Week 9- Mesolimbic System and Substance Abuse

Question 1

How is dopamine regulated in the mesolimbic system?

Answer 1

Natural process of reward:
The dopamine neuron on the VTA (DA ne VTA) is activated.
DA is released in Nacc.
Reward is experienced.
DA also binds to the GABA neuron in the Nacc (GABA ne Nacc).
DA activates GABA ne NAcc, which fires.
GABA inhibits DA ne VTA, stopping DA release in NAcc.

Question 2

How specifically does each class of the seven classes of substances work in (affect) the mesolimbic circuitry?

OPIATES

Answer 2

Reinforce drug taking behavior
Mu opioid receptors
Stimulation of dopamine release
Steps:
The dopamine neuron on the VTA (DA ne VTA) is activated.
DA is released in NAcc.
Reward is experienced.
DA also binds to the GABA neuron in the NAcc (GABA ne NAcc).
Normally, DA activates GABA ne NAcc, which fires, releasing inhibitory GABA in the VTA. However, opiods provide inhibitory feedback to the GABA negative feedback loop (stopping the brakes).
In addition, opioids provide inhibitory feedback to the GABA interneuron, another way opioids stop the brakes.
This allows the DA ne VTA to continue to fire.

Question 3

How specifically does each class of the seven classes of substances work in (affect) the mesolimbic circuitry?

ALCOHOL

Answer 3

Steps:
The dopamine neuron on the VTA (DA ne VTA) is activated.
DA is released in NAcc.
Reward is experienced.
DA also binds to the GABA neuron in the NAcc (GABA ne NAcc).
Normally, DA activates GABA ne NAcc, which fires, releasing inhibitory GABA in the VTA. However, alcohol neutrally blocks the binding of GABA on the DA ne VTA, (stopping the brakes).
This allows the DA ne VTA to continue to fire.

Question 4

How specifically does each class of the seven classes of substances work in (affect) the mesolimbic circuitry?

Sedative hypnotics & Benzodiazepines

Answer 4

Different receptor types in brain and HPA axis involved.

a1Bxyx- inhibits GABA interneuron
a3Bxyx- direct action on DA ne VTA

Inhibition in HPA axis causes relaxation effect of benzos.

Steps:
The dopamine neuron on the VTA (DA ne VTA) is activated.
DA is released in NAcc.
Reward is experienced.
DA also binds to the GABA neuron in the NAcc (GABA ne NAcc).
DA activates GABA ne NAcc, which fires.
GABA inhibits DA ne VTA, stopping DA release in NAcc.
At the same time, other moderating circuits that activate the GABA interneuron are active, a second inhibitory system.
When sedative hypnotics and benzodiazepines are present, they neutrally block the postsynaptic GABA receptors (not activating the neuron, and blocking transmission of the signal). When GABA (inhibitory) is stopped, dopamine release is permitted to continue

Question 5

How specifically does each class of the seven classes of substances work in (affect) the mesolimbic circuitry?

Marijuana & THC

Answer 5

Steps:
The dopamine neuron on the VTA (DA ne VTA) is activated. This is encouraged by the additional activation of the DA ne VTA by THC.
DA is released in NAcc.
Reward is experienced.
DA also binds to the GABA neuron in the NAcc (GABA ne NAcc).
Normally, DA activates GABA ne NAcc, which fires, releasing GABA in the VTA. However, THC inhibits the release of GABA (activating the brakes through activation of the CB1 receptor).
Typically, GABA would inhibit DA ne VTA, stopping DA release in NAcc. However, THC inhibits this inhibitory input (double negative), thereby removing the brakes and allowing the DA ne VTA to continue to fire.

Question 6

How specifically does each class of the seven classes of substances work in (affect) the mesolimbic circuitry?

NICOTINE

Answer 6

Steps:
The dopamine neuron on the VTA (DA ne VTA) is activated. This is enhanced by a. excitatory glutamate projections from the PFC, b. by excitatory Ach projections from the LDT/PPT, andd c. by direct activation of the DA ne VTA.
DA is released in NAcc.
Reward is experienced.

Question 7

How specifically does each class of the seven classes of substances work in (affect) the mesolimbic circuitry?

HALLUCINOGENS

Answer 7

Steps:
The dopamine neuron on the VTA (DA ne VTA) is activated. This is enhanced by excitatory input from projections from the raphe nucleus. Since hallucinogens act as serotonin agonists, increased activation of DA ne VTA occurs.
At the end of the neuron, at the terminal button, excitatory projections from the raphe nucleus typically assist with DA release. Hallucinogens act as agonists for serotonin, activating more dopamine release from the DA ne VTA.
Reward is experienced.

Question 8

How specifically does each class of the seven classes of substances work in (affect) the mesolimbic circuitry?

STIMULANTS

Answer 8

Natural process of reward:
The dopamine neuron on the VTA (DA ne VTA) is activated.
DA is released in NAcc.
Reward is experienced.
In the case of meth, DA is also released without activation of the DA ne VTA because meth makes presynaptic vesicle walls leaky.
DA leaks everywhere, including into the synapse, where it is experienced as pleasure.
When all of the DA is released, the enzymes that break down DA are overwhelmed and take a while to do their job, explaining the duration of the high.
Related to both meth and cocaine, reuptake by presynaptic transporters is prevented, making the DA last longer in the synapse, causing increased pleasure.
DA also binds to the GABA neuron in the NAcc (GABA ne NAcc).
DA activates GABA ne NAcc, which fires.
GABA inhibits DA ne VTA, stopping DA release in NAcc.