Effect of β-adrenoceptors on the Activity of Dopaminergic Neurons in the Ventral Tegmental Area

Margaret E Gompers, Susanna M O Hourani, Ying Chen. FHMS, University of Surrey, Guildford, UK

The mesocorticolimbic dopamine pathway in the brain is well known for its involvement in reward and addiction. This pathway originates in the ventral tegmental area (VTA) which receives inputs from other brain regions, including noradrenergic innervation from locus coeruleus (LC). LC neurons have long been known to be affected by cocaine and opiates and the withdrawal from them, and interactions between the dopaminergic and noradrenergic systems are known to occur. In the VTA, somatodendritically released dopamine predominantly activates dopamine D2 receptors to inhibit dopamine neuron activity, but can also activate α2-adrenoceptors1. Noradrenaline is known to activate not only α1 and α2-adrenoceptors but also dopamine D2 receptors2.

The β-adrenoceptor antagonist, propranolol, has recently shown promising results in animal studies of addiction3,4,5 and in treatment of human cocaine addicts6. However, any effect of β-adrenoceptors in the dopaminergic system is yet to be investigated. This study aims to determine the roles of β-adrenoceptors in the VTA.

In vitro extracellular recordings of VTA dopaminergic neuronal firing rate were used to measure effects of receptor agonists applied in coronal midbrain slices from male CD1 mice (aged 4-12 weeks). Receptor antagonists were pre-applied for 10 minutes prior to agonist addition (6 minutes). Repeated measures ANOVA was used to compare cell firing rates during baseline measurement, antagonist application (where appropriate), agonist application and wash out of all drugs.

Application of the β-adrenoceptor agonist, isoprenaline (1 µM), caused a significant increase in firing rate of 0.22 ± 0.06 Hz (n = 5, p < 0.01) above baseline (1.29 ± 0.28 Hz). The increase was prevented by propranolol (10 µM, -0.01 ± 0.03 Hz, n = 4, p > 0.05), confirming the activation of β-adrenoceptors. In addition, dopamine (50 µM), when applied in the presence of the dopamine D2 receptor antagonist sulpiride (10 µM), caused a similar excitatory response (increase of 0.42 ± 0.04 Hz, n = 70, p < 0.001) which was also blocked by propranolol (10 µM, n = 7, p < 0.05). Dopamine-induced excitation was still seen in the presence of the D1 and D2 dopamine receptor antagonist flupenthixol (30 µM, 0.25 ± 0.02 Hz, n = 4, p < 0.01) or the α1-adrenoceptor antagonist prazosin (1 µM, 0.31 ± 0.10 Hz, n = 5, p < 0.05), showing selective activation of β-adrenoceptors.

β-adrenoceptors are, therefore, present in the VTA and mediate an excitatory effect, which can also be induced by dopamine. The effect may also lead to long-lasting plastic changes in dopamine neurons that underlie drug addiction.

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2. Grenhoff, J et al. (1995) Eur J Neurosci 7: 1707-1713

3. Fricks-Gleason, AN & Marshall, JF (2008) Learn Memory 15: 643-648

4. Otis, JM & Mueller, D (2011) Neuropsychopharmacol 36: 1912-1920

5. Milton, AL et al. (2008) Learn Memory 15: 88-92

6. Kampman, KM et al. (2006) Drug Alcohol Depen 85: 129-137