Cocaine & Amphetamines 6.3

Cocaine in Human Brain

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

Neural systems involved in drug-induced behavioral effects

DA critical for reinforcing & locomotor effects of amphetamine and cocaine

Evidence from many studies:

Pharmacological studies, Lesion studies, Neurochemical studies, Genetic studies

Pharmacological Studied: Antagonists

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

Similar effects with locomotor effects

Pharmacological Studied: Transporter Blockers

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 - e.g. ADD medication

• Selective blockers of SERT - e.g. Prozac, SSRIs

• Other local anesthetics (Na⁺ channel blockers) - lidocaine

DAT blockade appears to be core mechanism by which cocaine & amphetamine are reinforcing

Strong correlation between DAT binding potency & reward potency of different drugs

• similar results for locomotor activation

Lesion Studies

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

• similar results with locomotor effects

Neurochemical Studies

Similar time course for amphetamine effects on:

• DA release in striatum

• Locomotor effects

Similar results seen for reinforcing effects

Repeated amphetamine treatment produces sensitization of locomotor & reinforcing effects, as well as sensitization of DA levels in striatum

Genetic Studies: Knockout

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

• similar to effects of DAT blockers, like cocaine

Genetic Studied: Knock-in

DAT knock-in mice (DATki) have mutation that makes DAT insensitive to cocaine but normal otherwise

Show loss of cocaine reinforcement (self-administration)

Inverted-U shape for fixed ratio dose-response curve

Completely blocks locomotor effects

Show normal food self-administration despite lack of cocaine self-administration

Dopamine Pathways

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

Stimulant-induced DA in dorsal striatum (nigrostriatal) = stereotypies (no purpose for repetition of movement)

Dopamine & Reward Learning

Once learned, reward-associated cues (conditioned stimuli, CS) elicit dopamine release

Reward cues can also drive motivation for the reward

Cocaine cues drive dopamine & craving

Humans & rats:

Addicted individuals show dopamine release related to viewing cocaine cue vs. neutral cue

Cur-induced dopamine release in dorsal striatum correlate with craving

Effect sensitizes with time, after longer periods of withdrawal

Therapeutics for Stimulant Addiction

No clinically licensed therapeutics for cocaine/amphetamine treatment

Best treatments currently available: Psychosocial treatment, Cognitive behavioral therapy (CBT), or Relapse prevention therapy

Neurotoxicity with Amphetamines

Amphetamine, Meth, & MDMA: can cause depletion of monoamines & degeneration of nerve terminals depending on drug & dose

Sometimes long-lasting

Amphetamine Neurotoxicity Breakdown

Amphetamine/Methamphetamine:

• high doses (10-50x normal street dose in rats, primates more sensitive)

• high extracellular DA necessary

MDMA:

• only 2x normal street dose in some cases

Affects DA & 5-HT terminals

• Amphetamines: damage to DA terminals

• MDMA: damage to 5-HT terminals

• Methamphetamines (more toxic): damage to both DA and 5-HT terminals

Methamphetamine Neurotoxicity

Humans & Baboons: long-lasting decrease in DAT availability (effect of methamphetamine)

Abstinent methamphetamine & methcathinone users (average period of abstinence: 3 years)

• still have a lack of DAT in the brain

Higher doses cause larger changes in DAT binding

Rats: long-lasting decreases in TH & DAT after meth

Higher doses caused longer-lasting damage to DA terminals

MDMA Neurotoxicity

Acute adverse effects of MDMA reflect dehydration & hyperthermia, not overdose

Several reports of subtle cognitive deficits in regular MDMA users

Humans & Squirrel Monkeys: long-lasting decrease in SERT availability after chronic MDMA

• axons destroyed in cortex, hippocampus, & striatum (not recovered even after >7 years)

Mechanisms of Neurotoxicity

MDMA, Amphetamine, Methamphetamine:

Block monoamine transporters & cause DA release

Several factors play role in toxicity:

Hyperthermia, Reactive oxygen species, High extracellular dopamine