neuropharmacology of drugs of abuse Flashcards
What are the key areas within the brain associated with drug addiction?
Reward prediction and pleasure…
• VP = Ventral Pallidum
• NAcc = Nucleus Accumbens
Cognitive control – decision making/judgement and control reward centre…
•PFC = Prefrontal Cortex
•ACC = Anterior Cingulate Cortex
Motivation drive and salience attribution (give value to a reward) …
• OFC = Obitofrontal Cortex
Learning and memory…
•Amygdala (emotional connection to drug).
•Hippocampus (strong memories of drugs – cause relapse).
describe the key neural circuits of addiction
An important part of the reward system in drug addiction consists of dopaminergic neurons in the mesolimbic pathway which projects from the ventral tegmental area (VTA) to the nucleus accumbens (NAcc). Upon activation, these neurons release dopamine inside the NAcc.
Other VTA and mesolimbic projects extend into the frontal cortex as well as the amygdala where they release dopamine when activated.
These neural circuit connections are an essential part of the reward pathway whether it involves eating food or social interaction therefore normal functioning of this pathway is very important.
Drugs of abuse hijack the neural reward system and puts the dopaminergic mesolimbic pathway in a state of hyper activation – they increase the rewards by overstimulating key areas of the brain by increasing dopamine production thereby strengthening or initiating development of addiction.
what is the evidence for dopaminergic/mesolimbic involvement in neural reward?
Microdialysis studies in rodents where a cannula is inserted into the NAcc of a mouse. Dopamine levels in this area of the brain are then measured with amphetamine administration and food administration. Increase of dopamine is much lower with food than with amphetamines.
Describe in depth the stages in addiction cycle
Drug intake begins with social drug-taking during which the drug induces a hedonic, pleasurable effect which will trigger further drug administration. This is called positive reinforcement, when drug taking is triggered by the positive, pleasurable effects of the drug.
The mesolimbic dopaminergic system which consist of dopaminergic neurons projecting from the VTA to the NAcc have long been considered the major neurobiological substrate mediating all drugs’ positive reinforcement.
After further administration of the drug, people tend to move to a pattern of escalating compulsive use due to tolerance and finally to dependence which is characterised by a state of emotional and physical withdrawal symtoms (anxiety, depression ect) in short and sometimes long periods of abstinence. Now this negative emotional state triggers the craving, the wanting of the drug, which will drive the drug administration which is called negative reinforcement. In other words, the suppression of the mesolimbic pathway (decreased dopamine levels) which presents as the aversive, dysphoria experience of drug withdrawal now drives drug intake NOT the positive hedonic property of the drug.
Recruitment and activation of stress pathways e.g. the amygdala starts being hyperactive, the HPA axis starts being hyperstimulated
what is involved in the acute effects of drugs (positive reinforcement)?
Dopamine has been found to be more important in motivation drive than in pleasure. In contrast, the endogenous opioids such as endorphins are indicated more with pleasure effects. There are other neurotransmitters such as GABA (inhibitory neurotransmitter involved in acute effects of drugs e.g. alcohol), CRF (involved in acute administration of drugs).
NT: DA, GABA, GLUT, CRF, opioid peptides.
name the different acute targets for drugs of abuse
All drugs of abuse active the mesolimbic pathway (dopamine)
- Opioids - Agonist at mu (and delta and kappa) opioid receptors.
- Cocaine - Dopamine transporter blocker - indirect DA agonist.
- Amphetamine - Dopamine releaser - indirect DA agonist.
- Alcohol - Facilitates GABAA + inhibits NMDA receptor function.
- Nicotine - Agonist at nACh receptors.
- Cannabinoids - Agonist at CB1 receptors.
- Phencyclidine - NMDA receptor antagonist.
- Hallucinogens - 5-HT2A agonists.
describe the psychostimulants, amphetamine
Amphetamine-like drugs (methylphenidate & MDMA):
- Amphetamines will induce the leaking of dopamine outside of the vesicle into the synaptic bouton
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
- Stereotyped behaviour
- Anorexia
- decreased physical and mental fatigue (improves monotonous tasks)
- Peripheral sympathomimetic actions (increased blood pressure & decreased gastric motility)
- Confidence improves/lack of tiredness
Therapeutic uses:
ADHD (methylphenidate), appetite suppressants, narcolepsy
describe cocaine’s (Central stimulant) mechanism of action
Cocaine is an indirect DA agonist which acts by blocking the dopamine transporters thereby preventing reuptake of DA, maintaining high synaptic concentration of DA and therefore causing increased response.
describe heroin (opioid)
Opioids produce intense euphoria via acting on MOP
- Diamorphine (heroin) high abuse potential
Tolerance Seen within 12 – 24 hours
Opioids like heroin act on opioid receptors which are found on GABAnergic neurones = opioids inhibit the release of GABA= disinhibits the mesolimbic pathway
Different drugs induce dopamine in different ways
describe alcohol (general depressant)
Mechanism of action:
Potentiates GABA-mediated inhibition: Acts on GABA (inhibitory) receptors= open GABA receptors (chloride channels)= influx of chloride= inhibit neighbouring neurones
Inhibits presynaptic Ca2+ entry through voltage-gated Ca2+ channels
• Inhibits transmitter release
Disinhibits mesolimbic DAergic neurons (increases reward)
Induces the release of endogenous opioid peptides. The reward effect is decreased by naltrexone (narcotic antagonist that decreases craving for alcohol and blocks opiate effects) (endogenous opioid involvement).
Pharmacological effects:
- Slurred speech, motor in-coordination, increased self-confidence, euphoria
- Impaired cognitive and motor performance
- Higher levels linked to labile mood: euphoria and melancholy, aggression and submission
what are the acute effect of drugs of abuse on HPA axis?
Stress causes the release of CRH from the hypothalamus. This acts on the anterior pituitary to induce release of ACTH. ACTH acts on the adrenal glands to cause release of cortisol. Cortisol induces negative feedback. Drugs abuse will alter stress reactivity by disrupting the HPG axis – this disturbs coping mechanisms.
- Opioids inhibit HPA axis in humans – acts as de-stressor.
- Cocaine activates HPA axis – acts as stressor.
describe the withdrawal syndrome caused by different types of drugs of abuse
Physical, characterised by abstinence syndrome (LC):
Sweating, gooseflesh (cold turkey), irritability, aggression.
Psychological, craving to avoid withdrawal effects
- Psychostimulants e.g. cocaine: deep sleep, lethargy, depression, anxiety & hunger – almost opposite to effects of cocaine use.
- MDMA (ecstacy):Depression, anxiety, irritability, aggression.
- Heroin: Sweating, gooseflesh (cold turkey), irritability, aggression.
- Nicotine: Irritability, hunger, weight gain, impaired cognitive and motor performance, craving (persisting many years).
- Alcohol: Tremor, nausea, sweating, fever, hallucinations, seizures, confusion, agitation, aggression.
what are the chronic effects of drugs?
Mechanism of dependence and tolerance–>
Chronic drug administration causes homeostatic adaptive changes to oppose the drug action. Withdrawal of the drug can cause a rebound effect e.g alcohol can cause convulsions, amphetamine can cause sedation.
Chronic drug administration results in neuroadaptive changes:
- Depressants can induce ↑ in Ca2+ channels.
- Stimulants e.g. amphetamine can lead to depletion of NT.
- Hallucinogens that act via 5-HT2 receptors can lead to down-regulation of the 5-HT2 receptor.
- Opioids lead to an increase in activity of adenylyl cyclase and increase in cAMP as the receptor is desensitized by the drug.
Opioids e.g. heroin: act on MU opioid receptor (GPCR Gi) = cAMP decreases as it inhibits adenylate cyclase. Person who develops addiction: take lots of heroin= bombard MU opioid receptor= receptor will try opposing this= desensitises= adenylate cyclase increases= cAMP starts rising = start stimulating neurones- even noradrenergic neurones
negative reinforcement (dependence) is also a chronic effect of drugs. describe the 3 important changes that cause dependence
- Suppression of the rewards system – drives emotional withdrawal symptoms.
- Recruitment of the stress axis and activation of the amygdala/hypothalamus.
- Hypo functioning of prefrontal cortex – decision making and judgement is impaired.
Mechanism of dependence (DA) - STUDIES:
Studies using fMRI imaging found decreased frontal cortex activity with use of drugs. Lack of control is partly due to the reduced frontal cortex functioning.
Receptors:
look at dopamine receptors by using PET (microinject a radiotracer= binds to dopamine receptors)
- Decreased D2 receptors within striatum of cocaine and heroin and alcohol addicts
The lower the levels of D2 receptors= the more you crave the drug= to stimulate the D2 receptors and go back to reward
what does the orbitofrontal cortex have to do with anything?
- The orbitofrontal cortex is the region involved in attribution of saliency to the drug
- Orbitofrontal cortex activity is increased and is associated with a craving of the drug.
Memory of taking the drug is really strong
