Neuropharmacology of Drugs of Abuse

Question 1

Neuroanatomical regions involved in addiction and their function

Answer 1

DAergic neurones that project from the VTA to NA
NA = reward centre of the brain
Amygdala = fear, relationships
Hippocampus = memory, learning, regulates HP (stress) axis
Caudate putamen = part of basal ganglia- involved in habit formation
Pre frontal cortex = decision making
Orbital FC = gives value to the rewards

Question 2

Positive reinforcement drugs:

Answer 2

NT: DA, GABA, GLUT, CRF, opioid peptides

Question 3

Targets for drugs of abuse

Answer 3

Opioids- agonist at mu (and delta + kappa) opioid receptors
Cocaine- dopamine transporter blocker- indirect DA agonist
Amphetamines- dopamine releaser- indirect DA agonist
Alcohol- facilitates GABAa and inhibits NMDA receptor function
Nicotine- agonist at nACh receptors
Cannabinoids- agonist at CB1 receptors
Phencyclidine- NMDA receptor antagonist
Hallucinogens- 5HT2a agonists

Question 4

Psychostimulants- amphetamine-like drugs (methylphenidate+MDMA): what do they do and what are their pharmacological effects?

Answer 4

Release cytosolic monoamines (DA)
Prolonged use is neurotoxic- degeneration of amine-containing nerve terminals, cell death

Pharmacological effects:
Increased alertness and locomotor stimulation (increased aggression)
Euphoria/excitement
Stereotypes behaviour
Anorexia
Decreased physical + mental fatigue (improves monotonous tasks)
Peripheral sympathomimetic actions (increased BP + decreased gastric motility)
Confidence improves/lack of tiredness

Question 5

therapeutic uses of psychostimulants?

Answer 5

ADHD (methylphenidate), appetite suppressants, narcolepsy

Question 6

Central stimulants- cocaine: effects & pharmacological effects/ pharmacokinetics

Answer 6

Blocks catecholamine reuptake (increases DA, stimulant effect)

Pharmacological effects:
Euphoria
Locomotor stimulation- fewer stereotyped behaviours than amphetamine
Heightened pleasure- lower tendency for delusions, hallucinations and paranoia

Pharmacokinetics:
HCl salt, inhaled and i.v administration
Nasal inhalation less intense, leads to necrosis of nasal mucosa
Freebase form (‘crack’), smokes, as intense as i.v route

Question 7

Psychotomimetics- MDMA (ecstasy)

Answer 7

Inhibits monoamine transporters (mainly 5HT)
Also releases 5HT
Large increase in 5HT (followed by depletion)
5HT increase linked to psychotomimetic effects
DA increase linked to euphoria (followed by rebound dysphoria

Question 8

Opioids-heroin

Answer 8

Opioids produce intense euphoria via acting on MOP
Diamorphine (heroin) high abuse potential
Tolerance seen within 12-24 hours
Opioid disinhibition effect

Question 9

General depressants- alcohol: MOA

Answer 9

MOA:
Potentiates GABA-mediated inhibition
Inhibits presynaptic Ca2+ entry through VGCC- inhibits transmitter release
Disinhibits mesolimbic DAergic neurons (increases reward)
Induces release of endogenous opioid peptides- reward effect decreased by naltrexone (endogenous opioid involvement)

Question 10

General depressants- alcohol: pharmacological effects

Answer 10

Cocaine addicts have hyper-responsivity HPA
CRF in extended amygdala increased in withdrawal
CRF antagonist block withdrawal in animal models
CRF dysregulation long lasting (tolerance kicks in)

Question 11

General depressants- alcohol: relapse

Answer 11

Induced by drug priming, drug related cues, stress
NT: glutamate, DA, GABA, CRF, opioid peptides, NA, cortisol

Question 12

Neurobiological changes that take place during the transition from non-addicted to addicted brain

Answer 12

Regulation of CREB by addictive drugs

CREB- transcription factor

Role of dopamine in addiction

Role of endogenous opioids in addiction

Role of GABA in addiction

Question 13

Role of endogenous opioids in addiction

Answer 13

Mu agonists are reinforcing and cocaine reinforcement is modulated by opioid antagonists
Mu antagonists are effective in limiting craving and relapse
Injections of opioids into the VTA generate self-administration
Mu opioids facilitate intracranial self-stimulation
Mu opioid receptor knockout mice show loss of addictive responses to opioids, alcohol, cannabinoids and nicotine
Proenkephalin knockout mice show loss of addictive response to cannabinoids and nicotine
Alcohol and nicotine induce the release of endogenous opioids
Cocaine induces MOP and KOP upregulation which is persistent

Question 14

Role of dopamine in addiction:

Answer 14

Intake of drugs of abuse leads to increase in dopamine in nucleus accumbens and other limbic regions
Psychostimulants induce reward via a DA dependent mechanism
D2 knockout mice show no effect on withdrawal symptoms of morphine after chronic administration
Opiate and alcohol SA persists when SA projections are destroyed (DA independent mechanism)
Nicotine activates dopaminergic system via nicotinic receptors VTA and Nacb
D2 antagonists are largely ineffective in drug addiction treatment

Question 15

Role of GABA in addiction

Answer 15

Firing of dopaminergic neurones in VTA is inhibited by GABA interneurons
Opioids indirectly remove this inhibition by presynaptic inhibition of GABA interneurons and is responsible for the rewarding effects of opioids
GABAb agonist (baclofen) reduces nicotine reward in humans
Cannabinoids inhibit GABA release- effects of cannabinoids mediated indirectly via opioid receptors
GABA agonist in amygdala decrease alcohol SA
Chronic alcohol decreased GABA and increased NMDA