Week 11 - Drugs of Dependence Flashcards
physical dependence
occurs when pharmacological adaptation leads to tolerance – in which more drug is needed to achieve the same effect.
If the drug is stopped, physical withdrawal symptoms emerge, due to adaptations being transiently experienced in the absence of drug. If there are withdrawal symptoms, there is physical dependence
psychological dependence
may also lead to involves emotional-motivational withdrawal symptoms – many daily drug users show both dependences.
addiction
occurs in a small minority of people who initiate drug use – addiction
leads to compulsive and out-of-control drug use as a component of physical dependence.
Origins of substance dependence
Many variables work simultaneously to influence the probability and likelihood that a beginning user will develop physical/psychological dependences and/or an addiction to a compound.
Generally speaking, these variables can be organized into three categories:
agent (drug), host (user), and the environment in which use occurs.
Reinforcement is the ability of drugs to produce effects in the user which make reuse more likely and desirable.
The more reinforcing the drug is, the more likely the user will seek to re-use, possibly leading to abuse.
Drug dependence
- brains reward mechanisms produced slight mood elevation to intense pleasure
- D2 receptors are involved in the reward dimension of addiction but not withdrawal aspects
- genetics play a role in susceptibility to addiction
Innate tolerance
genetic lack of sensitivity observed in first-time use (?)
Acquired tolerance
Acquired tolerance develops due to prolonged exposure to a drug.
pharmacokinetic (change in distribution and metabolism), and pharmacodynamic (regulation of receptor numbers)
Acute tolerance
a process whereby the brain and central nervous system enact processes to immediately mitigate the effects of a given substance
a decreasing drug effect relative to drug-plasma levels (DPL) over a period of minutes to a few hours
Reverse tolerance
in response with repeated use
basically instead of becomign tolerant to the same dose of a drug over time, your body react more (reponse wise)
Cross tolerance
repeated use of one drug affects tolerance of other drug classes
Animal Drug Models
Generally, animals are good models of self-administration of drugs with positive effects.
Dopamine is released in the nucleus accumbens when a rat presses a lever that delivers reinforcing brain stimulation to its ventral tegmental area (VTA)
Physical reward pathways in the rat and human brain
reward pathways:
dopamine released from brain’s mesolimbic system. System comprises of nucleus accumbens where reward perception and reinforcement occur, and the (VTA) ventral tegmental area is reponsible for dopamine production, and thw prefrontal cortex governs decision making.
When activated by pleasurable stimulu, the pathway triggers c cascade of responses motivating individuals to seek out repeating the experiences.
- the mesolimbic tract including the ventral tegmental area (VTA), the nucleus accumbens, and the frontal cortex.
- Collateral communication also occurs to the amydala and hippocampus such that affective and memory systems are impacted, and 5-HT, glutamate, NA, GABA and endogenous opioids may play roles as well.
In animals and humans many abused substances share one
physiological effect:
an increase DA release in the
nucleus accumbens.
Drugs which block DA receptors in this region can generally produce bad feelings – dysphoria.
dopamine D2 receptor in the nucleus accumbens
seems to be key
Transgenic mice without D2 receptors do not demonstrate reward properties of morphine administration;
Interestingly, these animals still went through physical withdrawal syndrome…
This suggests that the D2 receptors are involved in the reward dimension of addiction, but not the withdrawal aspects.
How does the brain cope with change?
The CNS has “plasticity” in that it can
modify its hardware to best function
in a changing environment.
This change in receptor numbers is
profoundly sensitive to the presence
of CNS drug, depending upon the
concentration used and time period of treatment.
From ligand-receptor interaction to long-term physical and behavioral changes in the CNS
Drugs of abuse can alter the release of an endogenous ligand (i.e., release of DA, 5HT, NA) or serve as ligands themselves (e.g., THC isomers, opioids, nicotine, etc.).
Interaction with a receptor initiates a cascade of signaling in the neuron that can involve ion channels, kinases, phosphatases, and other enzymes.
Strong signals can be propagated to the nucleus where transcription factors are initiating mRNA synthesis to temporarily alter protein expression patterns.
The newly synthesized proteins may change the physiology, structure, and connectivity of neurons. Some of this hard wiring of information generated by drugs might be irreversible and cannot be extinguished.
Thus, some drugs are able to lead
to neuroplastic changes.
What affects a drug’s abuse liability?
Rapidity of onset:
when coca leaves are chewed, cocaine is absorbed slowly, and this results in low cocaine levels within the blood and CNS.
Crack cocaine is alkaloid cocaine which can be readily vaporised
by heating, which when inhaled, produce blood levels comparable to iv administration of drug.
Availability
Cost
Purity/potency
Mode of Administration
- chewing (absorption through mucus membranes), GI tract, intranasal, subcutaneous, IV, inhalation
opioid dependence
- increased in purity has led to increased dependence
- MOA of heroin/morphone at µ and D2 receptors in reward pathways
- via µ opioid receptors, opioid inhibit release of GABA = reduced inhibitory effect of GABA on DA neurons
= results in increased DA release = sustained benefit - tolerance occurs due to decrease in adenyl cyclase activity and a progressive uncoupling of receptor with 2nd messenger system
Cocaine depedence
- cocaine binds to an blocks DA reuptake transporters = increase [DA] in synaptic cleft = increase euphoria and “high”
Speed ball
opioid and cocaine
- heroin and cocaine have different MOA to increase DA in reward pathway = when combined has additive/synergistic effect
Cannabis
- very lipophilic = stored in body fat and excretion can take days
pharmacological effects:
- CNS - psychomimetic and depressant
- relaxation and euphoria
- greater intensity of senses
- analgesia, antiemetic actions
- slight bronchodilation
Cannabisinoid receptors:
- CB1 = presynaptic (located in brain) and activation inhibits NT release
- CB2 = in immune tissues and modulate pain
- tolerance is minor and so are withdrawal symptoms
- chronic use = decrease testosterone and impaired memory
Overdose
- like opioids, alcohol overdose can suppress breathing by decreasing the excitatory effect of glutamate
- death by stimulants is primarily due to indirect increase of NA
Withdrawal
- withdrawal from ling acting drugs = delay onset
- withdrawal from short acting drugs = more intense but shorter duration
- precipitated withdrawal = when antagonist is given to displace the drug = causes rapid and intense effects
- spontaneous withdrawal = when cessation of drug taking
- symptoms of withdrawal are usually the opposite of effects of the drug = since re-sensitisation and re-regulation of receptors of CNS and PNS
Mechanisms of Intervening
- heroin addiction is treated with methadone = stabilises the peaks
- nicotine addiction is treated with bupropion = noncompetitive nicotine antagonist
- alcohol dependence is treated with naltrexone = opioid receptor antagonist that blocks the activation of DA reward centres
Amphetamine
MOA = competitively inhibiting DA transport and once in neuron it interferes with VMAT to impede filling of synaptic residues = [DA] concentration increases
Nicotine
- in low doses, nicotine has stimulatory effects but in high doses has relaxing effects
- nicotine temporarily stimulates all sympathetic and parasympathetic ganglia, skeletal muscle and CNA, followed by depression
- also causes receptor desensitisation = reduced effects with same dose
- with long term use, up-regulation of nicotine receptors
- due to this, tolerance to CNS effects is less than for peripheral effects
Ethanol use and abuse
- rapidly absorbed in the GI tract
- 1st pass metabolism but saturation of enzymes occurs quickly
- methanol= ethanol purposely contaminated with methanol to prevent consumption (to treat methanol poisoning give ethanol)
- chronic ethanol exposure alters the GABA A receptor by decreasing x1 subunits and increases a4 subunits = less positive allosteric effects
Ethanols effects in the CNS
in total = depressant
- enhance GABA A - mediated inhibition by the allosteric inhibition
- inhibits function of NMDA glutamate receptors = depressant
- inhibition of opening of voltage-dependent Ca2+ channels, reducing excitation
Cross tolerance of alcohol
- chronic ethanol use produces tolerance to alcohol and cross-tolerance to benzodiazepines
