1 Dopamine neurons in the ventral tegmental area fire faster in 2 adolescent rats than in adults

20 Adolescence may be a period of vulnerability to drug addiction. In rats, elevated firing activity of 21 ventral tegmental area (VTA) dopamine neurons predicts enhanced addiction liability. Our aim 22 was to determine if dopamine neurons are more active in adolescents than in adults, and to 23 examine mechanisms underlying any age-related difference. VTA dopamine neurons fired faster 24 in adolescents than in adults, measured with in vivo extracellular recordings. Dopamine neuron 25 firing can be divided into non-bursting (single spikes) and bursting activity (clusters of high 26 frequency spikes). Non-bursting activity was higher in adolescents compared with adults. 27 Frequency of burst events did not differ between ages, but bursts were longer in adolescents 28 than in adults. Elevated dopamine neuron firing in adolescent rats was also observed in cell29 attached recordings in ex vivo brain slices. Using whole-cell recordings we found that passive 30 and active membrane properties were similar across ages. Hyperpolarization-activated cation 31 currents (Ih) and small conductance calcium-activated potassium (SK) channel currents were 32 also comparable across ages. We found no difference in dopamine D2-class autoreceptor 33 function across ages, although the high baseline firing in adolescents resulted in autoreceptor 34 activation being less effective at silencing neurons. Finally, AMPA receptor-mediated sEPSCs 35 occurred at lower frequency in adolescents; GABAA receptor-mediated sIPSCs occurred both at 36 lower frequency and smaller amplitude in adolescents. In conclusion, VTA dopamine neurons 37 fire faster in adolescence, potentially because GABA tone increases as rats reach adulthood. 38 This elevation of firing rate during adolescence is consistent with it representing a vulnerable 39 period for developing drug addiction. 40