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Pharmacodynamics of addictive substances 

Pharmacodynamics of addictive substances
Pharmacodynamics of addictive substances
Addiction (Oxford Psychiatry Library)

Professor David J. Nutt

and Dr Liam J. Nestor


Key points

  • Pharmacodynamics refers to the effect of substances on the body.

  • The pharmacodynamic effects of substances take place at receptors.

  • Agonists mimic the effects of neurotransmitters at receptors.

  • Antagonists block the effects of neurotransmitters at receptors.

  • Addictive substances can alter brain pharmacodynamics.

  • Brain pharmacodynamics can be influenced by genetics.

In Chapter 5, we were introduced to pharmacokinetics—the effect of the body on addictive substances. In this chapter, we will discuss pharmacodynamics—the effects of addictive substances on the body (i.e. in the brain). Acutely, addictive substances target various neurotransmitter systems in the brain (see Table 6.1). The pharmacological actions of these substances at receptors results in their physiological and behaviourally reinforcing effects.

Table 6.1 Primary target and main effects of addictive substances in the brain


Primary target

Main effects

Other actions



Stimulate mOR receptor


Stimulate delta and kappa opioid receptors





Less stimulation of mOR



Promote dopamine release

Increase dopamine

Increase norepinephrine, serotonin, and endorphins



Blocks DAT

Increases dopamine

Inhibits norepinephrine reuptake



Stimulates nicotinic receptor

Increases dopamine




Stimulate GABAA receptor

Increases GABA

Increases dopamine


Reduces glutamate


Stimulate GABAA receptor

Increase GABA



Gamma-hydroxybutyric acid

Stimulate GABAB and GHB receptors

Increases GABA

Increase dopamine




Stimulate CB1 receptor

Increases dopamine

Reduces GABA and norepinephrine release



Lysergic acid diethylamide

Stimulate serotinin 5-HT2 receptor

Mimics serotonin

Increases dopamine




Promotes serotonin release

Increases serotonin

Increases dopamine

SSRIs (e.g. fluoxetine)

Increases norepinephrine and serotonin?

The chronic use of addictive substances, however, leads to pharmacodynamic tolerance at receptors within neurotransmitter systems. This tolerance means that a greater amount of the substance is required to achieve the desired effect. This tolerance has significant implications for relapse during early abstinence, which has led to new treatments that target various neurotransmitter systems which are disturbed in substance addiction.

6.1 Receptors

The acute and chronic effects of addictive substances essentially take place at receptors located within different neural networks of the brain. Receptors are proteins located on the cell membrane of neurons. Dopamine, for example, is a monoamine neurotransmitter, which, when released from presynaptic neurons, binds with postsynaptic dopamine receptors to produce its physiological and behavioural effects.

The activation of some receptors by a neurotransmitter is coupled to biochemical transduction mechanisms in the postsynaptic neuron (i.e. second messengers). These are called G-protein coupled receptors, and adaptations at these receptors are complicit in substance addiction. Second messengers are chemicals whose concentration increases or decreases in response to receptor activation by a neurotransmitter or drug. In the case of dopamine, binding to the D1/5R activates an enzyme called adenylyl cyclase. The activation of this enzyme increases the formation of a coenzyme called adenosine triphosphate (ATP). ATP catalyzes cyclic adenosine monophosphate (cAMP), leading to the activation of calcium (Ca2+) channels.

Dopamine or agonist drugs binding to the D2/3/4R, however, have the opposite effect. This results in reduced formation of cAMP, as these receptors are negatively coupled to adenylyl cyclase. G-protein coupled receptors exert their effects slowly over seconds or minutes. Stimulants (e.g. cocaine, amphetamine), which are highly addictive in humans, are particularly powerful indirect agonists at these receptors, as they increase synaptic dopamine. Addictive substances, such as cannabis and heroin/morphine, also exert their effects at G-protein coupled receptors in the brain.

Ligand-gated receptors (ionotropic or channel-linked receptors), on the other hand, are made up of protein subunits that form a central ion channel. The ion channel is regulated by a ligand (drug or neurotransmitter) and is usually very selective for one or more ions (e.g. Na+, K+, Ca2+, or Cl). The stimulation of such receptors is converted into a postsynaptic electrical signal very rapidly (i.e. in the order of milliseconds). Nicotine, which is the main constituent of tobacco and highly addictive, exerts its acute effects within the brain by acting at ligand-gated nicotinic acetylcholine receptors (nAChRs). The nAChR is a Na+ and K+ ion channel. Likewise, alcohol, which is powerfully addictive, exerts its effects in the brain at fast-acting ligand-gated GABAA receptors. GABAA receptors conduct Cl- ions.

6.2 Receptor agonists

Most addictive substances exert their effects directly (i.e. by mimicking a neurotransmitter) or indirectly (i.e. by modulating neurotransmitter activity) at specific receptors in the brain. The binding of an agonist to the receptor on the cell membrane of a neuron triggers a response in that neuron. Substances of addiction that act as direct agonists are alcohol, cannabis, heroin/morphine, and nicotine. When these substances are consumed and reach the brain, they interact directly with their receptors to elicit their intrinsic effects in the nerve cell.

Cocaine and amphetamine, however, act as indirect agonists at receptors. Following their consumption and entrance into the brain, they act to first increase the synaptic availability of the neurotransmitter (i.e. dopamine—and also norepinephrine and serotonin). Cocaine blocks the reuptake of synaptic dopamine by inhibiting the presynaptic dopamine transporter (DAT). Blocking the DAT inhibits the reuptake of dopamine in the presynaptic nerve terminal. Amphetamines (e.g. crystal methamphetamine) enter presynaptic nerve terminals and increase neurotransmitter release. The increased availability of these neurotransmitters by cocaine and amphetamines, therefore, induces a greater chemical/receptor interaction and, thus, a greater response in the nerve cell.

Certain agonists have been specifically developed to act as a substitute in the management and treatment of addiction. Methadone, for example, is an opioid receptor agonist used to manage heroin addiction. Methadone acts as a substitute for heroin, as it is a full opioid agonist that mimics the actions of heroin (see Figure 6.1). Methadone, however, has a slower onset of effect and, when taken orally, is less reinforcing.

Figure 6.1 Receptor activation. Strength of receptor activation by a super, full, partial, and inverse agonist as well as an antagonist at the mu opioid receptor

Figure 6.1
Receptor activation. Strength of receptor activation by a super, full, partial, and inverse agonist as well as an antagonist at the mu opioid receptor

More recently, partial agonist replacement therapies for addiction (e.g. heroin) have been tested with a view to only partially stimulating receptors to reduce the risk of overdose. A partial agonist is a compound that activates the given receptor but has only partial efficacy at the receptor relative to a full agonist. Furthermore, the partial agonist also acts as a competitive antagonist in the presence of a full agonist. Here, it competes with the full agonist for receptor occupancy and produces a net decrease in receptor activation compared to that observed with the full agonist alone. For example, the partial mu opioid receptor agonist buprenorphine affords itself this mechanism of action (see Figure 6.1) and has become an alternative to methadone in the treatment and management of heroin addiction. Should a heroin-addicted individual decide to take methadone (or heroin) in the presence of buprenorphine, its effects would be blocked.

6.3 Efficacy

Intrinsic efficacy refers to the ability of an agonist to alter the conformation of a receptor. This efficacy is measured by the strength of the response elicited by the agonist. Also, the strength of this response acts as a predictor of efficacy for compounds (see Figure 6.1). Importantly, the more efficacious the agonist, the more potentially lethal it is when an overdose is taken.

6.4 Receptor antagonist

Antagonists are substances that have no intrinsic activity at receptors. They merely block an endogenous (i.e. neurotransmitter) or exogenous (i.e. drug) agonist from stimulating the receptor. While most addictive substances are agonists, there are substances that exert there effects (indirectly) by antagonizing (or blocking) certain receptors in the brain. Probably the best known of these substances are those that block the N-methyl d-aspartate (NMDA) receptor. NMDA receptor antagonists include (but are not limited to) ketamine (K), dextromethorphan (DXM), phencyclidine (PCP), and nitrous oxide (N2O). These substances are popular recreational drugs due to their dissociative and hallucinogenic properties as well as their ability to induce euphoria.

Within the context of substance abuse and addiction, antagonists at different receptors in the brain have also been used to treat addiction. The mu opioid receptor antagonist naltrexone (see Figure 6.1), for example, is used for rapid detoxification (i.e. ‘rapid detox’) regimens for opioid dependence. Naltrexone has also been used to prevent relapse during the early stages of abstinence, given the emerging research evidence that the endorphin system is upregulated in substance addiction. Antagonists can also be added to agonists (e.g. buprenorphine + naltrexone) to reduce the risk of iv abuse.

6.5 Inverse agonists

Inverse agonists are compounds that bind to the same receptor as an agonist but instead induce a pharmacological response that is opposite to the agonist—they have negative efficacy. For example, the binding of an inverse agonist to a G-protein coupled receptor will induce the opposite response to that of an agonist in postsynaptic second messengers systems. The most common inverse agonist used in substance addiction is naloxone. Naloxone is used to counter the effects of opiate (e.g. heroin or morphine) overdose—specifically to counteract life-threatening depression within the respiratory centre of the brain (i.e. medulla oblongata).

6.6 Conclusion

Pharmacodynamics is the effect of substances or endogenous neurotransmitters at their receptors. Chronic substance use alters the functioning of neurotransmitter systems and their receptors—they can alter the pharmacodynamics of the brain. These changes in brain pharmacodynamics have significant implications for the effects of medications which are used to manage and treat substance addiction. Genetic polymorphisms at receptors in the brain, however, may alter pharmacodynamics and predispose some individuals to addiction.

References and Further Reading

Boileau I, Assaad JM, Pihl RO, et al. (2003). Alcohol promotes dopamine release in the human nucleus accumbens. Synapse, 49, 226–31.Find this resource:

    Bossong MG, van Berckel BN, Boellaard R, et al. (2009). Delta 9-tetrahydrocannabinol induces dopamine release in the human striatum. Neuropsychopharmacology, 34, 759–66.Find this resource:

      Nutt, D. J. (2010). Antagonist-agonist combinations as therapies for heroin addiction: back to the future? J Psychopharmacol, 24(2), 141–145.Find this resource:

        Rosa-Neto P, Gjedde A, Olsen AK, Jensen SB, Munk OL, Watanabe H, and Cumming P (2004). MDMA-evoked changes in [11C]raclopride and [11C]NMSP binding in living pig brain. Synapse, 53, 222–33.Find this resource:

          Schiffer WK, Volkow ND, Fowler JS, Alexoff DL, Logan J, and Dewey SL (2006). Therapeutic doses of amphetamine or methylphenidate differentially increase synaptic and extracellular dopamine. Synapse, 59, 243–51.Find this resource:

            Sirohi S, Dighe SV, Madia PA, and Yoburn BC (2009). The relative potency of inverse opioid agonists and a neutral opioid antagonist in precipitated withdrawal and antagonism of analgesia and toxicity. Journal of Pharmacology and Experimental Therapeutics, 330, 513–19.Find this resource:

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