Nucleus accumbens high-frequency stimulation selectively impacts nigrostriatal dopaminergic neurons

Abstract

High-frequency stimulation of the nucleus accumbens, also known as deep brain stimulation (DBS), is currently used to alleviate obsessive compulsive symptoms when pharmacotherapy is ineffective. However, the mechanism by which DBS achieves its therapeutic actions is not understood. Imaging studies and the actions of dopaminergic drugs in untreated patients suggest that the dopamine (DA) system likely plays a role in the pathophysiology of obsessive compulsive disorder. Therefore, we examined whether DBS would impact the DA system as a potential component of its therapeutic actions. The activity of DA neurons in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) were recorded in anesthetized rats under high-frequency stimulation. DA neuron activity was measured in terms of number of neurons firing, average firing rate and firing pattern. DBS of the nucleus accumbens core did not significantly affect VTA activity or discharge pattern. On the other hand, DBS caused a potent decrease in the number of SNc DA neurons firing spontaneously. Such an effect could contribute to the disruption of pathological habit formation in the SNc-dorsal striatal projection system that may have therapeutic implications for the treatment of obsessive compulsive disorder.

Medial septum differentially regulates dopamine neuron activity in the rat ventral tegmental area and substantia nigra via distinct pathways

“…In contrast, cVP inhibition would disinhibit the SNr, inhibiting the SNc, leading to the opposite effect of MS activation on VTA and SNc DA activity shown here. This model is consistent with previous reports showing that inactivation/lesion of the globus pallidus [39,40] and high-frequency stimulation of the NAc [23] also lead to decreases in SNc DA neuron activity.…”

“…Another knowledge gap related to the vSub-NAc-VP pathway is that no studies have examined its role in the regulation of substantia nigra pars compacta (SNc) DA transmission, a region that is affected by NAc stimulation [23] and has a clear role in psychopathology [24]. The comparison between regulation of VTA and SNc by this pathway is imperative because it was recently demonstrated that DREADD inactivation of rostral ventral pallidum (rVP) terminals in VTA prevented cue-induced reinstatement of cocaine-seeking behavior, whereas inactivation of caudal ventral pallidum (cVP) terminals in VTA or rVP terminals in SNc had no effect on cocaine-seeking reinstatement [25].…”

Deep Brain Stimulation in the Nucleus Accumbens for Binge Eating Disorder: a Study in Rats

“… High-frequency DBS of the NAC core inhibits release of dopamine by a decrease in spontaneous firing of dopaminergic neurons of the substantia nigra pars compacta (SNc) via a feedback loop from the striatum. Imbalance in the dopaminergic SNc-dorsal striatum projection system is thought to play a role in pathological habit formation, e.g., in obsessive compulsive disorder (OCD) [ 7 ]. By stimulating NAC core in the anticipatory phase, a decrease in dopamine release reduces craving and thus less eating.…”

“…If electrophysiological gating is dysfunctional, irrelevant (food) cues can lead to pathologic behavior, e.g., overeating. DBS-NAC with 50 Hz activates gamma oscillations and may therefore restore dysfunctional electrophysiological gating [7].…”

Clinical Outcome and Mechanisms of Deep Brain Stimulation for Obsessive-Compulsive Disorder

“…If the result is unexpected, NAc activity successively potentiates when positive and attenuates when negative, which might implicate that the NAc, together with the midbrain dopaminergic system, facilitates reinforcement learning [ 63 ]. Although imaging studies point that DBS directly modulates this activity remains unclear, as NAc-DBS in acute rat brain slices had no effect on the discharge pattern or synchrony of local NAc neurons [ 51 ], and with NAc-DBS, the bursting pattern of dopaminergic neurons in nigrostriatal and mesolimbic areas in healthy anesthetized rats appeared to be unaltered [ 66 ]. One study connected direct local recordings of NAc neurons with surface EEG of the frontal cortex and found top-down-directed synchrony from the frontal cortex to NAc in low-frequency bands during reward anticipation in OCD patients [ 67 ].…”