Phosphodiesterase 4 inhibition affects both the direct and indirect pathway: an electrophysiological study examining the tri-phasic response in the substantia nigra pars reticulata.

Fronto-striatal circuits constitute the neurobiological basis of many neuropsychiatric disorders. Part of the intracellular signaling within these circuits, including its dopaminergic modulation, is regulated by the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling cascade. Based on the overall expression in human fronto-striatal circuitry, we tested the effects of a cAMP selective phosphodiesterase 4 (PDE4) inhibitor on the tri-phasic response in the dorsomedial substantia nigra pars reticulata (SNr) upon stimulation of the infralimbic cortex in rats. Our results show for the first time that stimulation of the cognitive infralimbic cortex leads to a tri-phasic response in SNr neurons. In addition and in line with previous biochemical and behavioral studies, PDE4 inhibition by roflumilast affects the direct pathway as well as the indirect pathway of which the latter appears more sensitive than the former.

Spike-timing relationship of neurochemically-identified dorsal raphe neurons during cortical slow oscillations.

The firing activity of dorsal raphe neurons is related to arousal state. However, it is unclear how this firing activity is precisely related to cortical activity, in particular oscillations occurring during sleep rhythms. Here we conducted single-cell extracellular recordings and juxtacellular labelling while monitoring electrocorticogram (ECoG) activity in urethane anaesthetised rats, to relate activity in neurochemically identified groups of neurons to cortical slow-wave activity (SWA). We observed that electrophysiological heterogeneity in dorsal raphe neurons revealed different neurochemical groups of DRN neurons and was mirrored by significant differences in the phase and strength of coupling to the cortical slow oscillations. Spike firing relationship of clock-like neurons, identified as 5-HT (5-hydroxytryptamine) or serotonin neurons, was higher during the inactive component of the oscillations. In contrast, half of the identified bursting 5-HT neurons did not exhibit strong cortical entrainment; those that did fired most during the inactive component of the SWA. Two groups of putatively non-5-HT neurons (irregular slow-firing and fast-firing) exhibited significant coherence and fired most during the active component of the SWA. These findings indicate that within the DRN electrophysiologically and neurochemically discrete neuronal groups exhibit distinct relations to cortical activity.

Phasic responses in dorsal raphe serotonin neurons to noxious stimuli.

Serotonin is widely implicated in aversive processing. It is not clear, however, whether serotonin neurons encode information about aversive stimuli. We found that, in the dorsal raphe of anesthetized rats, most neurochemically-identified clocklike serotonin neurons were phasically excited by noxious footshocks, whereas most bursting serotonin neurons were inhibited. These results suggest that discrete groups of serotonin neurons differentially code for aversive stimuli.