|Figure 1: A pictorial depiction of drug tolerance.
As an individual is repeatedly exposed to the substance,
a greater dose is needed to achieve the same feeling as
before, also known as drug tolerance. 
Addiction research has identified tolerance to play a key role in substance addiction and misuse. Tolerance is frequently seen behaviorally as a need to increase the dose to reach the desired effect. Substance tolerance is typically divided into metabolic tolerance and cellular tolerance. Specifically, cellular tolerance includes molecular changes happening at the target site of the drug, and also changes to the learning and reward systems in the brain or sometimes referred to as learned tolerance.
Tolerance to pain managing medications is frequently seen in the clinical setting. A study involving 206 subjects in 2005 found greater than ten-fold dose increase for patients undergoing an opioid pain management program. In illicit opioid users, the amount of dose escalation can be even more drastic as subjects compulsively seek to create the same psychological and physiological effect as the previous dose.
Understanding the role of tolerance in substance dependence can allow for better prevention when medications with high misuse potential are prescribed, and can allow for better treatments for those struggling with substance dependence.
Table of Contents
1. Clinical Definition of Tolerance
Tolerance is one of the diagnostic criteria for substance dependence as outlined in the Diagnostic and Statistical Manual for Mental Disorders, 4th edition (DSM-IV-TR). DSM-IV-TR defines tolerance as either an increase in the dose of the substance used to achieve the same desired effect or a decrease of effect when the same dose of the substance is given. Based on this clinical definition, the most obvious symptom of tolerance is dose escalation, where individuals who have experienced tolerance to a substance seek to increase their dose to compensate for the decreased physiological or psychological effects.
2. Metabolic Tolerance
Metabolic tolerance leads to the same effect of dose escalation due to decreased concentration of drug at the target site, however, this decrease is not due to adaptive measures taken by the cells at the target site (for cellular tolerance, see below). Metabolic tolerance of a substance results in a real decrease in concentration of drug arriving at the target site, and as a result, a decreased physiological response to the drug.
2.1 Bioavailability and the First-Pass Effect
The first-pass effect described the phenomenon where the concentration of drug taken into the body is reduced through enzyme metabolism before it reaches systemic circulation, and eventually its target site. This effect dramatically decreases a substance’s bioavailability, or the amount of active drug present in the systemic circulation. This phenomenon occurs when the substance must first pass through the hepatic portal system before reaching systemic circulation, allowing the substance to be delivered to the liver where great metabolic activity occurs.
|Induction of CYP1A2|
|Figure 2: Induction of the enzyme CYP1A2 after taking various
amounts of coffee (measured in cups, 1 cup = 75 mg of caffeine). This study
found increased caffeine intake resulted in increased presence of CYP1A2 enzymes.
The first-pass effect is a significant problem for substances taken orally. As the substance becomes absorbed in the gastro-intestinal tract, it is delivered to the liver through the portal vein. This phenomenon increases the time for the substance to reach systemic circulation, and decreased the concentration of the drug that becomes available to be delivered to the target. Other methods of drug administration, including intravenous injection and inhalational aerosol, may bypass the first-pass effect straight to the systemic circulation, allowing for a more rapid onset and a higher bioavailability.
2.2 Enzyme Induction
Enzyme induction occurs when the amount or the activity of a drug metabolizing enzyme is increased due to the exposure to a substance. As a result of enzyme induction, there may be greater rate of inactivation if given an active substance, or a greater activation if given an inactive precursor, commonly known as a pro-drug.
Many substances have been known to induce some common drug metabolizing enzymes. CYP2E1 is one of the major drug metabolizing enzymes in the human body for ethanol, and is induced by both nicotine and alcohol. Nicotine also can induce CYP1A2, the enzyme responsible for the metabolism of caffeine, which may explain the increased tolerance to caffeine among smokers.
Substances of misuse and addiction, including but not limited to opioids, alcohol, nicotine, stimulants, all commonly induce changes in the available dopamine in the nucleus accumbens along with dopaminergic synapses in other areas of the brain to create its pleasurable effects. Acute exposure may lead to small changes at the synapse; however, chronic use may result in long-term changes at the receptor and cell level, and also at the level of larger neural systems including changes to the reward system.
3.1 Receptor Tolerance
The initiation of the physiological response to any substance starts at the receptor level. Typically, the cellular effects within the cell depend largely on the receptor and the different intracellular signaling pathways it initiates. G-protein coupled receptors (GPCR) are a class of receptors typically targeted by substances of misuse. (For a more in-depth analysis of the GPCR and drug that target them, see review Kitanaka, 2008, and neurowiki article Receptors in Addiction)
|Receptor Downregulation in Opioid Tolerance|
|Opioid Tolerance. Created by Dennis Wei (University of Toronto)|
3.1a µ Opioid Receptor (MOPr)
|Internalization of the MOPr|
|Figure 3: A pictorial representation of the binding
of an agonist to the MOPr, and the resulting internalization
of the MOPr through the Arr3 mediated mechanism
The µ-opioid receptor (MOPr), a G-protein coupled receptor, has been identified to play a role in opioid tolerance. In the presence of a high concentration of an opioid, the cell typically responds in two ways. First, it may aim to decrease the expression of MOPr at the surface of the cell. In addition, it may also aim to target the receptors that remain on the cell surface by decreasing their efficacy for coupling and eliciting downstream effects.
The binding of an agonist to the MOPr leads to phosphorylation of the receptor by the G-protein-coupled receptor kinase 2, increasing the affinity of the MOPr for arrestin 3 (Arr3). The binding of Arr3 leads to the desensitization of the receptor through uncoupling, and recruits clatharin and dynamin to initiate the internalization of the MOPr.  When Arr3 knockout mice are given chronic morphine treatment, they exhibit a failure to develop behavioural antinociceptive tolerance to the drug compared to wild type. However, more recent research suggests a possible distinction between densensitizaiton and internalization as causes for tolerance at the MOPr, and that Arr3 may not be the sole cause of tolerance. Specifically, research looking at cultured locus coeruleus neurons found MOPrs to still exhibit desensitization when the gene for Arr3 is knocked out. In addition, molecules downstream of the MOPr, such as cAMP, may also directly control neural excitability, leading to a tolerance of the whole signaling system despite what is occurring at the level of the MOPr receptor.
3.2 System Tolerance
Much research has gone into identifying changes in neural networks as a result of substance misuse. It was found that adaptations, including changes in synaptic strength and neurochemical balances, occur throughout different neural networks as a result of increased or decreased electrical activity of a group of targeted neurons. As a result, changes in a few cells of a neural network as a result of increased drug exposure may result in changes and adaptations of other neurons and synapses throughout the cellular network. For example, although morphine does not bind to nor act on dopaminergic neurons, they influence the dopaminergic neurons in the ventral tegmental area to elicit tolerance to morphine’s rewarding effects.
|Functional changes caused by
the use of methamphetamine
|Figure 4: Methamphetamine creates its effect
through the release of the dopamine stores in the
pre-synaptic neuron. However, this large release of
dopamine can cause permanent damage to the
dopaminergic synapses. This image shows the amount
of functional dopaminergic synapses in naïve subjects
and meth abusers with varying lengths of abstinence
3.2a The Reward Pathway
Most addictive drugs achieve some of its effects through the activation of the reward system . The activation of the reward system leads to the reinforcement of behaviours, and is composed of the mesolimbic and mesocortical pathway. The mesolimbic pathway involves dopaminergic neurons from the ventral tegmental area which synapse onto neurons in the nucleus accumbens. Substances manipulate the amount of dopamine available at the synaptic clefts in this pathway to create pleasurable effects associated with them.
Methamphetamine profoundly alters the dopaminergic neurons by increasing the available dopamine in the synaptic cleft, thus causing the initial euphoric and other stimulatory effects of the drug. However, with prolonged use, methamphetamine can alter the function of the dopamine D1 receptor function, specifically in the striatum, leading to signs of tolerance.
Cocaine addiction also primarily depends on the changes that occur to the reward pathway. Specifically, the D3 autoreceptors and the extracellular signal-regulated kinase (ERK) pathway have been implicated to play an important role in cocaine-induced plasticity in the mesencephalic dopaminergic system.
3.2b Synaptic Plasticity
In addition to eliciting pleasurable feelings, most addictive substances also greatly affect the brain’s mechanisms of synaptic plasticity leading to changes in learning and memory. Specifically, many substances are found to affect both long-term potentiation (LTP) and long-term depression (LTD), mechanisms proposed to underlie synaptic plasticity. When these long term changes occur, the subject usually demonstrates inappropriate learning, such as the tolerance and misuse of addictive substances.
With opioids, LTP was significantly inhibited at excitatory synapses in the CA1 region in the hippocampus when subjects are put on a chronic intermittent morphine treatment. With the use of cocaine, a single dose can induce an increase in the ratio of AMPA to NMDA receptor on excitatory synapses in the Ventral Tegmental Area (VTA). Furthermore, cocaine dependent plasticity in the VTA and behavioural sensitization appears to be dependent on the hypothalamic peptide orexin. In addition, synaptic plasticity was also seen in the Nuclelus Accumbens (NAc), with greater synapse-to-neuron ratio in the NAc shells of the cocaine-treated and morphine-treated rats, and greater increase also in the NAc core of the cocaine-treated rats.
|Functional changes caused by
the use of methamphetamine
|Figure 5. A schematic representation of the experimental
design used to study the role of the environment of the drug
administration on the tolerance of the drug.
3.2c Contextual Conditioning
Learning to associate the environment with the substance of abuse has also been indicated as a form of tolerance. Experiments aimed to study environmental or contextual conditioning will usually pair an environment with a substance, so that the environment becomes a conditioned stimulus for the addition of the drug for the subject. Over time, the subject’s brain exhibit compensatory mechanisms when only the environment is presented, leading to a need for dose escalation or a tolerance of the drug’s effects. Several brain areas, including the nucleus accumbens and prefrontal cortex, exhibited greater neural activity when only the environment was presented in a group of mice where environment was paired with methamphetamine IP injection.