Enhancing excitability of dopamine neurons promotes motivational behaviour through increased action initiation.

Motivational deficits are a key symptom in multiple psychiatric disorders, including major depressive disorder, schizophrenia and addiction. A likely neural substrate for these motivational deficits is the brain dopamine (DA) system. In particular, DA signalling in the nucleus accumbens, which originates from DA neurons in the ventral tegmental area (VTA), has been identified as a crucial substrate for effort-related and activational aspects of motivation. Unravelling how VTA DA neuronal activity relates to motivational behaviours is required to understand how motivational deficits in psychiatry can be specifically targeted. In this study, we therefore used designer receptors exclusively activated by designer drugs (DREADD) in TH:Cre rats, in order to determine the effects of chemogenetic DA neuron activation on different aspects of motivational behaviour. We found that chemogenetic activation of DA neurons in the VTA, but not substantia nigra, significantly increased responding for sucrose under a progressive ratio schedule of reinforcement. More specifically, high effort exertion was characterized by increased initiations of reward-seeking actions. This effect was dependent on effort requirements and instrumental contingencies, but was not affected by sucrose pre-feeding. Together, these findings indicate that VTA DA neuronal activation drives motivational behaviour by facilitating action initiation. With this study, we show that enhancing excitability of VTA DA neurons is a viable strategy to improve motivational behaviour.

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

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.