Neuropharmacology drug abuse Flashcards
List the brain regions associated with addiction
Nucleus accumbens and ventral tegmental area, playing a critical role in reward recognition and pleasure
Anterior cingulate and prefrontal cortex- involved in cognitive control
Orbitofrontal cortex- gives motivation and drive- saliency to rewards
Amygdala- emotional dependence with drugs
Hippocampus- memory of the drug. Hippocampus and amygdala work together here
CPu (cordate putamen) at the centre of brain, part of striatum involved in habit formation
Dopamine neurotransmission
When stimulated by a drug, substantia nigra and ventral tegmental area releases dopamine into nucleus accumbens and prefrontal cortex
Amphetamine administration leads to major surge of dopamine
Dopamine levels in response to food- still some increase but much smaller than in drugs of abuse
It’s even released before getting the drug
Stages in addiction cycle
Drug addiction is defined as a chronic relapsing disorder characterised by compulsive seeking of the drug, loss of control over drug taking and emergence of negative emotional states (anxiety, dysohoria, irritability) and physical states when the drug is not provided (withdrawal symptoms).
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 which is process also triggered by natural rewards. The mesolimbic dopaminergic system which consist of dopaminergic neurons projecting from the VTA to the Nacb are long been considered the major neurobiological substrate mediating all drugs positive reinforcement (including alcohol, opioids, canabis, nicotine. They all induce dopamine release in the nucleus accumbens.
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 aversive, dysphoria experience of drug withdrawal drives now the drug intake NOT the positive hedonic property of the drug. Regions of the extended amygdala such as the amygdala, hypothalamus, hippocambus as well as nucleus accumbens and release of NA, CRF, GABA are known to be involved in the aversive negative reinforcement in dependent people.
There is a basically a transition from positive reinforcement in non dependent people to negative reinforcement in dependent people which drives the drug intake. Relapse is very likely in the withdrawal period (induced by the drug itself, stressors, cues), and therefore the cycle is repeated.
Discuss the effects of acute administration of drugs of abuse on the brain
Acute effects of drugs involve positive reinforcement
The dopaminergic system of VTA to nucleus accumbens is activated
opioid peptide and nicotinic receptors on nucleus accumbens, amygdala
CRF is corticotropin releasing factor which is a regulator of the HPA axis
What are the different acute targets for different targets i.e opioids, cocaine, amphetamine, alcohol, nicotine, cannabinoids, phencyclidine, hallucinogens
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 mechanism of action of psychostimulants like dopamine
Amphetamine-like drugs (methylphenidate & MDMA)
Release cytosolic monoamines (DA)
Prolonged use neurotoxic
Degeneration of amine-containing nerve terminals, cell death
Pharmacological effects:
alertness and locomotor stimulation ( aggression)
Euphoria / excitement
Stereotyped behaviour
Anorexia
physical and mental fatigue (improves monotonous tasks)
Peripheral sympathomimetic actions ( blood pressure & gastric motility)
Confidence improves/lack of tiredness
Therapeutic uses
ADHD (methylphenidate), appetite suppressants, narcolepsy
Mechanisms of central stimulants like cocaine
The presynaptic neurone has DAT (dopamine transporter), the postsynaptic neurone has D1 and D2 receptors
The reuptake of dopamine into DAT is blocked resulting in accumulation of dopamine
Blocks catecholamine reuptake ( 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’), smoked, as intense as i.v route
Describe the mechanism of psychomimetics like MDMA (ecstasy)
MDMA (ecstasy)
Inhibits monoamine transporters (mainly 5-HT)
Also releases 5-HT
Large 5-HT (followed by depletion)
5-HT linked to psychotomimetic effects
DA linked to euphoria (followed by rebound dysphoria
LSD – derived from fungus. Psilocybin from psilocybin mushrooms, mescaline derived from Mexican cactus. Psilocybin very similar to LSD
Not sure how reducing firing rate in raphe nucleus leads to psychotomimetic action
LSD is chemical derivative of lysergic acid (occurs in the cereal fungus, ergot). All 3 give hallucinations – sounds may be perceived as visions etc. Occasionally a ‘bad trip’ occurs – with paranoid delusions.
LSD acts on inhibitory autoreceptors inhibiting 5-HT neuronal firing – not sure how this is linked to hallucinogenic effect. Tolerance develops quickly but these drugs are not self-administered in animals (in fact tend to be aversive) & no withdrawal syndrome.
MDMA – effect on 5-HT and DA system. 5-HT = Psychotomimetic effects, DA = euphoria
Phencyclidine – NMDA antagonist effect linked to behavioural effects – similar manifestation of schizophrenia.
Describe the mechanism of action for opioids such as heroin
Opioids produce intense euphoria via acting on MOP
Diamorphine (heroin) high abuse potential
Tolerance
Seen within 12 – 24 hours
Diamorphine more lipid soluble than morphine – more rapid effect when given iv
Heroin derived from acetylation of morphine or extracts of opium poppy. In some countries codeine is demethylated in labbs to morphine (‘homebake’ procedure. Yields a white crystalline powder which is cut with inert sugars (e.g. glucose) and sold as heroin.
In rats abrupt discontinuation of the opioids results in irritability, loss of weight, body shakes, writhing, jumping & signs of aggression – much less apparent if drugs withdrawn gradually. In humans this is seen as restlessness, runny nose, diarrhoea, shivering and goose pimples (cold turkey).
NAergic pathways may play a role in abstinence syndrome – lofexidine (central 2-agonist) can suppress some of the symptoms (especially diarrhoea & vomiting).
Dependence – in locus coeruleus receptors inhibit adenyly cyclase activity – with chronic ingestion activity of enzyme increases to compensate – withdrawal of the opioid then results in excessive accumulation of cAMP and rebound neuronal excitability.
Methadone – if take morphine with methadone then don’t get the high.
Psychological dependence responsible for the craving and drives the drug seeking behaviour.
Opioid disinhibition effect
The mesolimbic pathway- dopamine from ventral tegmental area to nucleus accumbens is blocked by opioids
Because overtime there is locmotion sensitization drug-seeking self admin
Interneurones there to control release of dopamine into nucleus accumbens
opioid receptors such as MOP and DOP located in synpatic boutons of GABA nergic neurones
heroine- activation of these opioid receptors result in inhibition of release of GABAless of inhibitor neurotransmitter- will start firing a lot fo dopamine
General depressants- alcohol
Mechanism of action:
Potentiates GABA-mediated inhibition
Inhibits presynaptic Ca2+ entry through voltage-gated Ca2+ channels
Inhibits transmitter release
Disinhibits mesolimbic DAergic neurons ( reward)
Induces the release of endogenous opioid peptides
Reward effect by naltrexone (endogenous opioid involvement)
Pharmacological effects
Slurred speech, motor in-coordination, ’d self confidence, euphoria
Impaired cognitive and motor performance
Higher levels linked to labile mood: euphoria and melancholy, aggression and submission
Recommended dose of alcohol is 21 Units / week for men and 14 for women.
Alcohol – potentiates GABA inhibition similar to Bz. At higher doses mood becomes more labile with euphoria and melancholy, aggression and submission – can lead to violence. Physical abstinence syndrome - tremor, nausea, sweating and sometimes hallucinations and seizures.
Relationship between plasma ethanol concentration and effect is highly variable – effect is greater during rising than during falling phase
alcohol works by potentiating effects on GABA channels. activates GABA receptors, causing chloride channel to open causing hyperpolarisation and inhibiton.
alcohol inhibits neurotransmitter release from neurones
alcohol is also able to release endogenous peptides such as endorphins- pleasurable effects of alcohol
if you block these opioid peptide recpeptors, maltrexone reduces alcohol administration,, via blocking some of the positive effects of opioids
Describe mechanism of action for social drugs such as nicotine/tobacco
Nicotine, highly addictive
Pharmacological effects
nACh receptors, alpha4β2 subtype
Receptors, ligand-gated cation channels (pre- and post-synaptic)
Enhance transmitter release and neuronal excitability including opioid peptides
Cortex & hippocampus (cognitive function) and ventral tegmental area (DA release and reward)
alertness, irritability (dependent on dose and situation)
Nicotine - Highly addictive drug – responsible for more damage to health than all other drugs (including alcohol).
Rats will self-administer nicotine
Tolerance to some effects of nicotine – especially the nausea and vomiting. Nicotine acts on nAChR of the 4β2 subtype – these are highly expressed in the hippocampus and cortex (improving cognitive function) and ventral tegmental area (VTA) from where DAergic neuron project to the nucleus accumbens (reward pathways).
Nicotine acts of nicotinic receptors- ion gated ion channels.
Acute effect of drugs of abuse on HPA axis
Opioids inhibit HPA axis in humans
Cocaine activates HPA axis
opioids inhibit HPA axis, inhibiting stress coping mechanism- one of the motivational triggers for using drugs
eg. cocaine acts on KOP-r on hypothalamus, increases CRF production, acting on the anterior pituitary. The anterior pituitary produces more ACTH which acts on the adrenal glands to produce more corticosterone
Discuss the effect of chronic administration of drugs of abuse on the brain (dependence).
In the addiction cycle this means relapse from protracted withdrawal to compulsive use (followed by dependence and withdrawal back to protracted withdrawal)
What is withdrawal syndrome
Physical, characterised by abstinence syndrome (LC)
Sweating, gooseflesh (cold turkey), irritability, aggression
Psychological, craving to avoid withdrawal effects
Psychostimulants: deep sleep, lethargy, depression, anxiety & hunger
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
