SELECTIVE DOPAMINE D4 RECEPTOR ACTIVATION SHIFTS THE BALANCE BETWEEN CORTICO-HIPPOCAMPAL DELTA AND THETA OSCILLATIONS IN AWAKE FREELY MOVING RATS
Authors: Kocsis *Bernat , Kuang Junyi , Kafetzopoulos Vasileios , Deth Richard 
Published: February 2025

Abstract

Background
The present study used electrophysiological recordings in freely behaving rats to investigate the effects of Dopamine 4 receptor (D4R) activation on slow oscillations during waking states, in which these rhythms play an essential role in interregional communication between prefrontal cortex (PFC) and hippocampus (HC). Network oscillations are essential for all cognitive functions. Oscillatory deficits are well established in psychiatric diseases and are recapitulated in animal models [1-3]. They are significantly and specifically affected by pharmacological interventions using psychoactive compounds [4-8]. D4R activation was shown to enhance gamma rhythm in PFC and HC of freely moving rats [7] and to specifically affect slow delta and theta oscillations in the urethane anesthetized rat model [8].

Aims and Objectives
The goal of this study was to test the effect of D4R activation on slow network oscillations at delta and theta frequencies during wake states, potentially supporting enhanced functional connectivity during dopamine-induced attention and cognitive processing. The second goal of this study was to test the potential D4R effect on the balance of frequency-tagged bidirectional relationships between the PFC and HC in freely moving rats by recording from the thalamic nucleus reuniens (RE) which provides an anatomical link between the two structures in both directions.

Method
Network activity was recorded in the PFC, HC, and RE, in control conditions and after injecting the selective D4R agonist A-412997 (3 and 5 mg/kg, systemic administration). Delta (1-4Hz) and theta (5-10Hz) peak power and coherences were analyzed in two post-injection segments, the first immediately after injection with visible alterations (19+/-3 min, range: 5-40 min) and the second lasting until the first sleep period (19+/-2 min; range: 5-36 min) and statistically compared with controls, 20-50 min episodes with motor activity pre-injection and 6.5+/-1.0, 11.3+/-1.2, and 16.3+/-0.6 hours after injection.

Results
We found that systemic administration of A-412997 elicited lasting (~40 min) wake state and drastically enhanced narrow-band delta oscillations in the PFC and RE. The effect was dose-dependent, being significant after 5 mg/kg but not after 3 mg/kg drug injection. In contrast, moderate increase in theta power did not show region or dose-dependence, but appeared in all structures after both doses. The frequency of theta oscillations decreased in most experiments, being significant over the group at the lower dose. A-412997 also preferentially enhanced delta synchrony over theta coupling within the PFC-RE-HC circuit, strongly strengthening PFC-RE coupling.

Discussion & Conclusion
The present data demonstrate involvement of D4R mechanisms in reorganization of the structure of theta-delta coupling in the PFC-RE-HC network. In conjunction with our prior studies [7, 8], this shows that administration of a D4R agonist elicits a lasting awake state, enhanced gamma activity, and preferentially enhanced synchronous delta activity over theta coupling within the PFC-RE-HC circuit. Modulation of fast beta and gamma network oscillations, by slow delta and theta rhythms play a key role in behavior-dependent interregional, cortico-hippocampal coupling. Thus, our findings indicate that the D4R may contribute to cognitive processes, at least in part, through acting on wake delta oscillations.

References
1.Lanre-Amos, T. &Kocsis, B. Hippocampal oscillations in the rodent model of schizophrenia induced by amygdala GABA receptor blockade. Front Psychiatry 1, 132 (2010).
2.Pittman-Polletta, B.R., Kocsis, B., Vijayan, S., Whittington, M.A. &Kopell, N.J. Brain rhythms connect impaired inhibition to altered cognition in schizophrenia. Biol Psychiatry 77, 1020-1030 (2015).
3.Pittman-Polletta, B., Hu, K. &Kocsis, B. Subunit-specific NMDAR antagonism dissociates schizophrenia subtype-relevant oscillopathies associated with frontal hypofunction and hippocampal hyperfunction. Sci Rep 8, 11588 (2018).
4.Hajos, M., Hoffmann, W.E. &Kocsis, B. Activation of cannabinoid-1 receptors disrupts sensory gating and neuronal oscillation: relevance to schizophrenia. Biol Psychiatry 63, 1075-1083 (2008).
5.Kocsis, B. Differential role of NR2A and NR2B subunits in N-methyl-D-aspartate receptor antagonist- induced aberrant cortical gamma oscillations. Biol Psychiatry 71, 987-995 (2012).
6.Ly, S., Pishdari, B., Lok, L.L., Hajos, M. &Kocsis, B. Activation of 5-HT6 receptors modulates sleep-wake activity and hippocampal theta oscillation. ACS Chem Neurosci 4, 191-199 (2013).
7.Kocsis, B., Lee, P. &Deth, R. Enhancement of gamma activity after selective activation of dopamine D4 receptors in freely moving rats and in a neurodevelopmental model of schizophrenia. Brain Struct Funct 219, 2173-2180 (2014).
8.Thorn, C.W., Kafetzopoulos, V. &Kocsis, B. Differential Effect of Dopamine D4 Receptor Activation on Low-Frequency Oscillations in the Prefrontal Cortex and Hippocampus May Bias the Bidirectional Prefrontal-Hippocampal Coupling. Int J Mol Sci 23 (2022).