Altering Signal to Noise Ratio through Monoamine Signaling
August 25, 2015 at 10:32 PM | categories: mph
Contents
1 Increase Signal to Noise Ratio to Help Attention
Volkow et al. [5] suggested that increased endogenous dopamine (DA) following dopamine transporter (DAT) blockade by methylphenidate (MPH) attenuates background firing rates, increasing the signal-to-noise ratio of striatal cells, thereby improving attention and reducing distractibility.
D-AMPH and MPH alter superior colliculus responsiveness in a stimulation intensity-dependent fashion [1] The effects of d-AMPH and MPH on these responses were correlated with the intensity of the eliciting stimulus—a substantial number of responses elicited by low intensities were reduced in amplitude while those elicited by higher intensities were largely unaffected [1]. The effects of d-AMPH and MPH on response amplitude were mimicked by the application of 1 μm serotonin (5-HT), which produced identical effects to the psychostimulants [1]. In contrast, a higher concentration [10 μm] produced almost universal response suppression, but again this was more pronounced at low intensities [1]. The role of 5-HT in the actions of d-AMPH and MPH was confirmed by the fact that their effects were completely abolished by prior application the 5-HT receptor antagonist metergoline [1].
2 Effects in the Superior Colliculus
The suppressive effects of d-AMPH and MPH are mediated presynaptically, although post-synaptic AMPA/NMDA ratio is also reduced at high intensities after application of d-AMPH and MPH [1]. d-AMPH and MPH increased the signal-to-noise ratio in the superior colliculus by differentially affecting the impact of weak and strong activations: suppressing the former and retaining the latter [1]. The effects of d-AMPH and MPH on collicular responses could be abolished by a 5-HT antagonist and mimicked by application of a low concentration of 5-HT itself. Mediation by 5-HT is perhaps not surprising given the known pharmacology of psychostimulants and monoaminergic innervation of the superior colliculus. That is to say, it is widely accepted that d-AMPH and MPH act to increase synaptic levels of the monoamines DA, norepinephrine (NE), and 5-HT [1].
5-HT is the primary monoamine in the superficial layers of the SC [1]. While there are no previous reports of 5-HT changing the signal-to-noise ratio in the SC, there is evidence of monoamines fulfilling that role elsewhere in the brain, the classic example being dopamine-induced increases in signal-to-noise ratio in the striatum and frontal cortex [2, 4]. However, previously reported examples of monoamine-mediated changes in the ratio, including those caused by 5-HT, have all arisen because of suppression of spontaneous background activity, producing a net increase in signal size [1]. Dommett et al. [1] however reports a change in signal-to-noise ratio due to an entirely novel mechanism: a change in the relationship between weak and strong signals (rather than signal and background), suppressing weak signals and retaining strong signals.
These results provide crucial insights into the mechanism by which d-AMPH and MPH decrease distractibility and improve sustained attention in normal subjects but also suggest that these drugs may at least in part act in the SC to the same effect in attention-deficit/hyperactivity disorder (ADHD): a suggestion which is in line with evidence reviewed elsewhere [3] that the SC is dysfunctional in ADHD. Consistent with the possibility that the colliculus may be dysfunctional in the disorder, and that 5-HT induced modulation of the SC is therapeutically important, 5-HT selective drugs, such as fluoxetine, appear to have therapeutic efficacy in ADHD [1].
Acronyms
- 5-HT
- serotonin
- ADHD
- attention-deficit/hyperactivity disorder
- DAT
- dopamine transporter
- DA
- dopamine
- MPH
- methylphenidate
- NE
- norepinephrine
References
[1] E. J. Dommett, P. G. Overton, and S. A. Greenfield. Drug therapies for attentional disorders alter the signal-to-noise ratio in the superior colliculus. Neuroscience, 164(3):1369–76, Dec 2009. doi: 10.1016/j.neuroscience.2009. 09.007.
[2] E. A. Kiyatkin and G. V. Rebec. Dopaminergic modulation of glutamate-induced excitations of neurons in the neostriatum and nucleus accumbens of awake, unrestrained rats. J Neurophysiol, 75(1):142–53, Jan 1996.
[3] P. G. Overton. Collicular dysfunction in attention deficit hyperactivity disorder. Med Hypotheses, 70(6):1121–7, 2008. doi: 10.1016/j.mehy.2007.11. 016.
[4] E. T. Rolls, S. J. Thorpe, M. Boytim, I. Szabo, and D. I. Perrett. Responses of striatal neurons in the behaving monkey. 3. effects of iontophoretically applied dopamine on normal responsiveness. Neuroscience, 12(4):1201–12, Aug 1984.
[5] N. D. Volkow, G. Wang, J. S. Fowler, J. Logan, M. Gerasimov, L. Maynard, Y. Ding, S. J. Gatley, A. Gifford, and D. Franceschi. Therapeutic doses of oral methylphenidate significantly increase extracellular dopamine in the human brain. J Neurosci, 21(2):RC121, Jan 2001.