Dopamine increases ventral tegmental area dopaminergic neuronal firing by acting on β-adrenoceptors

Helen Morgan, Margaret Gompers, Susanna Hourani, Ying Chen

University of Surrey, Guildford, UK

The ventral tegmental area (VTA) is a midbrain region from which the mesocorticolimbic dopamine (DA) pathways originate. DA neurotransmission in the VTA has been particularly implicated in behavioural sensitization to psychostimulants. DA D1 receptor activation in particular was found to be essential in this process. DA receptors are G-protein coupled and their activation leads to the modulation of the cAMP signalling cascade. DA is also known to inhibit neuronal firing in the VTA via the activation of D2 receptors. Here, we report our observation of an excitatory effect of DA in the VTA and our investigation into the neural mechanisms underlying this effect.

VTA dopaminergic neuronal firing was recorded extracellularly in midbrain slices prepared from male CD1 mice aged 4-12 weeks. We confirmed that the firing rate of DA cells was decreased by dopamine (50 μM) or the specific D2 agonist quinpirole (0.03 - 1 μM). This inhibition was prevented by the D2 antagonist sulpiride (10 μM). However, in the presence of sulpiride (10 μM), the application of DA (50 μM) for 6 min caused a small but consistent increase in firing rate in all neurons recorded (12% from basal firing rate of 1.75Hz ± 0.26, n = 6, p < 0.01, One-way ANOVA). This effect was thus thought to be mediated by DA D1 receptors. However, the application of a D1 –selective agonist SKF38393 (10 μM) did not mimic the effect of DA, and the excitation was not inhibited by the D1 and D2 antagonist flupenthixol (30 μM, n = 4). It is thus unlikely that D1-like receptor activation is involved.

It was previously reported that the VTA receives noradrenergic input from the locus coeruleus. Alpha- adrenergic receptors present on VTA DA neurons were shown to mediate an excitatory effect of noradrenaline (NA) (Grenhoff et al, 1995). We have thus examined whether the excitatory effect of DA could be mediated by adrenoceptors. In the presence of the alpha 1 antagonist prazosin (1 μM), the excitatory effect of DA was still observed (n = 5, p < 0.05). However, in the presence of the beta antagonist propranolol (10 μM), DA failed to increase the firing rate (n = 4, p > 0.05). In addition, isoprenaline (10 μM), a selective beta adrenoceptor agonist, significantly increased the firing rate in the presence of sulpiride (n = 6, p < 0.05). This suggests that the excitation by DA in the VTA was mediated by beta adrenoceptors.

Interaction between DA and NA was previously shown in the VTA with NA activating D2 receptors to inhibit DA neuronal firing. Our results reveal a novel interaction between DA and NA systems in the VTA, with DA activating beta adrenoceptors to increase the excitability of DA cells.

Grenhoff et al, 1995 European Journal Neurosci. 7:1707