Cortical dopamine D5 receptors regulate neuronal circuit oscillatory activity and memory in rats.

INTRODUCTION: The dopamine D5 receptor (D5R) shows high expression in cortical regions, yet the role of the receptor in learning and memory remains poorly understood. This study evaluated the impact of prefrontal cortical (PFC) D5R knockdown in rats on learning and memory and assessed the role of the D5R in the regulation of neuronal oscillatory activity and glycogen synthase kinase-3 (GSK-3ß), processes integral to cognitive function. MATERIALS AND METHODS: Using an adeno-associated viral (AAV) vector, male rats were infused with shRNA to the D5R bilaterally into the PFC. Local field potential recordings were taken from freely moving animals and spectral power and coherence were evaluated in, and between, the PFC, orbitofrontal cortex (OFC), hippocampus (HIP), and thalamus. Animals were then assessed in object recognition, object location, and object in place tasks. The activity of PFC GSK-3ß, a downstream effector of the D5R, was evaluated. RESULTS: AAV-mediated knockdown of the D5R in the PFC induced learning and memory deficits. These changes were accompanied by elevations in PFC, OFC, and HIP theta spectral power and PFC-OFC coherence, reduced PFC-thalamus gamma coherence, and increased PFC GSK-3ß activity. CONCLUSION: This work demonstrates a role for PFC D5Rs in the regulation of neuronal oscillatory activity and learning and memory. As elevated GSK-3ß activity has been implicated in numerous disorders of cognitive dysfunction, this work also highlights the potential of the D5R as a novel therapeutic target via suppression of GSK-3ß.

The Antidepressant-Like and Analgesic Effects of Kratom Alkaloids are accompanied by Changes in Low Frequency Oscillations but not ΔFosB Accumulation.

Mitragyna speciosa ("kratom"), employed as a traditional medicine to improve mood and relieve pain, has shown increased use in Europe and North America. Here, the dose-dependent effects of a purified alkaloid kratom extract on neuronal oscillatory systems function, analgesia, and antidepressant-like behaviour were evaluated and kratom-induced changes in ΔFosB expression determined. Male rats were administered a low or high dose of kratom (containing 0.5 or 1 mg/kg of mitragynine, respectively) for seven days. Acute or repeated low dose kratom suppressed ventral tegmental area (VTA) theta oscillatory power whereas acute or repeated high dose kratom increased delta power, and reduced theta power, in the nucleus accumbens (NAc), prefrontal cortex (PFC), cingulate cortex (Cg) and VTA. The repeated administration of low dose kratom additionally elevated delta power in PFC, decreased theta power in NAc and PFC, and suppressed beta and low gamma power in Cg. Suppressed high gamma power in NAc and PFC was seen selectively following repeated high dose kratom. Both doses of kratom elevated NAc-PFC, VTA-NAc, and VTA-Cg coherence. Low dose kratom had antidepressant-like properties whereas both doses produced analgesia. No kratom-induced changes in ΔFosB expression were evident. These results support a role for kratom as having both antidepressant and analgesic properties that are accompanied by specific changes in neuronal circuit function. However, the absence of drug-induced changes in ΔFosB expression suggest that the drug may circumvent this cellular signaling pathway, a pathway known for its significant role in addiction.

Transient Dose-dependent Effects of Ketamine on Neural Oscillatory Activity in Wistar-Kyoto Rats.

Ketamine is a promising therapeutic for treatment-resistant depression (TRD) but is associated with an array of short-term psychomimetic side-effects. These disparate drug effects may be elicited through the modulation of neural circuit activity. The purpose of this study was to therefore delineate dose- and time-dependent changes in ketamine-induced neural oscillatory patterns in regions of the brain implicated in depression. Wistar-Kyoto rats were used as a model system to study these aspects of TRD neuropathology whereas Wistar rats were used as a control strain. Animals received a low (10 mg/kg) or high (30 mg/kg) dose of ketamine and temporal changes in neural oscillatory activity recorded from the prefrontal cortex (PFC), cingulate cortex (Cg), and nucleus accumbens (NAc) for ninety minutes. Effects of each dose of ketamine on immobility in the forced swim test were also evaluated. High dose ketamine induced a transient increase in theta power in the PFC and Cg, as well as a dose-dependent increase in gamma power in these regions 10-min, but not 90-min, post-administration. In contrast, only low dose ketamine normalized innate deficits in fast gamma coherence between the NAc-Cg and PFC-Cg, an effect that persisted at 90-min post-injection. These low dose ketamine-induced oscillatory alterations were accompanied by a reduction in immobility time in the forced swim test. These results show that ketamine induces time-dependent effects on neural oscillations at specific frequencies. These drug-induced changes may differentially contribute to the psychomimetic and therapeutic effects of the drug.