Mechanical Stimulation Alters Chronic Ethanol-Induced Changes to VTA GABA Neurons, NAc DA Release and Measures of Withdrawal

Abstract

Therapeutic activation of mechanoreceptors (MStim) in osteopathy, chiropractic and acupuncture has been in use for hundreds of years with a myriad of positive outcomes. It has been previously shown to modulate the firing rate of neurons in the ventral tegmental area (VTA) and dopamine (DA) release in the nucleus accumbens (NAc), an area of interest in alcohol-use disorder (AUD). In this study, we examined the effects of MStim on VTA GABA neuron firing rate, DA release in the NAc, and behavior during withdrawal from chronic EtOH exposure in a rat model. We demonstrate that concurrent administration of MStim and EtOH significantly reduced adaptations in VTA GABA neurons and DA release in response to a reinstatement dose of EtOH (2.5 g/kg). Behavioral indices of EtOH withdrawal (rearing, open-field crosses, tail stiffness, gait, and anxiety) were substantively ameliorated with concurrent application of MStim. Additionally, MStim significantly increased the overall frequency of ultrasonic vocalizations, suggesting an increased positive affective state.

Whole-Body Vibration Prevents Neuronal, Neurochemical, and Behavioral Effects of Morphine Withdrawal in a Rat Model

“…As WBV has previously been shown to decrease EtOH-induced changes to NAc DA release [ 60 ], WBV effects on morphine-induced changes to NAc DA release were next observed. Dialysate samples were collected from the NAc before and after a 1 mg/kg morphine challenge in isoflurane-anesthetized rats ( Figure 2 ).…”

“…We have previously demonstrated that VTA GABA neurons develop tolerance to an acute opioid challenge and enhanced baseline firing rate during opioid withdrawal [ 43 ]. As WBV reduces EtOH effects on VTA GABA neurons [ 60 ], we hypothesized that WBV would similarly reduce morphine effects on VTA GABA neurons. We recorded VTA GABA neuron firing rate in vivo under isoflurane anesthesia in rats that had undergone five days of saline or morphine injections with or without concurrent WBV treatment ( Figure 1 ).…”

“…We next examined the effect of WBV on anxiety related to opioid withdrawal, a common factor in opioid use relapse [ 7 , 8 , 9 ]. As we have previously shown that WBV reduces anxiety associated with EtOH withdrawal [ 60 ], we hypothesized that WBV would also reduce anxiety associated with morphine withdrawal. The relative level of anxiety displayed in rats was measured via the elevated-plus maze [ 62 ] before rats received any drug or treatment (“baseline”), after 5 days of drug and treatment administration (“intoxicated”), and 24-h after the final drug administration wherein morphine-dependent rats had entered a withdrawal state (“withdrawal”).…”

“…Further, projections from the NAc then cause a depression in VTA GABA neuron firing, which results in VTA DA neuron disinhibition and a subsequent increase in firing. We have recently reported that WBV at frequencies shown in these previous studies to modify VTA neuronal activity and enhance DA release reduces neuronal and behavioral indices of withdrawal from EtOH, including anxiety [ 60 ]. The current study was designed to investigate if these neuromodulatory changes by WBV are sufficient to alter sub-chronic opioid effects on VTA GABA neurons, DA release, DOR expression on CINs in the NAc, and anxiety in the elevated-plus maze procedure.…”

“…VTA effects are driven by cholinergic interneurons (CINs) and DOR number and translocation in the NAc [ 59 ]. Furthermore, we have shown that whole-body vibration (WBV) at 80 Hz reduces adaptations in VTA GABA neurons and DA release in response to a reinstatement dose (2.5 g/kg) of ethanol (EtOH) [ 60 ]. Behavioral indices of EtOH withdrawal (e.g., anxiety) were also substantively ameliorated with concurrent application of WBV, and WBV significantly increased the overall frequency of ultrasonic vocalizations, suggesting an increased positive affective state [ 61 ].…”