Dopamine neurons in the ventral tegmental area (VTA) are implicated in affective functions. However, it is unclear to what extent dopamine neurons in substantia nigra pars compacta (SNc) play such roles. TH-Cre transgenic mice received adeno-associated viral vectors encoding channelrhodopsin2 (ChR2), halorhodopsin (NpHR), or control vector into the VTA or SNc, resulting in selective expression of these opsins in dopamine neurons. Mice with ChR2 learned instrumental responding to deliver photostimulation into the VTA or SNc and also sought for the compartment where they received photostimulation (i.e., operant place preference). Operant place preference scores were highly correlated with self-stimulation responses. In contrast, mice with NpHR avoided the compartment where they received photostimulation into the VTA, SNc, or dorsal striatum, whereas control mice did not. These observations suggest that the excitation and inhibition of SNc dopamine neurons elicit positive and negative affective effects, respectively, similar to those of VTA dopamine neurons.

Sleep is a vital function of the nervous system that contributes to brain and bodily homeostasis, energy levels, cognitive ability, and other key functions of a variety of organisms. Dysfunctional sleep induces neural problems and is a key part of almost all human psychiatric disorders including substance abuse disorders. The hypnotic effects of cannabis have long been known and there is increasing use of phytocannabinoids and other formulations as sleep aids. Thus, it is crucial to gain a better understanding of the neurobiological basis of cannabis drug effects on sleep, as well as the role of the endogenous cannabinoid system in sleep physiology. In this review article, we summarize the current state of knowledge concerning sleep-related endogenous cannabinoid function derived from research on humans and rodent models. We also review information on acute and chronic cannabinoid drug effects on sleep in these organisms, and molecular mechanisms that may contribute to these effects. We point out the potential benefits of acute cannabinoids for sleep improvement, but also the potential sleep-disruptive effects of withdrawal following chronic cannabinoid drug use. Prescriptions for future research in this burgeoning field are also provided.

Midbrain dopamine neurons are implicated in motivation and learning. However, it is unclear how phasic excitation of dopamine neurons, which is implicated in learning, is involved in motivation. Here we used a self-stimulation procedure to examine how mice seek for optogenetically-induced phasic excitation of dopamine neurons, with an emphasis on the temporal dimension. TH-Cre transgenic mice received adeno-associated viral vectors encoding channelrhodopsin-2 into the ventral tegmental area, resulting in selective expression of the opsin in dopamine neurons. These mice were trained to press on a lever for photo-pulse trains that phasically excited dopamine neurons. They learned to self-stimulate in a fast, constant manner, and rapidly reduced pressing during extinction. We first determined effective parameters of photo-pulse trains in self-stimulation. Lever-press rates changed as a function of the manipulation of pulse number, duration, intensity, and frequency. We then examined effects of interval and ratio schedules of reinforcement on photo-pulse train reinforcement, which was contrasted with food reinforcement. Reinforcement with food inhibited lever pressing for a few seconds, after which pressing was robustly regulated in a goal-directed manner. In contrast, phasic excitation of dopamine neurons robustly potentiated the initiation of lever pressing; however, this effect did not last more than 1 s and quickly diminished. Indeed, response rates markedly decreased when lever pressing was reinforced with inter-reinforcement interval schedules of 3 or 10 s or ratio schedules requiring multiple responses per reinforcement. Thus, phasic excitation of dopamine neurons briefly potentiates the initiation of approach behavior with apparent lack of long-term motivational regulation.