Re: What happens biochemically to an organism during drug withrawl?

I wasn't able too find too many articles that explicitly dealt with the mechanisms of rebound phenomena after drug withdrawal (do a PubMed search on "Rebound Phenomena AND Drug Abuse"). Most of what I read rather addressed the complex syndrome of addiction /drug-seeking behavior and its implications. Tolerance (habituation) to a drug’s effects, withdrawal, rebound, and the like are all phenomena that have to be viewed in the context of the so-called reward-deficiency syndrome which is described in some detail in Blum et al.(1996): check out the on-line version!

I will start with a brief introduction to the neurobiology of reward: in the (more primitive parts of) the brains of higher mammals (such as the limbic system and midbrain) one finds structures that signal how pleasur- able or rewarding a certain stimulus is (in a natural setting these plea- surable stimuli would include food, sex, social contact, etc.). These structures comprise the so called meso(cortico)limbic dopaminergic reward system with the ventral tegmental area (VTA) and its target area, the Nucleus accumbens (NAc) being the final waystations in the reward cascade.

Natural stimuli and most drugs of abuse somehow or other influence the dopamine level at the synapses in the NAc (cf. Blum et al., 1996; Julien, 1997; Self and Nestler, 1995). Increased dopamine levels result in decreased firing rates in the NAc neurons and this signal somehow is interpreted as a feeling of pleasure or reward. (Just on the side : Other areas that probably contribute to the reward system are the prefrontal cortex, certain hippocampal areas, and the lateral hypothalamus.)

Some individuals seem to be genetically predisposed to addictive behavior (and as a matter of fact also to impulsive/compulsive behavior and some neuropsychiatric disorders such as Tourette's syndrome, cf. Blum et al., 1996) (Table 1) since they apparently need an extra boost of dopamine in their meso- (cortico)limbic reward structures which is brought about by the use of stimulants/drugs (e.g., cocaine blocks the reuptake of dopamine into presynaptic terminals in the NAc by decreasing the dopamine transporter's affinity for dopamine; this leads to an increased concentration of dopamine in the synaptic cleft). These persons share a certain polymorphism in an allele (A1) for the D2 dopamine receptor gene and were reported to have a 30 % lower density/number of D2 dopamine receptors on their N. accumbens cells (see Blum et al, 1996) which might account for the fact that they show a stronger drug seeking behavior than other persons.

Self and Nestler (1995) & Blum et al. (1996) give an overview of current research into the biochemical/physiological basis of addictive behavior all the way down to the molecular level.

Documented biochemical differences between habituated and non-habituated subjects/animals (most research is done on rodents, since "virtually all drugs that are reinforcing in [humans] are also reinforcing in laboratory animals"; Self and Nestler, 1995, p. 466) include (among others described in Blum et al., 1996; Self and Nestler, 1995) :
a) in the animal model an increase in the density of presynaptic dopamine transporter molecules in the NAc has been observed after chronic cocaine administration.
b) in a similar series of experiments researchers found a decrease in the number of postsynaptic dopamine receptors (NAc).
Both adaptations lead to a negative effect on dopamine signalling and are believed to lead to compensatory intake of higher doses of stimulant/drugs.
c) chronic alcohol administration can influence gene expression: it was found that the level of GABA(A)-receptor specific mRNA changes (see Julien, 1997) though this does not automatically imply any changes at the protein level (the number of receptors expressed might not change). GABA(A)-receptors are ion channels for chloride which inhibit the effect of inhibitory synapses impinging on the VTA neurons (i.e. in effect there is less inhibition and more dopamine release in the NAc).
For better understanding once again look at the figure from Blum et al. (1996)
d) tolerance to morphine and similar opioids seems to brought about by an induction of degrading enzymes (cytochrome P450 and others) which leads to faster elimination of the stimulant drug. Therefore a higher drug dose is then required to maintain a desired drug concentration in the body fluids (see Julien, 1997).
In addition the opioid receptor's sensitivity seems to decrease as well though it was not mentioned how this happens (Julien, 1997). Covalent modification, e.g. phosphorylation(dephosphorylation seems to be a good guess since it is known that chronic exposure to drugs such as cocaine and amphetamines leads to changes in protein kinase activity (cf. Self and Nestler, 1995).
e) along with the biochemical changes there is evidence for structural changes in the VTA-NAc pathway as well. Some cytoskeletal proteins are found at lower levels after a chronic drug regimen (cocaine/morphine) which might change axonal transport rates, e.g. for tyrosine hydroxylase, a key enzyme involved in the production of dopamine (Self and Nestler, 1995, pp. 480 & 481).

I hope this answers some of your questions and I also hope you didn't find this reply too technical. Feel free to email me in case you have further questions.

References (I included a couple of original and review articles I did not refer to in the main body just to give you an idea of how much research there is on this topic. These papers are marked with asterisks.):
Blum K, Cull JG, Braverman ER, Comings DE (1996): Reward Deficiency Syndrome. American Scientist, Vol. 84, 132 - 145. On-line version: http://www.amsci.org/amsci/Articles/96Articles/Blum-full.html
**Fitzgerald LW, et al. (1995): Molecular and cellular adaptations in signal transduction pathways following ethanol exposure. Clin Neurosci. 1995; 3(3): 165-173. Review.
PubMed Abstract **Haefely W (1986): Biological basis of drug-induced tolerance, rebound, and dependence. Contribution of recent research on benzodiazepines. Pharmacopsychiatry. 19(5): 353-361.
Julien RM (1997): A primer of drug action: a concise nontechnical guide to the actions, uses, and side effects of psychoactive drugs. 7th edition, W.H. Freeman and Comp.
I would recommend to start with this book as an introduction because of its systematic and easily intellegible approach to the to the biology of drugs.
**Koob GF, et al.(1997): The neurobiology of drug addiction. J Neuropsychiatry Clin Neurosci. 1997; 9(3): 482-497. Review.
PubMed Abstract
**Nestler EJ (1997): Molecular mechanisms of opiate and cocaine addiction. Curr Opin Neurobiol. 7(5): 713-719. Review.
PubMed Abstract
**Nestler EJ, et al.: Molecular and cellular basis of addiction. Science. 278(5335): 58-63. Review.
PubMed Abstract
**Nestler EJ, et al.: (1996) Molecular mechanisms of drug addiction: adaptations in signal transduction pathways. Mol Psychiatry. 1(3): 190-199. Review.
PubMed Abstract
**Nestler EJ. (1996): Under siege: The brain on opiates. Neuron. 16(5): 897-900. Review.
Self DW and Nestler EJ (1995): Molecular Mechanisms of Drug Reinforcement and Addiction. Annu Rev Neurosci 18: 463-495.
**Self DW, McClenahan AW, Beitner-Johnson D, Terwilliger RZ, Nestler EJ (1995): Biochemical adaptations in the mesolimbic dopamine system in response to heroin self-administration. Synapse 21(4):312-318
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**Self DW, Terwilliger RZ, Nestler EJ, Stein L (1994): Inactivation of Gi and G(o) proteins in nucleus accumbens reduces both cocaine and heroin reinforcement.
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**West R, et al. (1994): Overview: a comparison of withdrawal symptoms from different drug classes. Addiction. 89(11): 1483-1489.
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**Wise RA (1996): Neurobiology of addiction. Curr Opin Neurobiol 6(2):243-251. Review.
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**Wise RA (1996): Addictive Drugs And Brain Stimulation Reward. Ann Rev Neurosci 19: 319-340.
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