David Nutt is Edmund J. Safra Professor of Neuropsychopharmacology and Director of the Neuropsychopharmacology Unit at Imperial College London. He leads an interdisciplinary research group with a particular focus on brain imaging, especially positron emission tomography. He is currently Chair of the Independent Scientific Committee on Drugs and Past-President of the European College of Neuropsychopharmacology, Vice-President of the European Brain Council, President of the British Neuroscience Association, an Editor of the Journal of Psychopharmacology and psychiatry drugs advisor to the British National Formulary.
Cox et al Reference Cox, Benkelfat, Dagher, Delaney, Durand and Kolivakis1 address an issue that has long been assumed to be a central aspect of brain function – the interplay of different neurotransmitters – but for which we have very little evidence so far. The 5-hydroxtryptamine (5-HT) system is perhaps the easiest to manipulate in that many studies have shown that simply by reducing the access of the 5-HT precursor L-tryptophan to the brain using a dietary manipulation (the tryptophan depletion technique) 5-HT function falls. This results in major alterations in brain function such as the loss of the antidepressant and anxiolytic effect of selective serotonin reuptake inhibitors (SSRIs) Reference Bell, Abrams and Nutt2 and the shortening of rapid eye movement (REM) sleep latency. Reference Evans, Golshan, Kelsoe, Rapaport, Resovsky and Sutton3 However, by and large, such changes in 5-HT function have not revealed much evidence of significant interactions with other neurotransmitters. In particular, when the tryptophan depletion approach was used to test a 5-HT link in the action of noradrenaline-acting antidepressants no measureable interaction was detected. Reference Delgado, Miller, Salomon, Licinio, Krystal and Moreno4
So is dopamine different? It seems that this might be the case as in Cox et al’s Reference Cox, Benkelfat, Dagher, Delaney, Durand and Kolivakis1 study lowering 5-HT function by tryptophan depletion led to a reduction in the actions of cocaine to release dopamine that was to some extent paralleled by a reduction in cocaine craving. This finding fits with some preclinical literature that suggests 5-HT restrains dopamine neuronal function, which is sometimes seen clinically when elevating 5-HT by SSRIs causes symptoms attributable to low dopamine function such as akathisia and dystonias.
Low brain 5-HT function has long been associated with impulsive and aggressive traits Reference Virkkunen, Rawlings, Tokola, Poland, Guidotti and Nemeroff5 that themselves may be predictors of stimulant misuse. The possibility that cocaine users might exacerbate their addiction by being in a state of relative L-tryptophan deficiency from poor diet and reduced appetite should also be considered.
Implications for practice
Whether these new findings will contribute to the treatment options for cocaine or other stimulant dependence is less clear. In general, SSRIs have proved ineffective as anti-addiction agents except where they ameliorate primary anxiety or depressive disorders. Reference Lingford-Hughes, Welch and Nutt6 The magnitude of the modulatory effect of 5-HT to limit dopamine release may be too little to offset the major impact of cocaine, which in preclinical studies can increase brain dopamine release up to ten-fold.
It also asks the question, to what extent might 5-HT regulate the effects of other drugs of addiction. Preclinical studies lead us to believe that 5-HT is central to the actions of MDMA (3,4-methylenedioxymethamphetamine) and psychedelics but this has been little explored in humans, and interactions with other drugs of misuse such a heroin and alcohol for which dopamine is less important might also repay investigation. In addition, future studies should consider the possible contribution of genetic variations in 5-HT functionality. Obvious targets are polymorphisms of the 5-HT reuptake site (‘ss’ or ‘ll’ variants) or those of tryptophan hydroxylase-2 (the main synthetic enzyme for 5-HT).
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