neurobiology and neuropharmacology of substance use disorders Flashcards
positive reinforcement vs negative reinforcement
positive reinforcement –> they feel good after, is “rewarding”; gives a “rush”
negative reinforcement –> the drug alleviates anxiety or depression or alleviates withdrawal syndrome
major opiates and their actions on a timeline
morphine, heroin, oxycodone, and fentanyl
initial N/V, rush(few minutes),
euphoria (1-2 hrs),
sedation/dissociation (2-4 hrs) and analgesia (2-4 hrs)
higher doses can cause respiratory depression, sedation, immune disturbances and constipation
5 target pathways of the drugs of abuse
- 3 mediated by DA
- 1 mediated by NE
- 1 mediated by 5HT
dopamine pathway
increased DA leads to…
fibers project from the VTA to the nuc. accumbens and prefrontal cortex
(midbrain to forebrain)
**feedback control is provided by GABA neuron regulation
increased DA in the nuc accumbens leads to euphoria
enkephalins effect in the dopamine pathways
what do they inhbiit?
enkephalins elevate DA in the nucleus accumbens
Enkephalins, released from enkephalin neurons, enhance dopamine release from VTA dopamine neurons in the N. Accumbens by inhibiting GABA release. Also, enkephalins directly inhibit GABA neurons in N. Accumbens.
GABA turns off dopamine firing
**they inhibit activity of GABA neurons in the VTA and nuc accumbens so that dopamine neurons can remain active
target for opiates (morphine) in the dopamine pathway is on the
GABA neurons
inhibits gaba release so that dopamine release is enhanced
during opiate withdrawal,
DA pathways become less active; less DA release in Nuc. accumbens, PFC (loss of euphoria/reward feedback)
• NE release from locus ceruleus pathways to forebrain and spinal cord, normally reduced by acute opiate action, is increased; locus ceruleus neurons firing rate increased (anxiety)
NE pathway (lovus ceruleus) is activated
opiates effect on DA pathway vs NE pathways
activates DA pathways and reduces NE pathways
features of an opiate dependent state
reduced effect of all opiates (cross tolerance)
little cross tolerance to other centrally acting drugs
physical dependence - withdrawal syndrome after both discontinuation or administration of an antagonist (naloxone = trtmt drug)
**but it IS possible to be dependent on opioids and maintain normal life (fentanyl) = anesthesiologist occupational hazard!!!
opiate withdrawal timeline (morphine/heroin)
6-12 hrs: lacrimation, rhinorrhea, yawning, gooseflesh,
12-24 hrs: restless sleep
16-96 hrs: dilated pupils, gooseflesh, tremor, weakness, anorexia, nausea, vomiting, intestinal spasms (cramps), diarrhea, muscle and back pain, muscle spasms / jerks, CNS stimulation (ejaculation, orgasm), depression, weight loss, acid-base balance changes, dehydration and ketosis
Maximum symptoms at 48-72 hrs after last dose
Symptoms abate within 7 - 10 days
opiate withdrawal time course is more rapid/intense in _______ and slower, less intense in ______
more rapid/intense in meperidine dependence
slower, less intense in methadone dependence
opiate withdrawal in the newborn
Babies born to opiate-addicted mothers suffer withdrawal on delivery.
Symptoms include:
- irritability,
- excessive high pitched crying,
- tremors,
- violent sucking on fists,
- hyperactive reflexes,
- increased bowel activity,
- vomiting, and fever.
treatment is small doses of opiates to wean baby off of it.
after initial detox, ______ is common, _____ continues for months or years, and ________ syndrome occurs
relapse is common
craving
conditioned withdrawal syndrome - induced by a return to an environment in which drugs have previously been used; shows all the features of opiate withdrawal
two opiate antagonists?
they can cause….
naloxone
naltrexone
withdrawal symptoms
compensatory changes that occur with opiate tolerance
- µ opioid receptor are desensitized
- little down regulation (little reduction in # of receptors)
- neurons become less sensitive to drug
Compensatory changes:
- signal transduction pathways modified
- patterns of gene expression altered
***withdrawal effects are opposite to acute effects of the drug!!
When circuits are balanced (A) there is appropriate inhibitory control and decision making. During addiction (B), enhanced expectation value of the drug in the reward, motivation and memory circuits overcomes the control circuit, favoring a positive feed-back loop initiated by the consumption of drug.
