Motivational Systems, Drugs, And Addiction Flashcards
What are the two main dopamine systems
Mesolimbic system
Nigrostriatal system
What is the main dopamine projection system
Mesolimbic system
Motivational loop and motor loops
Nigrostriatal
What does the nigrostriatal system consist of
From SN to caudate N and putamen
What nucleus participates in the motivational and motor loops
Caudate
What does the mesolimbic system consist of
From tegmental area to prefrontal cortex, nucleus accumbens (ventral striatum), amygdala, hippocampus, other limbic regions
What is the mesolimbic system important for
Selective attention (prefrontal), natural reward seeking, and involved in drug addiction
Where is the nucleus accumbens positioned
At anterior end of striatum and in a ventral position
What two structures does the nucleus accumbens continue with
Caudate and putamen
Anterior commisure and the ventral pallidum
Portion of striatum lying ventral to anterior commissure crossing
What loops are the nigrostriatal DA system involved with
Motor loops and cognitive loops
What loops are the mesolimbic DA system involved with
Motivational (emotive) loop
What striatal region is involved in the motivational loop
Ventral striatum
What striatal region is involved in the motor loop
Putamen and caudate
What striatal region is involved with the cognitive loop
Caudate nucleus
What are dopamine neurons activated by
Emotionally positive (and negative) stimuli and cues that indicate these rewards are available
- food/nutrients
- socal: fam/friends/mates
- sexual arousal/activity
- music
- money
Dopamine release in target regions
Nucleus accumbens
-critical for normal behavior and reward seeking
Impairment in dopamine release can lead to reduction in
- eating, other rewarding activities, spontaneous physical activity, normall mediated by dopamine regulation of: accumbens, orbital cortex, amygdala, hypothalamus
- attention and working memory (prefrontal)
What part of the mesolimbic system is strongly activated by various drugs
Ventral tegmentum
Nucleus accumbens
What are the drugs that affect the nucleus accumbens
- amphetamine
- cocaine
- opiates
- THC
- phencyclidine
- ketamine
What drugs affect the ventral tegmental area
- opiates
- ethanol
- barbiturates
- benzodiazepines
- nicotine
How do they test to see what parts of the brain are affected by certain drugs
They directly stimulate a part of the brain and see if rats will press lever for more.
Activation of the mesolimbic dopamine system following drug use
Serves to reinforce the emotive or motivational loop circuits, which reinforces drug seeking and drug use. Drugs usually induce greater activation of the mesolimbic dopamine system than natural rewards
Activation of the mesolimbic dopamine system following drug use, including activation of the amygdala and hippocampus
Also serves to add a strongly positive emotional value to any sensory cues associated with drug use or drug availability
Appetitive learning
Sensory cues that were previously emotionally neutral sensory stimuli gain a strongly positive emotional value. These stimuli alone gain the ability to activate the mesolimbic dopamine system and this stimulus induced is believed to be involved in drug-craving
Other than dopamine what else is likely to contribute to drug induced reward and addiction
Use-dependent changes in other NT, intracellular signaling pathways, transcription factors
A patter of chronic, escalating, and compulsive drug use despite adverse consequences.
Addiction
Stages of addiction development
- repeated drug use escalates in frequency or dose or both
- tolerance: higher doses needed
- psychological dependence: continued use required to maintain normal function
- dysphoria and withdrawal: periods of non use lead to emotional distress or depressed moods
- relapse: triggered by exposure to drug or associated cues
What happens to the VTA, nucleus accumbens, and prefrontal cortex during drug abuse
Structural and neurophysiological plasticity
Drug induced neurophysiological plasticity include schanges in
Dopamine and other NT receptors, synaptic re-uptake transporters, intracellular signaling pathways downstream to metabotropic NT receptors, transcription factors
Drug induces structural plasticity
Synapse number and density, dendritic arbor, axon terminals
Drug addiction in different people
Significant individual variability in whether initial drug use leads to addiction
-risk factors: trauma, physical/sexual abuse, MDD, anxiety
Blocks pre synaptic dopamine re-uptake transporter
Cocaine
Blocks pre-synaptic dopamine re-uptake transporter and can also cause reversal of flow of dopamine through re-uptake transporter back into synapse
Methamphetamine
Amps synaptic signaling
Amphetamine psychosis: manic, delusional, paranoia
Methampehtamine and MDMA (ecstasy)
What can the use of methamphetamine and MDMA cause
Potential neurotoxicity
What is enkephalin synthesized from
Gene
What is dynorphin synthesized from
A gene
What is B-endorphin synthesized from
A post translational cleavage product of the pituitary hormone PMC, which is also cleaved to produce ACTH, which stimulates adreanl cortex to release cortisol
Membrane metabotropic receptors for endogenous opioids
Mu
Kappa
Delta
Mu receptors
Bind enkephalin and opioids drugs
Kappa receptors
Bind dynorphoin
Delta receptors
Bind enkephalin
Opioids receptor functions
Widely distributed in the brain, so diverse functions
- emotional response to pain
- appetite and craving salt, sweets, food
- playability of food
- reward seeking of various kinds
- mood
Neurobiological basis of addiction
Possible contributing factors
- rewarding activities and stimuli increase endogenous opiates
- synthesized and released as NT by dopamine neurons
- opiate drugs can become mroe rewarding than natural stimuli
- reduce anxiety or other negative emotions: learned self medication
Psychoactive substance in marijuana
THC
Receptors of endogenous canabinoids
Anandamide
2-AG
What are anandamide and 2-AG synthesized from
Phospholipids
What do anandamide and 2-AG act as
Retrograde messengers: released from post synaptic sites, diffuse across synapse and bind to pre synaptic auto receptors to regulate pre synaptic NT release, mainly glutamate and GABA release
-two proteins coupled receptors: CB1 and CB2 generally inhibitory
Where is CB1
Widely in the brain
Where is CB2
Mainly in hypothalamus
Prefrontal cortex and cannabinoids and THC
Act similarly to local inhibitory internuerons, so excess activation of CB1 can slow or impair cognitive function
Reward systems and marijuana
Enhances mesolimbic dopamine system activity
Hypothalamus and marijuana
Activates the orexic systems and suppresses the HPA axis (cortisol) by inhibiting activity of CRH releasing neurons in hypothalamic paraventricular nucleus
Hallucinogens and marijuana
Proabably indirect effect of inhibiting ongoing sensory info processing in favor of spontaneous neuronal activity in sensory cortex
Potential for addiction: marijuana
Controversial
PCP and ketamine effects
Euphoric, hallucinogenic, can lead to psychotic symptoms
Neural mechanism of PCP and ketamine
- reward system activation: mesolimbic dopamine system
- hallucinogenic properties: blockade of NMDA-type glutamate receptors
When does ketamine act like PCP
At low levels
What is ketamine normally
General anesthetic
Mechanism of alcohol (and nicotine)
Non specific inhibitory mechanisms via action at axons
-specific sites of action currently under investigation: inhibition of glutamate and serotonin receptors, possibly other undiscovered specific mechanisms
What neurons does ethanol activate directly (and nicotine)
VTA
What should primary care provider look at when looking at drug use
Look beyond drugs use itself to the underlying drivers
Major drivers of addiction besides activation of reward system
- self medication of anxiety
- self medication of other negative emotions
- self medication of Dx or unDx mental health disorders
