Sciences de la Santé
Mechanisms of tolerance and withdrawal syndrome In addition to a compulsion to take the agent of abuse, 2 major features of addiction are tolerance and withdrawal syndrome.
Tolerance is either the diminishing effect of the drug after repeated ingestion at a constant dose, or the need to increase the dose, reduce the interval between doses, or both, to produce a constant effect. It results from molecular and cellular adaptations to counterbalance the effects of the drug. A pharmacokinetic adaptation can occur( for example with alcohol) in which the hepatic clearance of the drug is increased. More commonly, a pharmacodynamic adaptation occurs in which there is a downregulation in membrane receptors expression, leading to reduced receptor availability.
Withdrawal syndrome refers to the signs and symptoms that follow the abrupt discontinuation or reduction in drug use. These symptoms are usually the exact opposite of those produced by the drug. This is due to alterations in the basal physiological state of cells and circuits caused by the drug. As long as drug use continues, this altered physiology is masked and symptoms do not occur, but as soon as drug consumption ceases, the abnormal state is unmasked and results in a withdrawal syndrome. The consequence of this is complete drug dependence.
Figure 3- Effetcs of Opioids on Locus cereleus
Animal models that were used to explain the molecular mechanisms of these adaptive changes have used opioids as examples. Although the possibility to extrapolate the results to other substances remains conflictual 6. This mechanism is related to the locus ceruleus, the major noradrenergic nucleus in the brain. It has a crucial role in the regulation of arousal, responses to stress and autonomic nervous system activity( Figure 3).
16 Été 2018
An acute administration of opiates activates the µ opioid receptors in the locus cereleus which activate a K + channel. This results in a reduced firing rate of the locus ceruleus neurons. However, over time, the µ receptors become phosphorylated by some G-protein – coupled receptors via an activation of various molecular pathways. Thus, µ receptors become partially uncoupled from the K + channels and the firing rate tends to regain its normal level.
To counterbalance the K + efflux produced by the µ receptor stimulation, the cell increases the conductance of Na +. Thus, when the drug consumption is stopped and the K + efflux is no longer activated, a rapid hyperexcitability state is created which results in a burst firing responsible for the withdrawal syndrome.
Factors influencing addiction Only a minority of people who use drugs ultimately become addicted. Many genetic, developmental and social factors contribute to the determination of a person’ s susceptibility to become addicted. Environment is responsible for addiction as much as the drug itself, for instance people do not often get addicted to morphine used as analgesic in hospital care because the environment is not in favor.
- Pharmacologic and physicochemical properties of drugs: these properties influence how the drug is consumed; for example, water solubility facilitates the injection of the drug, volatility favors the inhalation and heat resistance favors smoking. They also influence the effects of the drug; for example, liposolubility increases the passage of a drug through the blood – brain barrier, a rapid onset produces a stronger response and a short half-life produces more abrupt and intense syndromes of withdrawal.
- Personality and psychiatric disorders: some psychologic profiles favor drug addiction more than others, particularly risk-taking or novelty-seeking people. Likewise, several psychiatric disorders increase the risk of abuse, such as depression, schizophrenia, bipolar disorder, etc. And, not quite surprisingly, a combination of a mental disorder and a drug addiction significantly complicates the management and outcome.
- Genetic factors: they are far more implicated in addiction than what was previously thought. They act mainly on influencing the metabolism and the molecular effects of the drugs. For example, a family history of alcoholism increases the chances of developing this addiction independently of childhood alcohol consumption. This likelihood decreases if an allele coding for a reduced aldehyde dehydrogenase activity is inherited. The same phenomena can be observed with various drugs, such as heroin( polymorphisms of µ opioid receptor), codeine( polymorphism of the cytochrome P-450 2D6 gene), nicotine( polymorphisms of the cytochrome