Addiction (2) Flashcards
What is the definition of addiction?
state of compulsive drug use despite serious negative consequences such as medical illness, risk of significant life problems, and putting social valuables at risk
The substitution of drug rewards for
natural rewards suggests what?
neuropathology of addiction resides in the same neural system that mediates behavior for detecting, liking, wanting and acquiring natural reward.
A key aspect of drug addiction is what?
high relapse rate.
What is drug tolerance?
Decrease effects of a drug that develops
with continued use; first administration of a drug produces a characteristic dose-response curve; after repeated administration, curve shifts to the right, larger doses (risk of overdose) are needed to produce the same effect.
What is drug sensitization?
Enhanced effects of a drug that
develops with intermittent use. After intermittent administration of the drug the curve shifts towards the left, greater effects are achieved with a similar or lower dose.
Leads to long term changes in neural
circuitry; a key reason for the development
of salient incentive or “want” or “craving.”
What is innate tolerance?
Individual variations in sensitivity to a drug present before the administration; due to polymorphism in genes encoding drug receptors, and components of drug metabolism
What is Acquired Tolerance and Pharmacokinetic tolerance?
increase ability to excrete drug with the
time, leading to relatively lower plasma drug
concentration.
What is Pharmacodynamic tolerance?
Changes in drug-receptor interactions caused by: short term decrease in receptor # or binding affinity due to inactivation of receptor, internalization or degradation, and by long term changes in receptor # caused by alteration gene regulation
What is physical dependence and withdrawal?
Adverse physical symptoms and signs that result from the withdrawal of a drug, In absence of drug altered set point produces effects opposite of the drug, varies with diff drugs,
What causes physical dependence and withdrawal?
alteration in homeostatic set points to compensate for abused/misused drugs, drug-induced alterations in cell physiology and circuits; unmasked by drug cessation
Explain the concept of a reward?
Rewards (food, sex, cocaine) lead to “feel good” or “pleasure” sensation (hedonic)initiates learning process -> liking -> indentifying cues that predict avail., assign values and motivationstate (withdrawal early)-> increase want (incentive salience) -> positive reinforcement
What causes compulsion in addict?
sensitization (hypersensitivity) of component that mediates “Want (=incentive salience)”, neural substrate responsible is separable, yet interconnected, from neural subs. for pleasure/liking
Motivational behavior involves what processes? So it may involve higher centers such as what?
cognition, emotion, self-perception and
execution; PFC, amygdala, insular cortex, and dorsal striatum (caudate and putamen)
Sensitization of neural substrate for “want” is powerfully modulated by what?
earning and circumstances/environment surrounding drug administration (associative learning)
Rats, with electrodes in specific brain areas press a lever to self-administer electric stimulation or press lever to eat food. Which areas was stimulation preferred over food?
medial forebrain bundle, nucleus accumbens (NAc), ventral tagmental area (VTA), and lateral hypothalamus
What is conditioned place preference (CPP)?
rewarding properties of a drug are associated with a particular characteristics of a given environment
Natural rewards and addictive drugs
increase synaptic dopamine where? The source?
Nucleus accumbens (Nac); Ventral tegmental area (VTA)
VTA innervates what other limbic structures besides Nac? What does this do?
prefrontal cortex (PFC)- value to a reward is cognitively assigned in association with amygdala
What are the regions of the Nac? Functions?
shell- emotion regulating areas of the brain (amygdala), pleasurable response to rewards; Core- resembles dorsal striatum and influences the “drug seeking” behavior
The regulation of a sequence of actions
required for obtaining an award depends
on what? why?
dorsal striatum (caudate and putamen) where action related decision, originated in PFC, are filtered and processed.
What is the role of dopamine in the Nac?
triggers the urge of “want” when reward related cues are encountered for which there is a “liking”, binds the hedonic
properties of a reward to motivation
(wanting), formation of reward-related association that regulates our behavior
What is the difference in dopamine levels to the Nac between natural rewards and drugs?
Natural rewards- brief bursts and pauses of
firing of VTA dopaminergic neurons;
addictive drugs (amphetamine) elevate synaptic dopamine levels for hours,
disrupting all normal patterns (tonic, phasic)
What is the role of the prefrontal cortex in the reward system?
exerting cognitive control that regulates
behavior (action) to obtain the reward w/o distractions and resisting obstacles; PFC assigns value, intensity of pursuit based on value, OFC intimately networked with amygdala, insular cortex, hypothalamus and medial frontal cortex
OFC (w/in PFC) is intimately networked with amygdala, insular cortex, hypothalamus and medial frontal cortex. This association provides what?
emotional and motivational underpinning to
the reward values held in the working
memory in PFC
What effect do addictive drugs have on OFC?
produce distorted and exaggerated dopamine signal in OFC, produces
overlearning of drug-related cues,
distorting value of drug over other
natural rewards.
Opiates (morphine & heroine) mimic what NT? effect what drug receptor and neurons?
Endorphins, μ and δ opioid, GABAergic
interneurons (-‐)
Psycho-stimulants (cocaine & amphetamines) mimic what NT? effect what drug receptor and neurons?
Dopamine (DA), DA transporter, VTA and DA
neurons
Nicotine mimic what NT? effect what drug receptor and neurons?
Acetylcholine, nAChR, VTA and DA neurons
Alcohol mimic what NT? effect what drug receptor and neurons?
GABA and Glu, GABAA and NMDA, VTA
inhibitory neurons and PFC neurons to NAc
Phencyclidine mimic what NT? effect what drug receptor and neurons?
Glu, NMDA, PFC neurons to NAc
Caffeine mimic what NT? effect what drug receptor and neurons?
Adenosine, Adenosine, Adrenergic
neurons
Marijuana mimic what NT? effect what drug receptor and neurons?
Anandamide, CB1, NAc
How does cocaine act in synapse in reward system?
inhibits monoamine reuptake
How does amphetamine act in synapse in reward system?
cause monoamine release
What intracellular signaling mediated changes in the reward circuitry convert drug induced signals to a long term alteration in neural functions?
Strengthening of synaptic activities (LTP-mediated), (strengthening of the PFC glutamatergic synapse on VTA neurons), changes in postsynaptic excitatory currents, mediated by NMDAR and AMPAR
What prevents sensitization to psychostimulants?
Administration of NMDAR antagonists, lesion of PFC
How does cocaine effect the ratio of AMPAR/NMDAR currents? (other substance abuse too)
shows an increase in basal excitatory
synaptic strength, a reflection of induced
synaptic modification.
Blocking of what prevents CCP response to cocaine? Overexpression of this causes what?
GluR1 (a subunit of AMPAR) in VTA; enhanced rewarding and motivational effects of drugs
What is the molecular mechanism of drug-induced stable behavioral and synaptic (LTP-mediated) plasticity?
gene expression changes to sustain long-term remodeling of reward circuitry; Transcription factor CREB activates expression of genes dynorphin and FosB, containing cAMP response element (CRE).
CREB activated by phosphorylation in reward-related areas (VTA, NAc, amygdala, and PFC) by psycho-stimulants and opiates.
What role do drug-induced dynorphin peptides play in drug-induced plasticity?
through NAc collaterals, feed back on VTA DA neurons and inhibit them through κ opiate receptor, persistent induction of dynorphin (long-term drug use) attenuates DA release decreasing sensitivity and leading to tolerance, Overexpression of CREB in NAc decreases sensitivity
