The intentional abusive action in the use of drugs, whether prescribed or recreational, to achieve effects such as stimulation, relaxation, analgesia or other effects is classified as substance misuse. A disorder that arises from this behaviour is called substance dependence and it includes continued abuse of the drug regardless of adverse effects accompanied with further use. These adverse effects primarily stem from adaptations of the brain that result from tolerance in the CNS. The adaptations of tolerance are often localized to the VTA leading to the nucleus accumbens, a pathway associated with reward[1].Specifically, functional tolerance is the process by which receptors that are bound by the substance of abuse are down regulated and desensitized[2]. This down regulation and desensitization that occurs is controlled by cellular mechanisms, which involve chemical messengers, secondary messengers and ultimately alteration of gene expression. Most of these physiological changes occur at the synapse, however they also involve extracellular proteins/enzymes that are involved in neurotransmitter reuptake and breakdown.

Furthermore, sudden cessation of drug use can result in even more drastic neuronal modifications. Users enter a state of withdrawal, characterized by symptoms typically opposite to the effects of the drug. The intensity of withdrawal symptoms can be thought of as roughly proportional to the users physical dependence, a factor associated with tolerance. As the cell bodies attempt to shift towards a new homeostatic state (or resume their old one; before drug exposure) they may undergo different conditions and changes, producing unpleasant, or even intolerable effects on the user. These are the symptoms of withdrawal and usually lead to subsequent craving and relapse. In particular, alterations at the receptor subunit level within e VTA have been shown to produce hyper excitability of neurons, making this part of the mesolimbic system susceptible to neurotoxicity, eliciting withdrawal[1]. Also during withdrawal, morphological alterations of presumably DA containing neurons have been related to neuronal malfunction within the VTA[3]. In addition biochemical changes can also be identified. Elevation or depletion of protein concentrations during withdrawal is yet another component that may induce craving and relapse [4]. Cellular adaptation, protein configuration, and receptor alterations are all key instruments in tolerance and withdrawal. Understanding these mechanisms can foster effective treatments for users and provide insight to the powerful effects of the mesolimbic pathway.


1.0 Functional Tolerance to Drug Abuse
  • 1.1aPhysiological Respons
  • 1.1bMechanisms inducing change
  • 1.1cBehavioural response

2.0 Withdrawal
2.1 Physical Effects of Withdrawal
2.2 Overview of Molecular Effects
2.3 Morphological Changes
  • 2.3a Structural Changes to the VTA
  • 2.3b Structural Changes to Nucleus Accumbens Neurons
2.4 Biochemical Changes
  • 2.4a NMDA receptor
  • 2.4b GABA receptor
  • 2.4c AMPA receptor
2.5 Protein Level Changes
  • 2.5a BDNF changes
2.6 Implications
  • 2.6a Craving and Relapse


  1. ^ Ortiz, Jordi, Lawrence W. Fitzgerald, Maura Charlton, Sarah Lane, Louis Trevisan, Xavier Guitart, William Shoemaker, Ronald S. Duman, and Eric J. Nestler. "Biochemical Actions of Chronic Ethanol Exposure in the Mesolimbic Dopamine System." Synapse 21.4 (1995): 289-98
  2. ^ Trajilo A. Keith, Akil Huda. Excitatory Amino Acids and Drugs of Abuse: A Role for N-methyl-D-aspartate receptors in drug tolerance, sensitization and physical dependence. Drug and Alcohol Dependance 28.2 (1995):139-154
  3. ^
    Giuliana P. Serra, M. Cristina Puddu, Marzia Foddai, and Marco Diana. "Morphine Withdrawal-induced Abnormalities in the VTA: Confocal Laser Scanning Microscopy." European Journal of Neuroscience 17.3 (2003): 605-12.
  4. ^ Grimm, Jeffrey W., et al."Time-Dependent Increases in Brain-Derived Neurotrophic Factor Protein Levels within the Mesolimbic Dopamine System after Withdrawal from Cocaine: Implications for Incubation of Cocaine Craving." The Journal of Neuroscience 23.3 (2003): 742-47.