lecture 39: brain reward pathways & drug dependence

what is drug dependence?

a state resulting from interaction b/w a living organism & a drug, including **compulsion** to take drug on continuous/periodic basis to experience psychic effects & sometimes avoid discomfort of its absence.

what is drug tolerance?

a state of reduced responsiveness to the effects of a drug caused by its previous administration OR to maintain the same response to a drug, one must administer higher doses w repeated admins

what is psychological dependence?

psychic drive that reqs admin of a drug to provide pleasure or to avoid discomfort

what is physical dependence ?

an adaptive state manifested by intense physical disturbances when drug is withdrawn

which 3 factors influence drug abuse?

1. drug availability
2. form of drug
* heroin vs opium
* cocaine vs cocoa leaves
* crack vs cocaine
3. route of admin
* oral vs intravenous vs inhalation

what is involved in the reward pathway in the brain (and which areas are affected by drugs)?

**dopaminergic mesolimbic & meso-cortical pathways**, which drugs can affect diff areas in these pathways

* nucleus accumbens (n. acc)
* ventral tegmental area (VTA)

what are DA neurons in VTA under control of ?

tonic control of **GABA interneurons** so their activity is normally suppressed due to GABA release from these interneurons

what are the 4 major DA pathways in the brain?

1. **nigrostriatal** (sub. nigra → caudate nucleus)
2. **mesolimbic** (VTA → n.acc)
3. **mesocortical** (VTA → cortex of hippocampus)
4. **tubero**-**infundibular** (median eminence → ant.pit)

what are DA1 & DA2 receptors, and how they act?

important DARs involved in the reward pathway of the brain

* D1 = E
* D2 = I

what DA neuron subtype is important in the mesolimbic system (and assoc. DARs?)

A10, WITH DA1 & DA2 RECEPTORS

how do A10 neurons and DA1/2 receptors mediate action of reward in the mesolimbic pathway?

1. A10 DA neruons project → n.acc
2. as majority of neurons in **n.acc** are **GABAergic**, they loop back onto VTA to __inhibit activity of DA neurons__
3. reward = increased activation of DA neurons which act….
* on VTA to *inhibit GABA release*
* directly on DA neurons to increase firing rate
* on n.acc to stim release of DA from terminals

how is morphine involved in the mesolimbic reward pathway (where does it act, what does it do, and when we remove what happens)?

* acts on µ-opioid GPCRs
* inhibits adenylate cyclase, decreasing \[cAMP\]
* opens K+ channels, hyperpolarise neuron
* cause __decreased GABA release__ in VTA
* leads to __increased DA release__ in n.acc by **disinhibition of DA neurons in VTA**
* when morphine is __removed__, there is a *spike in [cAMP]* linked to withdrawal signs in tolerance

how is nicotine involved in the mesolimbic reward pathway (where does it act, what does it do, and how does it act on GABA/glutamate neruons)?

* acts on cationic LGICs; nAChRs
* mainly on nerve terminals
* increased transmitter release by depolarising membrane
* nicotine acts on specific receptors on **GABAergic neurons** for GABA release in __rapid desensitisation__
* nicotine also acts on diff receptors on **Glutamate neurons** for Glu release in __slower desensitisation__

what treatments are available to help addicts in opioid overdose?

naloxone (remember the def of an opioid! any drug whose action **reverses** naloxone, thus it is used to treat OD)