Chemogenetic activation of dopamine neurons in the ventral tegmental area, but not substantia nigra, induces hyperactivity in rats

Abstract Hyperactivity is a core symptom in various psychiatric disorders, including attention-deficit/hyperactivity disorder, schizophrenia, bipolar disorders, and anorexia nervosa. Although hyperactivity has been linked to dopaminergic signalling, the causal relationship between midbrain dopamine neuronal activity and locomotor hyperactivity remains unknown. In this study, we test whether increased dopamine neuronal activity is sufficient to induce locomotor hyperactivity. To do so, we used designer receptors exclusively activated by designer drugs (DREADD) to chemogenetically enhance neuronal activity in two main midbrain dopamine neuron populations, i.e. the ventral tegmental area (VTA) and substantia nigra pars compacta (SN), in TH:Cre rats. We found that activation of VTA dopamine neurons induced a pronounced and long-lasting hyperactive phenotype, whilst SN dopamine neuron activation only modestly increased home cage locomotion. Furthermore, this hyperactive phenotype was replicated by selective activation of the neuronal pathway from VTA to the nucleus accumbens (NAC). These results show a clear functional difference between neuronal subpopulations in the VTA and SN with regards to inducing locomotor hyperactivity, and suggest that the dopaminergic pathway from VTA to NAC may be a promising target for the treatment of hyperactivity disorders.