Noradrenergic Transmission at Alpha1-Adrenergic Receptors in the Ventral Periaqueductal Gray Modulates Arousal

Abstract

Background.-Dysregulation of arousal is symptomatic of numerous psychiatric disorders. Previous research has shown that the activity of dopamine (DA) neurons in the ventral periaqueductal gray (vPAG) tracks with arousal state, and lesions of vPAG DA cells increase sleep. However, the circuitry controlling these wake-promoting DA neurons is unknown. Methods.-The present study combines Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), behavioral pharmacology, electrophysiology, and immunoelectron microscopy in male and female mice to elucidate mechanisms in the vPAG that promote arousal. Results.-DREADD-induced activation of locus coeruleus (LC) projections to the vPAG or vPAG DA neurons promoted arousal. Similarly, agonist stimulation of vPAG α1-adrenergic receptors (α1ARs) increased latency to fall asleep, while α1AR blockade had the opposite effect. α1AR stimulation drove vPAG DA activity in a glutamate-dependent, action potential-independent

Central norepinephrine transmission is required for stress-induced repetitive behavior in two rodent models of obsessive-compulsive disorder

“…Guanfacine and prazosin, but not propranolol, dramatically reduced MB. These results are consistent with the literature implicating a1AR activation in behavioral reactivity to novelty (Stone et al 2006), maintenance of generalized arousal (Broese et al 2012;Porter-Stransky et al 2019;Stone et al 2003), and stress-induced anxiety (Rasmussen et al 2016;Skelly et al 2014).…”

Noradrenergic circuits in the forebrain control affective responses to novelty

“…We found that over the course of 1 h, NE-deficient mice exhibited reduced locomotor activity and more rapid habituation in the novel test environment compared to control mice. These findings are congruent with previous reports from our lab and suggest that novelty may have reduced incentive value or intrinsic salience in NE-deficient animals (Cubells et al 2016;Porter-Stransky et al 2019;Weinshenker et al 2002a). Importantly, novel environments elicit an initial increase in locomotion in Dbh -/-mice that habituates over time, suggesting that spatial memory mechanisms that distinguish novel and familiar environments remain intact in the absence of NE.…”

Dopamine neurons in the ventral periaqueductal gray modulate isoflurane anesthesia in rats

“…6 Recently, chemogenetic activation of locus coeruleus (LC) inputs to vPAG-DA neurons, or of vPAG-DA neurons directly, delayed sleep latency and promoted arousal in mice. 14 These results also suggest that vPAG-DA neurons have a significant influence on modulating isoflurane anesthesia.…”

“…The ventral periaqueductal gray (vPAG) is a key neuronal region that mediates a variety of behaviors such as pain, fear, anxiety, and wakefulness. 4,14 More than 10 years ago, researchers found that lesions in DA neurons of the ventral periaqueductal gray area (vPAG) promote sleep and that the vPAG has diverse interconnections with arousal-and sleep-relevant regions. 15 We previously found that reductions of vPAG-DA neurons numbers shortened the induction time and prolonged the emergence time from propofol anesthesia, 16 contradicting previous findings that the dopaminergic system only affected recovery processes in general anesthesia.…”