Deep brain stimulation of the accumbens increases dopamine, serotonin, and noradrenaline in the prefrontal cortex.

Deep brain stimulation (DBS) of the nucleus accumbens (NAc) is effective in treatment-refractory obsessive-compulsive disorder and major depressive disorder. However, little is known about the neurobiological mechanisms underlying the rapid and effective changes of DBS. One of the hypotheses is that DBS modulates activity of monoamine neurotransmitters. In this study, we evaluated the effects of DBS in the NAc core on the extracellular concentration of monoaminergic neurotransmitters in the medial (mPFC) and orbital prefrontal cortex (OFC). Freely moving rats were bilaterally stimulated in the NAc core for 2 h while dopamine, serotonin, and noradrenaline were measured using in vivo microdialysis in the mPFC and the OFC. We report rapid increases in the release of dopamine and serotonin to a maximum of 177% and 127% in the mPFC and an increase up to 171% and 166% for dopamine and noradrenaline in the OFC after onset of stimulation in the NAc core. These results provide further evidence for the distal effects of DBS and corroborate previous clinical and pre-clinical findings of altered neuronal activity in prefrontal areas.

Unilateral deep brain stimulation in the nucleus accumbens core does not affect local monoamine release.

Recent publications have shown promising results of deep brain stimulation (DBS) in the nucleus accumbens for patients with obsessive compulsive disorder and major depressive disorder. Despite its increasing application in the clinical setting, the neurobiological mechanism of action of DBS is still uncertain. One of the possible effects of DBS might be phasic or tonic changes in monoamine release either locally in the target area or in a distant, connected region. In the present study we investigate whether unilateral DBS of the Nucleus Accumbens Core (NAc core) has a local effect on in vivo monoamine release. Freely moving animals were unilaterally stimulated with 300 µA or 400 µA (120 Hz, pulse width 80 µs) in the NAc core for 5 h. 1h before and during stimulation we measured dopamine, serotonin, their metabolites and noradrenaline using in vivo microdialysis. We found no significant effect of stimulation on extracellular concentrations of monoaminergic neurotransmitters or their metabolites in the NAc core during stimulation. Our results suggest that the rapid effects of DBS in the NAc are not a result of changes in local monoamine release in the NAc core. For future directions it is interesting to note that several microdialysis and electrophysiology studies have shown effects of DBS in areas distant from the stimulation target.

Behavioural effects of trishomocubanes in rats with unilateral 6-hydroxydopamine lesions.

Whilst dopamine replacement improves cardinal features of Parkinson's disease, chronic levodopa administration is associated with dose-related side effects and not all symptoms are ameliorated, necessitating the development of new treatments. Studies of trishomocubanes, a novel group of sigma ligands, have shown enhanced amphetamine-stimulated striatal release of dopamine and a potentially neuroprotective action in vitro and reversal of reserpine-induced catalepsy in vivo. Such effects warrant investigation in animal models of parkinsonism. Our study therefore examines two novel trishomocubane compounds, N-(3'-fluorophenyl)methyl-4-azahexacyclo[5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)]dodecan-3-ol (1) and, N-(3'-fluorophenyl)ethyl-4-azahexacyclo[5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)]dodecan-3-ol (2) in the 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease. A variety of motor behaviours were studied in rats given 6-OHDA lesions. Groups of lesioned rats were given either (1) or (2) or vehicle solution i.p. Acute administration of 3 mg/kg (1) resulted in a decrease in locomotor activity. Twenty-five milligrams per kilogram (2) caused a decrease in locomotor activity at t=10 and t=20 min of the locomotor test but this was not found when (2) was co-administered with either apomorphine or amphetamine. The decreased locomotor activity indicates that (1) and (2) may have sedative/anxiolytic effect(s). However, elevated plus maze data failed to demonstrate anxiolysis with (2). Quantification of dopaminergic neurons did not demonstrate any significant difference in the magnitude of cell loss between drug-treated vs. vehicle treated rats so no neuroprotective effect was demonstrated in this model at the doses utilised.