Amphetamine promotes cortical Up state: Role of adrenergic receptors

Abstract

Cortical neurons oscillate synchronously between the Up and Down state during slow-wave sleep and general anesthesia. Using local-field-potential recording in the rat prefrontal cortex (PFC), we have shown that systemic administration of methylphenidate promotes PFC Up states and reduces PFC slow oscillation, suggesting a depolarizing effect of the drug on PFC neurons. Here, we report that systemic injection of d-amphetamine produced similar effects. Our evidence further suggests that norepinephrine (NE) plays a major role in the effects of damphetamine since they were mimicked by the NE reuptake inhibitors tomoxetine and nisoxetine and completely blocked by the α 1 receptor antagonist prazosin. The effects of d-amphetamine persisted, however, in the presence of α 2 or β receptor blockade. Experiments with α 1 subtype-selective antagonists further suggest that d-amphetamine's effects depend on activation of central, but not peripheral, α 1A receptors. Unexpectedly, the putative α 1 receptor agonist cirazoline failed to mimic the effects of d-amphetamine. Previous studies suggest that cirazoline is also an antagonist at α 2 receptors. Furthermore, it is a partial, not full, agonist at α 1B and α 1D receptors. Whether or not these properties of cirazoline contribute to its failure to mimic d-amphetamine's effects remains to be determined. Methylphenidate and d-amphetamine are two most common medications for attention-deficit/hyperactivity disorder (ADHD). Both, however, are associated with adverse effects including abuse potential and psychotomimetic effects. Further understanding of their mechanisms of action will help develop safer treatments for ADHD and offer new insights into drug addiction and psychosis.

D-Amphetamine Accelerates Recovery of Consciousness and Respiratory Drive After High-Dose Fentanyl in Rats

“…Because the fentanyl dose chosen was very high and meant to mimic a fentanyl overdose, we chose the highest d-amphetamine dose (3 mg/kg) previously tested to maximize its effects when testing our hypothesis in this study. The effects of d-amphetamine in the absence of other drugs has been studied extensively in the context of neurophysiology (Lapish et al, 2012;Shen and Shi, 2020) and cardiorespiratory physiology (Mediavilla et al, 1979;Lin et al, 1980). However, future studies should include d-amphetamine dose-response studies to determine whether lower doses have differential effects on consciousness and respiration.…”

Amphetamine Promotes Cortical Up State in Part Via Dopamine Receptors

“…Throughout the experiment, body temperature was maintained at 36–37°C with a homeothermic blanket system (Harvard Apparatus, Holliston, MA). Local field potentials (LFPs) were recorded using methods described previously (Dela Peña et al, 2018 ; Shen et al, 2018 ; Shen and Shi, 2021 ). Briefly, glass electrodes were filled with sodium acetate (0.5 M) and pontamine sky blue (1%) and lowered into the medial PFC (from bregma: AP 2.8–3.2 mm, ML 0.5–1 mm, DV 2.5–3.5 mm) using a motorized microdrive (864/1, Harvard Apparatus).…”

“…The sign of LFPs was reversed so that upward deflections represent transitions to Up states. The slow drift in LFPs, caused by a 0.1 Hz high-pass filter used during recording, was estimated and removed using the Asymmetric Least Squares Smoothing method ( Shen et al, 2018 ; Shen and Shi, 2021 ). The voltage distribution of LFPs was computed every 10 s. LFPs above 0 mV were considered in Up states.…”

“…Evidence suggests that Up/Down oscillations during sleep and quiet wakefulness are crucial to memory consolidation, whereas their transition to a persistent Up state is essential for arousal and attention ( Harris and Thiele, 2011 ; Lee and Dan, 2012 ; Mcginley et al, 2015 ). In chloral hydrate-anesthetized rats, we have shown that D -amphetamine as well as methylphenidate dose-dependently increases the time that the prefrontal cortex (PFC) spends in the Up state (T UP ) ( Shen and Shi, 2021 ). Our evidence further suggests that this Up-state promoting effect of D -amphetamine depends on activation of central α 1A adrenergic receptors.…”

“…Our evidence further suggests that this Up-state promoting effect of D -amphetamine depends on activation of central α 1A adrenergic receptors. However, the selective dopamine (DA) transporter blocker GBR12909 also increases T UP , though its effect is smaller than that induced by a selective norepinephrine (NE) reuptake inhibitor ( Shen and Shi, 2021 ). This finding and the fact that D -amphetamine increases the release of both NE and DA ( Kuczenski and Segal, 1997 ; Rothman et al, 2001 ) point to the possibility that D -amphetamine promotes cortical Up state via both NE and DA receptors.…”