Addiction is a disease of the brain characterized by what behavioral abnormalities/progressions?
Reinforcing behavior (reward/hedonia) --> Compulsive behavior --> Loss of control
These develop gradually and progress during the course of repeated exposure and chronic exposure induces neuroplasticity
What is the "Reward Pathway"? What circuits are involved? How do drugs play in?
VTA --> NA --> PFC
Main reward path are Da Projection neurons from VTA to NA and from there to Neocortex and amygdala
Dopamine is the key player that gets modified by lots of natural endogenous agonists but drugs of abuse hijack this pathway and regulate dopamine more powerfully than our own endogenous centers
What is the Medial Forebrain Bundle?
Connection between the VTA and the basal forebrain including NA, PFC, and Amygdala
What is addiction?
State in which an organism engages in compulsive behavior and the behavior is reinforcing
Drugs of abuse cause Da release in Mesolimbic pathway more intensely than natural rewards
What is the action of Cocaine? Where does it act?
Cocaine blocks Da Reuptake transporters and so when Da is released in the NA from cell body in VTA then acts moreso on post-synaptic cell bc no reuptake
What are the longer, more significant Synaptic changes that cocaine induces in the brain? What happens w/ Continued use?
Increased Da on Post-synaptic receptors leads to activation of GPCR and increase production of cAMP to turn on gene transcription and change functions of cell
Increased firing impulses and abnormal firing patterns leaving the NA activate the reward system
Continued use of cocaine leads to System Down-Regulation and loss of positive reinforcements or pleasurable feelings from natural rewards .......escalates compulsive behavior to take more and reach same feeling
Cocaine leads to increase Da activity in the synapse. What are those effects? What about with higher doses?
At first - Euphoria, reduced fatigue and increased mental acuity
Then get paranoia and Hallucinations
Or get Tolerance vs Sensitization
What is Tolerance and what is sensitizatoin?
Tolerance: organism can no longer respond to a drug at a certain levels and needs higher doses for same effect
Sensitization: "Reverse Tolerance" based on genetic variability of person where repeated cocaine intoxication at dose that previously gave euphoria now induces Paranoid psychosis
[D2 receptor blocker relieves the symptoms]
What are the PET scan evidence of Neuro-adaptation to cocaine?
Decreased D2 receptor availability - chronic cocaine use leads to down-regulation
Drug cues stimulate craving - increased flow to amygdala and anterior cingulate cortex when shown pictures of cocaine
How does Methamphetamine work?
Methamphetamine binds VMAT and blocks it from putting Da into vesicles and so Da builds up in the terminal and then the transporter reverses and increased DA released into synapse NOT DEPENDENT ON SIGNAL/AP
Greatly enhances Da concentration in reward circuitry independent of neuron depolarization
What's different about Meth and Cocaine half lives?
Cocaine is 1-2 hours vs Meth is 10 hours
What are the affects of acute Meth administration?
Powerful sympathetic nervous stimulation
How do Opiates increase Da release? What's their mechanism of addicition?
Normally, Da neuron in VTA/NA in tonic GABA inhibition
Opiates bind Opiate Receptor on GABA neuron and decrease GABA release therefore release the brake and so more Da released by VTA neuron onto NA
What is dependence? How does it form with Heroin/opioids? Where in brain does this happen?
Heroin use leads to rapid development of tolerance to analgesic effects
Therefore, Drug use is repeated over time bc need more for same relief
Dependence happens with the drug is withdrawn and physiological reactions occur and occurs in Thalamic and Brainstem areas
How does MEthadone work?
Methadone is an addictive opiate that does not cuase euphoria or Respiratory depression
Blocks effects of heroin bc binds to the same receptors - prevents or reduces unpleasant withdrawal symptoms and allows pt to remain clearheaded
What is the natural THC? Where do endocannabinoids and THC act? What do the receptors do?
Anandamide - made out of lipid bilayers of neurons
THC and Endocannabinoids act on Cannabinoid Receptors which are GPCR w/ similar activity to D1 receptors and increase activity of Da neurons
Cerebellum - balance and movement
Hippocampus - thinking and memory
How does Nicotine work in the brian?
Nicotine binds to Nicotinic Ach receptor which is an ion channel and activation stimulates Da release
Binds to Ach-Receptor on Da neuron w/ much higher affinity than Ach does and increases Da release from that neuron
What happens with desensitization and nicotine?
Nicotine turns off its own receptor bc it overstimulates it a lot more than normal Ach stimulatout would and so it down-regulates
BUT THAT ALSO CAUSES UPREGULATION of receptors!!
Nicotine up-regulates Nicotine receptors due to constant "turning off"
What happens in a Nicotine Fit?
Bc Nicotinic receptor turns off and then subsequently upregulates itself, get increased Da release and increased D2 Reeceptors. THEN when you dont have enough Da for the D2 receptors that's when you get the nicotine fit!
What is the Neurobioligcal basis of addiction and how does addiction happen?
Acute Effects from drug - Euphoria and Hedonic Reinforcing behavior
Then Chronic Exposure leads to Adaption (cAMP molecular changes, altered function of neural circuits)
Behavioral abnormalities that characterize an addicted state = Drug-induced Neural plasticity
Then Activation of CREB and upreg CAMP
...Chronic use can lead to dysphoria
What are the treatments for addiction?
Withdrawal therapy - abrupt cessation (results in no physical dependence but high psychological dependence and often doesn't work)
Psychological Therapy - long term psychotherapy, behavioral modifications, social support and encouragement
Long-term Pharmacological Treatment - Methadone