Lecture 17 Reward pathways and dopamine

(Card 1) What is the difference between "Rewarding" and "Reinforcing"?

Rewarding: A subjective term, typically used for humans who can report a "feeling of great happiness or well-being" (euphoria).

Reinforcing: An objective measure used for all animals. A stimulus is reinforcing if an animal will perform a behaviour (e.g., press a lever) in order to obtain it.

1st Class Note (Transcript): The lecturer states they "essentially mean the same thing"; reinforcement is just the objective, measurable version of reward.

(Card 2) What is the difference between Psychological and Physical Dependence?

Psychological Dependence ("Addiction"): Characterised by craving, compulsive drug use, and a loss of control.

Physical Dependence: Occurs when stopping the drug causes a physical withdrawal syndrome.

1st Class Note (Transcript): Not all drugs that cause psychological dependence cause physical dependence.

Opiates and alcohol cause both, but psychostimulants (like cocaine and amphetamine) do not cause a significant physical dependence.

(Card 3) What was the Olds & Milner (1954) experiment, and what did it discover?

Experiment: Intra-Cranial Self-Stimulation (ICSS). They implanted electrodes into different parts of a rat's brain. The rat could press a lever to receive a direct electrical stimulus to that region. Discovery: They identified the brain's "reward pathway." When the electrode was in the Mesolimbic Pathway, rats would self-stimulate over 6,000 times per hour. 1st Class Note (Transcript): This was so reinforcing that rats would choose stimulation over food and water, "even until death".

(Card 4) What is the anatomy of the core "Reward Pathway"?

The core pathway is the Mesolimbic Pathway. It consists of dopaminergic neuron cell bodies in the Ventral Tegmental Area (VTA). These neurons project their axons to the Nucleus Accumbens (NAcc) (also called the Ventral Striatum), where they release dopamine.

(Card 5) What did the limited human ICSS studies in the 1960s reveal?

Context: These limited studies (mentioned in the transcript, not slides) had participants ask an experimenter to press the button for stimulation of this pathway. Finding: Participants reported the stimulation was intensely euphoric, with one describing it as feeling "like a really intense sexual orgasm". Effect: Participants "tended to fall deeply in love with the person who is in charge of the button".

(Card 6) How was dopamine confirmed as the key neurotransmitter in the reward pathway?

Two key lines of evidence: Microdialysis: During ICSS, a microdialysis probe (a semi-permeable tube) in the NAcc measured a large release of dopamine. Antagonist Studies: Administering Dopamine D1 or D2 antagonists directly into the NAcc reduced or inhibited the reinforcing effect of ICSS.

(Card 7) What are the three main dopaminergic pathways in the brain and their primary function/dysfunction?

Mesolimbic Pathway (VTA -> NAcc): The primary reward pathway. This is the focus of the lecture. Mesocortical Pathway (VTA -> Frontal Cortex): Implicated in schizophrenia (will be covered in later lectures). Nigrostriatal Pathway (Substantia Nigra -> Striatum): Controls motor function. Degeneration of this pathway causes Parkinson's Disease.

(Card 8) How do researchers show that drugs of abuse are reinforcing? What are the key exceptions?

Experiment: Drug self-administration. A rat is fitted with a catheter and learns to press a lever to receive an infusion of a drug (e.g., cocaine). Finding: Animals will self-administer most drugs that humans take recreationally (cocaine, opiates, nicotine, ethanol, THC, etc.) . Key Exceptions: LSD (Psychedelics): Animals will not self-administer. The transcript notes that humans are the only animal that will voluntarily take them. Diazepam (Benzos): Are self-administered but see Card 10.

(Card 9) What is the "clinching evidence" that most drugs of abuse hijack the mesolimbic pathway?

Lesion Studies: Chemically destroying the DA neurons in the pathway (using the neurotoxin 6-OHDA) inhibits drug self-administration. (destroying neurones)

Antagonist Studies: D1/D2 antagonists in the NAcc also inhibit drug self-administration. (destroying receptors)

Microdialysis (Di Chiara & Imperato, 1988): This "clinching" study showed that virtually all major drugs of abuse (amphetamine, cocaine, morphine, ethanol, nicotine) cause a large increase in dopamine release in the nucleus accumbens.

(Card 10) What are the two key exceptions to the rule that "drugs of abuse increase DA in the NAcc"?

LSD (Psychedelics): Are not self-administered by animals and do not increase DA. They are "dissociative" and not addictive in the same way.

Diazepam (Benzodiazepines): Are self-administered but do NOT increase DA in the NAcc.

1st Class Note (Transcript): This is thought to be a different form of reinforcement: self-medication to alleviate an underlying negative state (anxiety), rather than DA-driven euphoria.

(Card 11) How do psychostimulants (cocaine & amphetamine) increase dopamine in the NAcc?

They both act directly on the dopamine transporter (DAT) at the nerve terminal in the NAcc. Cocaine: Acts as a re-uptake inhibitor. It blocks the DAT, so dopamine stays in the synaptic cleft for longer. Amphetamine: Has a dual action: It inhibits re-uptake (blocks DAT). It also causes dopamine release from the terminal, likely by making the transporter work in reverse ("reverse transport").

(Card 12) How do opiates (morphine, heroin) increase dopamine in the NAcc? (Mechanism of Disinhibition)

Opiates work via disinhibition in the VTA. Opiates are \$\$\mu$$\$-opioid receptor (MOR) agonists. These MORs are located on inhibitory GABA interneurons in the VTA. Opiates (acting via Gi/o GPCRs) inhibit the GABA neuron. By inhibiting this "inhibitor," the DA neuron receives less inhibitory GABA input. It is "disinhibited" and becomes more active, firing more action potentials to the NAcc.

(Card 13) How does ethanol (alcohol) increase dopamine in the NAcc?

Ethanol is a "surprisingly complicated drug" that acts directly on DA neurons in the VTA. Main Mechanism: It decreases the after-hyperpolarization (AHP) of the DA neuron. Detail: The AHP is caused by K+ channels remaining open. Ethanol blocks these specific K+ channels. This allows the neuron to return to its resting membrane potential quicker, making it more likely to fire more action potentials. 1st Class Note (Transcript): Ethanol is taken in GRAM doses (e.g., ~25g in a pint of beer), not milligrams, showing its very low potency.

(Card 14) How does nicotine increase dopamine in the NAcc?

Nicotine has a very direct mechanism. It is an agonist at nicotinic acetylcholine receptors (nAChRs). These nAChRs are located directly on the cell bodies of the DA neurons in the VTA. When activated, these ligand-gated ion channels open, allowing Na+ influx. This influx depolarizes the DA neuron, making it more likely to fire action potentials and release DA in the NAcc.

(Card 15) How does cannabis (THC) increase dopamine in the NAcc?

THC works in a "very similar way to opioids" via disinhibition in the VTA. THC is an agonist at CB1 receptors. These CB1 receptors are located on inhibitory GABA interneurons in the VTA. THC (acting via Gi/o GPCRs) inhibits the GABA neuron. This disinhibits the DA neuron, which receives less inhibitory input and becomes more active, firing to release more DA in the NAcc.

(Card 16) Why did the mesolimbic dopamine pathway evolve? (The "Dopamine-Reward Hypothesis")

The pathway evolved to make "natural rewards" feel good, giving us the drive to obtain them for survival. Key examples include: Food: Especially high-fat, high-sugar foods. The transcript mentions that rats work hardest for cheesecake. Sex: Causes a large increase in NAcc DA. Music: The "chills" or "goosebumps" from music correlate strongly with DA release in the NAcc. This is thought to be a reward for social bonding.

(Card 17) What is the "Dopamine-Reward Hypothesis" and what does it not explain?

The Hypothesis: Drugs of abuse "hijack" or "mimic" the brain's natural mesolimbic pathway. They cause a large, rapid increase in dopamine in the NAcc, which is perceived as euphoria.

What it Explains: This is the initial drive for why people take drugs of abuse.

What it Doesn't Explain: It does not explain why some people become addicted (i.e., develop compulsive use), which is a more complex process involving long-term brain changes.