6.3. Cocaine & amphetamines: Neurobiology

Pharmacodynamics of cocaine (review)

- Cocaine blocks reuptake of monoamines: dopamine, norepinephrine, and serotonin

- DA is important for stimulating, reinforcing, and addictive properties

- In high concentrations, cocaine also blocks voltage-gated Na+ channels.

Pharmacodynamics of amphetamine (review)

- Amphetamines also block reuptake of monoamines(drugs vary in binding affinities for DAT, NET, SERT).

But amphetamine also causes DA release via:

- Entering nerve terminals (via DAT) and causing vesicles to release DA.

- Reversing the transporter (DAT) so that DA is transported out of cell.

At high doses: also inhibits MAO.

Cocaine and amphetamines areindirect agonists of monoamine systems (review)

Block monoamine transporters

- Cocaine (5-HT, DA, NE)

Block monoamine transporters & cause DA release(via release from vesicles and reverse transport)

- Amphetamine (DA, NE)

- Methamphetamine (DA, NE)

- MDMA (5-HT)

Cocaine in the human brain

Distribution of cocaine binding matches the distribution of DAT (densest in striatum)

Which neural systems are involved in drug-induced behavioral effects? (1)

DA is critical for the reinforcing and locomotor effects of amphetamine and cocaine. Evidence from many studies

Pharmacological studies: Antagonists

DA antagonists, but not NE antagonists, disrupt amphetamine reinforcement (self-administration).

Pharmacological studies: Transporter blockers (1)

Other drugs that block DAT are also self-administered by animals

Not readily self-administered by animals or abused by people:

- Selective blockers of NET

- Selective blockers of SERT

- Other local anesthetics (Na+ channel blockers)

Therefore, DAT blockade appears to be the core mechanism by which cocaine andamphetamine are reinforcing.

Lesion studies

Using 6-OHDA to lesion DA, but not NE, disrupts cocaine reinforcement (self-administration)

- VNAB/DNAB lesion (targets NE)

- Nucleus accumbens lesion (targets DA)

Neurochemical studies (1)

Similar time course for amphetamine effects on:

• DA release in striatum and

• locomotor effects

Neurochemical studies (2)

sensitization of locomotor and reinforcing effects, as well as sensitization of DA levels in striatum.

Genetic studies: Knockout

DAT knockout mice (DAT -/-) are spontaneously hyperactive, showing increased locomotion

Genetic studies: Knockin

DAT knock-in mice (DATki) have a mutation that makes DAT insensitive to cocaine but normal otherwise. They show loss of cocaine reinforcement (self-administration)

Which neural systems are involved in drug-induced behavioral effects?

DA is critical for the reinforcing and locomotor effects of amphetamine and cocaine.

Dopamine pathways (2)

Stimulant-induced DA in nucleus accumbens (mesolimbic) = locomotion & reinforcement

Stimulant-induced DA in dorsal striatum (nigrostriatal) = stereotypies

Dopamine and reward learning

- Reward-associated cues (conditioned stimuli, CS) elicit dopamine release.

- drive motivation for the reward.

Cocaine cues drive dopamine and craving

- Addicted individuals shows dopamine

release related to viewing cocaine cue

Cue-induced dopamine release in dorsal striatum correlates with craving

Cocaine cues drive craving in animals

In rats, cocaine-associated cues also trigger drug seeking

Therapeutics for stimulant addiction

No clinically licensed therapeutics for cocaine/amphetamine treatment.

Best treatments currently available:

• Psychosocial treatment

• Cognitive behavior therapy

• Relapse prevention therapy

Neurotoxicity with amphetamines (1)

Amphetamine, meth, and MDMA: Can cause depletion of monoamines and degeneration of nerve terminals

Neurotoxicity with amphetamines (2)

Amphetamine/methamphetamine neurotoxicity: High doses

High extracellular DA necessary

MDMA neurotoxicity

Neurotoxicity affects DA and 5-HT terminals

• Amphetamine: Damage to DA terminals

• MDMA: Damage to 5-HT terminals

• Methamphetamine (more toxic): Damage to both DA and 5-HT terminals

Methamphetamine neurotoxicity (1)

Humans: Long-lasting decrease in DAT availability

- Abstinent methamphetamine and methcathinone users 3 years

Methamphetamine neurotoxicity Animals

Baboons: Long-lasting decrease in DAT availability after meth

Rats: Long-lasting decreases in TH and DAT after meth

MDMA neurotoxicity (1)

- Acute adverse effects of MDMA reflect dehydration and hyperthermia

- Subtle cognitive deficits in regular MDMA users

MDMA neurotoxicity (2)

Humans: Long-lasting decrease in SERT availability after chronic MDMA

MDMA neurotoxicity in animals

Squirrel monkeys: Loss of serotonin axons after MDMA

- Fine 5-HT axons destroyed in cortex,hippocampus, striatum.