Lecture 16: Mansvelder and McGehee, 2000 Flashcards
What is drug addiction characterized by?
- compulsion to seek and take the drug
- uncontrolled ability to limit intake
- withdrawal symptoms when access to drug is blocked
What is the mesolimbic pathway?
Originates in the VTA (nucleus that contains dopamine neurons), then projects to the PFC and nucleus accumbens (ventral striatum, has MSNs). MSNs in nucleus accumbens also receive projections from dopamine neurons in VTA and from descending cortical neurons
What is the DA response calculation?
Reward occurred - reward predicted –> dopamine neurons do a prediction error calculation - they predict whether a reward is coming and make an assessment of the reward
What type of projections do the cortex send to the VTA?
Cortex sends glutamate projections to dopamine neurons in the VTA –> may modulate dopaminergic neurons
What occurred when they injected nicotine in rats?
In the nucleus accumbens, dopamine levels peaked right after injection, dorsal striatum was not as high. Ater 3 hours, dopamine levels had been elevated 40-50% following single injection –> may be due to synaptic plasticity
What is long term potentiation?
Long term enhancement of synaptic transmission, occurs if there is an increase in synchronous activity of pre- and post- synaptic neurons. Long term scale is greater than 1 hour. This is the mechanism of learning and memory
What does LTP require?
Presynaptic release of glutamate and activation of post synaptic NMDA receptors. There is a rise of intracellular calcium through NMDA receptors, which activates CamKII, which phosphorylates AMPA receptors and causes them to translocate to the cell surface membrane
What were the goals of the Mansvelder study?
Wanted to examine the mechanism of nicotine addiction due to altered neuronal activity of dopaminergic neurons in the VTA. Examined how nicotine exposure can modulate the plasticity of excitatory synaptic transmission of dopaminergic neurons in the VTA.
What is the circuitry of the rat brain?
Glutamate neurons from prefrontal cortex go to the VTA, VTA dopaminergic neurons then project to the nucleus accumbens. This paper looked at the input of the glutamate neurons on dopamine neurons
How did they record dopamine neurons?
They used whole cell patch clamp recordings of dopamine neurons in VTA while stimulating glutamatergic neurons of PFC. They stimulated the glutamatergic neurons and inhibited all GABA post synaptic currents to isolate AMPA current
What is the difference between the electrophys signals from dopaminergic and GABAergic neurons?
Slow inward current during hyperpolarization = dopamine neuron, small current which stops = GABA
What happened to the EPSCs when they applied nicotine at low stimulation vs max stimulation?
It increased in amplitude compared to baseline during low stimulation, during maximal stimulation there was not a significant change in response when they added nicotine –> nicotine has an effect on low stimulation but not max stimulation
How did they determine whether nicotine affects the presynaptic or postsynaptic side?
Looked at sEPSCs –> recorded post synaptic dopamine neurons receiving the glutamate inputs
Infusion of nicotine increased sEPSCs frequency, but did not change amplitude.
How could they tell whether the nicotine receptor was far or close to the terminals?
They looked at whether enhancement of sEPSCs were ap dependent or independent. If the receptor was far from the terminal, it would be AP dependent to lead to nt release, if it is close to terminal, it would be AP independent. They also did the same experiment in the presence of TTX –> still saw an increase in the frequency of sEPSCs –> nicotine has an effect presynaptically, but in a non ap dependent manner (close to terminals)
Is there a dose-dependent effect of nicotine?
There is a dose dependent effect for spontaneous EPSCs
