MIDBRAIN DOPAMINE SYSTEMS and SCHIZOFRENIA

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Disturbances of dopamine systems in the central nervous system can be responsible for a variety of neurological and neuropsychiatric disorders.

For example, degeneration of dopamine neurons of the substantia nigra (SN) underlies the development of Parkinson’s disease. Another important midbrain dopamine system is the ventral tegmental area (VTA). Dopamine neurons of the VTA project to mesolimbic and mesocortical brain structures and a hyperactivity in dopaminergic mesolimbic structures is thought to be involved in symptoms of the neuropsychiatric disorder schizophrenia. These symptoms can be (more or less) controlled with antipsychotic drugs (APDs). However, the exact mechanism of action of APDs is still not clear. In general, APDs have affinities for several neurotransmitter receptors, but they all have in common an antagonism of the dopamine D2 receptor. Since the majority of dopamine neurons of the different dopamine systems have dopamine D2 autoreceptors, APDs can affect the activity of dopamine neurons of different systems and thus induce side effects. For example, APDs can influence the activity of dopamine neurons of the SN, giving rise to so-called extrapyramidal sides effects, which include Parkinson-like symptoms.

To study the mechanism of action of APDs we have developed an in vitro rat midbrain slice preparation. With extracellular recording methods the activity of dopamine neurons of the SN and VTA can be recorded. Furthermore, with whole-cell patch clamp techniques we investigate the modulation of ion channels like e.g. the GIRK channel, a major player in dopamine neuron excitability.

Top: Recording chamber with a midbrain slice and two glass electrodes for extracellular recording.
Bottom: Examples of extracellular recordings of a dopamine neuron

The midbrain slice preparation is used to study several aspects of APD-mediated modulation of midbrain dopamine neuron activity.

1) In a PhD project by Annelies Olijslagers the serotonergic modulation of dopamine and GABA inputs to SN and VTA dopamine neurons was studied. The so-called atypical APDs have, in addition to their affinity for the D2 receptor, affinity for 5-HT2 receptors.

It was found that 5-HT2 receptors have different roles in modulating dopaminergic and GABA-ergic neurotransmission in SN and VTA dopamine neurons and this may be an underlying mechanism for atypical APD efficacy.

In follow-up studies we are further elucidating this differential serotonergic modulation.

Hypothetical scheme illustrating the effects of concomitant dopamine and GABA
neurotransmission in midbrain dopamine neurons under different 5-HT conditions.

2) Several neuropeptides affect the electrical activity of midbrain dopamine neurons. In two research lines we are studying the effects of ligands for the neurotensin receptor and the neurokinin-3 receptor, respectively.

It has been suggested that these neuropeptide receptors may be potential targets for (new) APDs. In our studies we investigate possible differential effects of neuropeptide ligands on SN and VTA dopamine neuron activity.

The neurotensin fragment NT8-13 increases the firing rate of a SN dopamine neuron

• Olijslagers, J. E., Werkman, T. R., McCreary, A. C., Kruse, C. G. and Wadman, W. J. (2006)
  Modulation of midbrain dopamine neurotransmission by serotonin, a versatile interaction between neurotransmitters and significance for antipsychotic drug action
  Current Neuropharmacology. 4, 59-68.

• Werkman, T. R., Glennon, J. C., Wadman, W. J. and McCreary, A. C. (2006)
  Dopamine receptor pharmacology: interactions with serotonin receptors and significance for the aetiology and treatment of schizophrenia. CNS Neurol Disord Drug Targets. 5, 3-23.

• Olijslagers, J. E., Perlstein, B., Werkman, T. R., McCreary, A. C., Siarey,
  R., Kruse, C. G. and Wadman, W. J. (2005)
  The role of 5-HT(2A) receptor antagonism in amphetamine-induced inhibition of A10 dopamine neurons in vitro. Eur J Pharmacol. 520, 77-85.

• Werkman, T. R., Olijslagers, J. E., Perlstein, B., Jansen, A. H., McCreary,
  A. C., Kruse, C. G. and Wadman, W. J. (2004)
  Quetiapine increases the firing rate of rat substantia nigra and ventral tegmental area dopamine neurons in vitro. European Journal of Pharmacology. 506, 47-53.

• Olijslagers, J. E., Werkman, T. R., McCreary, A. C., Siarey, R., Kruse, C. G. and Wadman, W. J. (2004)
  5-HT2 receptors differentially modulate dopamine-mediated auto-inhibition in A9 and A10 midbrain areas of the rat. Neuropharmacology. 46, 504-510.

• Werkman, T. R., Kruse, C. G., Nievelstein, H., Long, S. K. and Wadman, W. J. (2001)
  In vitro modulation of the firing rate of dopamine neurons in the rat substantia nigra pars compacta and the ventral tegmental area by antipsychotic drugs. Neuropharmacology. 40, 927-936.

• Werkman, T. R., Kruse, C. G., Nievelstein, H., Long, S. K. and Wadman, W. J. (2000)
  Neurotensin attenuates the quinpirole-induced inhibition of the firing rate of dopamine neurons in the rat substantia nigra pars compacta and the ventral tegmental area. Neuroscience. 95, 417-423.

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This page was last updated on 5 nov 2010

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