Drugs of abuse Flashcards
Reward pathways
Dopamine pathways play a role in reward and motivation, pleasure, euphoria, fine-tuning motor function, compulsion and perseveration.
Serotonin pathways play a role in mood, memory processing, sleep and cognition.
Serotonin pathways signal to the nucleus accumbens, involved in the mesolimbic dopamine pathway → serotonin signalling can modulate dopamine signalling.
Drugs of abuse and neurotransmission
Many drugs of abuse increase dopamine release in the nucleus accumbens, including: Opiates, Opioids , Nicotine, Amphetamine, Cocaine, Ethanol, Cannabis, Barbiturates, and Caffeine.
Other drugs enhance serotonin function, which innervates the nucleus accumbens, including the hallucinogens LSD and Ecstasy.
Others are NMDA antagonists, such as the hallucinogens Phencyclidine (PCP) and ketamine.
Activity of dopaminergic mesolimbic pathways is associated with reward.
VTA DA neurons respond to unpredicted reward by a phasic short lasting burst of activity which results in DA release from nerve terminals in the nucleus accumbens and frontal cortex.
A reward that is better than expected elicits a stronger neuronal activation. This is a positive prediction error response.
A fully predicted reward produces no response, and a reward that is worse than predicted induces a decrease in firing and DA release. This is a negative prediction error response.
Drugs of abuse enhance release of dopamine from VTA neurones by: blocking DAT, increasing dopamine release, or reducing GABAergic and negative feedback inhibition of dopamine pathways.
With chronic use, these drugs alter gene expression and attenuate the reward response to normal stimuli.
The faster, higher and more reliable the elevation in brain dopamine levels the greater the reward and the more likely addiction will occur.
Opioids
Agonists at the Gi-protein coupled opioid receptor μ.
Cause analgesia, euphoria and positive reinforcement, but also respiratory depression, which can be fatal.
Reduce GABAergic inhibition of dopamine.
Acute effects include euphoria, tranquillity and miosis.
Chronic effects include constipation, depression, insomnia, dependence, anhedonia and tolerance.
Withdrawal precipitates cravings, restlessness, insomnia, diarrhoea and cold flashes with goosebumps. Major withdrawal symptoms peak 48 - 72 hours after the last dose and subsides after about a week.
Cocaine
Causes euphoria, excitement and increased capacity to work.
Blocks DAT/SLC6A3, increasing synaptic dopamine. Actions are firing rate dependent.
Overactivity of the sympathetic system due to uptake blockade at higher doses causes hypertension, tachycardia, dilated pupils and palpitations.
Cocaine self-administration results in tolerance to the DAT-inhibiting and dopamine-elevating effects of cocaine. More drug is required to achieve the same effect.
Cannabis
THC mimics the effects of endogenous endocannabinoids, such as anandamide and 2-AG.
inhibits a wide range of neurotransmitter release in the brain and periphery via Gi-protein coupled cannabinoid receptors CB1 and 2.
In moderate doses, it causes a mild euphoric effect and analgesia.
In high doses, it has a dysphoric effect, particularly in naive users.
There is a very low risk of acute toxicity but there are concerns about the development of psychosis in chronic users.
It stimulates appetite through actions on feeding centres in the hypothalamus and possibly the gut.
Indirectly activate dopamine release by reducing GABA release and feedback inhibition. The endogenous cannabinoid, anandamide, enhances peak DA release by acting on CB1 receptors, and its effect is further enhanced by inhibiting the enzyme FAAH, involved in anandamide metabolism.
Amphetamines
Phenylethylamine drugs, such as methamphetamine and dexamphetamine, produce increased wakefulness and concentration with decreased fatigue and appetite.
They cause the release of monoamines from neuronal storage vesicles and block DAT, NET and SERT reuptake transporters, reverses transport and inhibits VMAT2, increasing synaptic DA, NA and 5-HT. Actions are firing rate independent.
Performance-enhancing (stimulants).
Cause euphoria, increase energy, self-esteem and confidence, aggression, excessive feelings of power, obsession and paranoia.
Psychosis can occur with chronic or high doses.
NA release causes increased BP and tachycardia.
Amphetamine is not neurotoxic, but methamphetamine is. In PET scans, we can see a reduction in DAT expression following methamphetamine use, suggesting a degeneration of dopaminergic neurons.
