produce reinforcing effects?

if at least one dose of the drug maintains response rates greater than those maintained by vehicle

what happens when the drug is the discriminant ?

signals to you characteristics about the response. provide information to the animal about the environment.

when is a drug considered to produce discriminative stimulus effects?

if subjects can be trained to discriminate drug from vehicle. appear to be necessary but not sufficient for abuse liability.

what is physical dependence

a state produced by drug exposure and characterized by the emergence of abstinence signs when the drug is withdrawn

how are studies of dependence/withdrawal done?

drug exposure → withdrawal → measure abstinence signs

what is the difference between spontaneous and precipitated withdrawal?

spontaneous has abrupt consequences days after. precipitated is when an antagonist is administered

how are abstinence signs measured?

physiology, unconditioned behaviors, and conditioned behaviors

what is intracranial self-stimulation (ICSS)

electrode implanted in “brain reward” circuit. lever pressing produces brain stimulation. dependent measure based on rate of intracranial self-stimulation

how is ICSS interpreted?

a drug is considered to facilitate ICSS if it increases the rate of ICSS. abuse liability is indicated if a drug facilitates ICSS

what is place conditioning

during training, subjects receive drug in one environment and vehicle in a separate environment. during testing, subjects have access to both environments, and change in time spent in the drug-paired place is measured

how can a drug be considered to produce a place preference

if it increases time spent on the drug-paired place.

what is the pharmacology of nicotine

colorless, oily, highly toxic alkaloid

found in nature only in tobacco plants

tertiary amine

water and lipid soluble

two stereoisomers, tobacco only contains (S)-nicotine

What are the effects of nicotine on the CNS

glutamate: memory & cognition, NE: stimulation, arousal, ACh: performance & memory , dopamine:pleasure, arousal ; GABA: anxiety ; b-endorphins: anxiety, tension; 5-HT: mood, appetite

what are the central effects of acute nicotine?

enhanced cognition and memory, euphoria, stimulation. appetite suppression, anxiety relief. gateway to sympathetic and parasympathetic nervous systems

what is the structure of the nicotinic receptor?

ligand gated ion channel, excitatory regulation of Ca2+ and Na+

what are the three basic states of nicotinic receptors

unoccupied and closed

occupied and closed

occupied and open

what is the only medicinal use of nicotine

treatment of nicotine addiction

what are potential benefits of selective nicotinic receptor targets

anti-inflammatory , pain relief, protection against aging, cognitive enhancer

what are some risks of nicotine by itself

is highly addictive, can be genotoxic and promote tumorgenesis , causes vasoconstriction which can exacerbate heart disease, can promote anxiety, can promote vulnerability to other drugs of abuse , can stimulate cancer cell signaling and is associated with a number of cancers, GWAS studies implicate some nicotinic receptors in cancer vulnerability

what is the bioavailability of inhaled tobacco products

smoked and vaped nicotine reaches the brain within 5-10 seconds

What is cigarette smoke in the gaseous phase?

CO. causes hypoxia, neurological damage, and harmful to fetus

what is cigarette smoke in the particulate phase?

nicotine (promotes addiction), tar (increases cancer risks)

does waterpipe or cigarette smoking have more tar, CO, and nicotine

waterpipe

what are smokeless tobacco relative risks to smoking

decreased risk for heart disease and lung cancer. increased risk of tooth decay, gingivitis, leukoplakia, tongue/mouth cancer, and pancreatic cancer

what is topography

what method a person uses to smoke

what are known toxic biproducts of ecigarettes

xylene, formaldehyde, and acetone

what is the rate and absorption of nicotine in the body

dependent on route of administration, affects the magnitude of nicotine’s effects, determines abuse liability

how is nicotine eliminated and metabolized in the body

dependent on route of administration , accelerated elimination increases tobacco use

how is nicotine absorbed in the body

90-98% from respiratory tract if inhaled, buccal absorption is pH dependent. readily absorbed through the skin

what delivery of nicotine has the greatest abuse liability

cigarette > nicotine > nasal spray > vapor inhaler > nicotine patch > nicotine gum

how is nicotine distributed in the body

wide and fast, levels varies according to routes of administration, crosses placenta, plasma ½ life is around 2 hours

where is 80-90% of nicotine metabolized?

in the liver, lung, and kidney

what is the natural progression of tobacco dependence

initial aversive experience, tolerance to aversive effects, pleasurable effects, social use, nicotine intake increases, withdrawal in the absence of nicotine

how does the mesocorticolimbic dopamine pathway support the reinforcing effects of nicotine

we have nicotinic receptors in the VTA, the amygdala, the incumbents, the prefrontal cortex. Nicotine causes dopamine release that can be at the level of the nucleus accumbens on those axon terminals, but also at the level of the VTA. self administration is interrupted if you lesion these dopamine receptors or block this pathway. If you block beta two receptors in the brain here or here, you will actually block nicotine. Activation of these areas is associated with self reported feelings of nicotine high and rush in humans. This is just to show you these beta two receptors are present on the dopamine, soma and dendrites as well as on these axon terminals. Because you get this desensitization when you're continuously using nicotine, you'll get an up regulation of your nicotinic receptors. This is due to homeostatic effects of receptor desensitization.

how is the mesocorticolimbic dopamine pathway altered by chronic nicotine exposure

repeated nicotine exposure results in upregulation of nicotinic receptors. repeated nicotine leads to elevated dopamine release. smoking-associated cues activate the NA, amygdala, cingulate, and frontal lobes in smokers but not non-smokers.

what are signs of withdrawal from tobacco

craving, headache, inability to concentrate, irritability, sleep disturbances, hunger

what are first line therapies for tobacco dependence

nicotine replacement therapy, norepinephrine/dopmaine reuptake inhibtor, nicotinic partial agonist (varenicline/chantix)

what is the concern with switching vs quitting

e-cigarettes/ENDS concerns as a federally approved method of tobacco cessation

what factors contribute to tobacco addiction

genetic vulnerability , exposure, stress, polydrug use, sex, mental illness, environmental factors, pharmacokinetics ,

what is AUD?

alcohol use disorder, a medical condition characterized by impaired ability to stop or control alcohol use despite adverse social, occupational, or health consequences

what is alcohol binge drinking

pattern of drinking alcohol that brings BAC to 0.08%

what are clinical signs of alcoholism in the head

increased risk for fracture, subdural hematoma

what are clinical signs of alcoholism in the stomach and duodenum

acute erosive gastritis; chronic hypertropic gastritis; peptic ulcer; hematemesis; increased cancer incidence

what are clinical signs of alcoholism in the cardiovascular system

Cardiomyopathy

what are clinical signs of alcoholism in neurological disorders

acute withdrawal syndromes ; amblyopia ; wernicke-korsakoff syndrome; cerebellar degeneration ; polyneuropathy; pellagra

what are clinical signs of alcoholism in the muscles

myopathy

what are chronic alcohol abusers more prone to

bacterial pneumonia , septicemia, tuberculosis , hepatitis C, HIV, increased risk for certain cancers, thiamine deficiency (Wernicke-korsakoff) , hyponatremia, having child born with fetal alcohol spectrum disorder

What is the pharmacology of ethanol

amphiphile : has both hydrophobic and hydrophilic characteristics. readily passes through biological membranes. tissue content proportional to water content. no appreciable ethanol-protein binding in plasma.

how is ethanol absorbed and metabolized

primarily from the small intestine, affected by concentration, food in stomach retards absorption, 90% metabolized under first order kinetics

what is the expected effect at 2-20mM of ethanol in the blood?

impaired coordination , euphoria

what is the expected effect at 21-40mM of ethanol in the blood?

ataxia, decreased mentation, poor judgement, labile mood

what is the expected effect at 41-60mM of ethanol in the blood?

marked ataxia, slurred speech, nausea and vomiting

what is the expected effect at 61-85mM of ethanol in the blood?

stage 1 anesthesia, memory lapse

what is the expected effect at 81 -100mM of ethanol in the blood?

Respiratory failture, coma, death

what are symptoms of alcohol withdrawal

anxiety and dysphoria, sympathetic hyperactivity, muscle cramping, hyper-reflexia, seizures, marked tremor, hallucinations, psychosis, circulatory collapse and death

what is treatment for alcohol withdrawal

graded institution of IM, IV benzodiazepines or barbiturates + thiamine

what are suggested causes for alcohol toxicity

cytokines(liver and brain), oxidative stress, excitotoxicity(brain)

what are neurobehavioral deficits in children with FAS/ARND

decreased intellectual functioning, attention deficits, hyperactivity, language difficulties , learning disabilities , impulsive behavior , visuospatial disabilities

how do neurobiological events continue in development of alcohol use disorder?

acute drug use will become chronic then compulsive. neuroplasticity will increase with use. the mesolimbic dopamine pathway will increase plasticity and potentiation of DA neuron firing. the ventral-dorsal-striatal loop will form habit. loss of function executive systems happens in the prefrontal systems. gain-of-function stress systems happens in the extended amygdala.

how do gaba receptors mediate ethanol enchancement

by allosteric enhancement, ligand gated ion channels

what is phasic inhibition

produced by high doses of GABA release for ethanol. at presynaptic terminal

what is tonic inhibition

lower doses of GABA release, less desensitization for ethanol. at extrasynaptic sites

how does ethanol interact with the ligand gated ion channel

interacts in a antagonistic way. can antagonize the effects of some neurotransmitters on their postsynaptic receptors. synaptic glutamate responses mediated by NMDA receptors are inhibited in a non-competitve fashion

what subunits are specific for behavioral actions of ethanol?

the water filled cavities of proteins provide binding sites for alcohols and anesthetics. such sites have been characterized for the GABAa and glycine alpha1 subunits. GABAa , glycine, and alpha subunits and NMDA subnits are important for specific behavioral actions of ethanol

how can ethanol indirectly modulate GABA release

it involves alterations in calcium-mediated vesicular release through ethanol actions on G-protein coupled receptors.ethanol can have actions on currents modulating intrinsic excitability of GABAergic neurons or modulate firing of these neurons through release of endogenous opiates acting on mu-opioid receptors