Preventing morphine reinforcement with high‐frequency deep brain stimulation of the lateral hypothalamic area

Abstract

Deep brain stimulation (DBS) has been proposed as a promising intervention for patients with treatment-refractory substance use disorder. Here, we investigated if high-frequency DBS in the lateral hypothalamic area (LHA) could affect drug-induced reinforcement. Rats were bilaterally implanted with bipolar stimulation electrodes in the LHA and trained to the morphine conditioned place preference. DBS (monophasic square pulses, 130 Hz, 100-microsecond pulse duration and 150 μA) was applied during the morphine-pairing trials (30 minutes daily for 4 days) or drug-free postconditioning test (15 minutes) to determine its effect on the acquisition or expression of morphine reward, respectively. LHA DBS during morphine-conditioning trials blocked subsequent preference for the drug-associated context. In contrast, DBS in the postconditioning phase failed to inhibit expression of morphine-induced conditioned place preference. These results were further controlled by ruling out significant changes by DBS in physical performance and anxiety-like behavior as measured by an open field test and by precluding anhedonia-like behavior as measured by sucrose consumption test. Our results suggest that LHA DBS can prevent development of morphine reward without diminishing the motivation for naturally rewarding stimuli. Therefore, the LHA could be a potential target for research in the field of DBS-based treatment of intractable substance use disorder. Further studies will be necessary to assess the translatability of these findings to the clinic.

Deep Brain Stimulation of the Lateral Hypothalamus Facilitates Extinction and Prevents Reinstatement of Morphine Place Preference in Rats

“…In the present study, we did not observe any change in locomotor activity by DBS. In addition, our previous study showed that LH DBS did not affect locomotor activity, anxiety level, body weight, and sucrose reward (8). But it should be noted that we applied DBS for a very short duration of time (20 min/day for nine days; or 40 min/day for four days in the previous study) that might not be enough to cause the likely complications.…”

“…Another study reported mostly negative results by showing that HF‐DBS of the MFB at the LH did not block amphetamine effect to reduce the threshold for ICSS, whereas it markedly augmented the effect of haloperidol to suppress ICSS reward (10). In our previous study, we have shown that HF‐DBS of the LH during the conditioning trials abolished acquisition of morphine place preference, though it did not affect sucrose consumption as a natural reward (8). Here, we extended previous findings by showing that HF‐DBS of the LH over the extinction phase facilitated the active inhibition of morphine place preference.…”

“…The LH has been subject to DBS‐induced neuromodulation in a number of preclinical studies of reward and addiction. These studies have shown that while DBS of the LH or the adjacent MFB did not affect sucrose (8,9) and ICSS (10) reward seeking, it did abolish morphine‐induced conditioned place preference (8) and cocaine seeking (9). In the present study, we attempted to extend previous findings by examining the effect of LH DBS applied during the extinction phase of morphine place preference on the duration of the phase and the drug priming‐ and stress‐induced reinstatement of morphine seeking behavior.…”

Deep brain stimulation of the orbitofrontal cortex prevents the development and reinstatement of morphine place preference

“…19 Our previous study also showed that DBS-like stimulation of the lateral hypothalamic area blocked morphine reinforcement in rats. 20 Additionally, DBS of the NAc proved effective in reducing subjective craving and abstaining from heroin consumption in a number of therapy-resistant opioidaddicted patients. [21][22][23] Considering the involvement of the OFC in addictive behaviors and the promising results from DBS application in preclinical and clinical studies of addiction, in the present study, we investigated the potential efficacy of DBS in the OFC for controlling addictive-like behaviors in rats.…”

Different Effects of Monophasic Pulses and Biphasic Pulses Applied by a Bipolar Stimulation Electrode in the Rat Hippocampal CA1 Region

“…The DBS commonly utilizes sequences of narrow pulses with a pulse width around 0.1 ms and a pulse frequency ~ 100-200 Hz (termed as high-frequency stimulation, HFS). Charge-balanced biphasic pulses (with a preceding negative pulse immediately followed by a positive one) are usually utilized in clinical DBS for safety [3,4], while negative monophasic pulses are used in animal studies for investigating DBS therapy [5][6][7].…”