Objective: Hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels are known to be involved in the generation of absence seizures (ASs), and there is evidence that cortical and thalamic HCN channel dysfunctions may have a proabsence role. Many HCN channel blockers are available, but their role in ASs has been investigated only by localized brain injection or in in vitro model systems due to their limited brain availability. Here, we investigated the effect on ASs of orally administered ivabradine (an HCN channel blocker approved for the treatment of heart failure in humans) following injection of the P‐glycoprotein inhibitor elacridar, which is known to increase penetration into the brain of drug substrates for this efflux transporter. The action of ivabradine was also tested following in vivo microinjection into the cortical initiation network (CIN) of the somatosensory cortex and in the thalamic ventrobasal nucleus (VB) as well as on cortical and thalamocortical neurons in brain slices.Methods: We used electroencephalographic recordings in freely moving Genetic Absence Epilepsy Rats From Strasbourg (GAERSs) to assess the action of oral administration of ivabradine, with and without elacridar, on ASs. Ivabradine was also microinjected into the CIN and VB of GAERSs in vivo and applied to Wistar CIN and GAERS VB slices while recording patch‐clamped cortical Layer 5/6 and thalamocortical neurons, respectively.Results: Oral administration of ivabradine markedly and dose‐dependently reduced ASs. Ivabradine injection into CIN abolished ASs and elicited small‐amplitude 4–7‐Hz waves (without spikes), whereas in the VB it was less potent. Moreover, ivabradine applied to GAERS VB and Wistar CIN slices selectively decreased HCN channel‐dependent properties of cortical Layer 5/6 pyramidal and thalamocortical neurons, respectively.Significance: These results provide the first demonstration of the antiabsence action of a systemically administered HCN channel blocker, indicating the potential of this class of drugs as a novel therapeutic avenue for ASs.

Aims: Serotonergic (5‐HT) modulation of the lateral habenula (LHb) activity is central in normal and pathologic conditions such as mood disorders. Among the multiple 5‐HTreceptors (5‐HTRs) involved, the 5‐HT_2CR seems to play a pivotal role. Yet, the role of 5‐HT_2ARs in the control of theLHb neuronal activity is completely unknown.Methods: Single‐cell extracellular recording of theLHb neurons was used in rats to study the effect of the general activation and blockade of the 5‐HT_2CR and 5‐HT_2AR with Ro 60‐0175 andSB242084,TCB‐2 andMDL11939, respectively. The expression of both receptors in theLHb was confirmed using immunohistochemistry.Results: Cumulative doses (5‐640 μg/kg, iv) of Ro 60‐0175 andTCB‐2 affected the activity of 34% and 63% of theLHb recorded neurons, respectively.LHb neurons were either inhibited at low doses or excited at higher doses of the 5‐HT_2A/CR agonists.SB242084 orMDL11939 (both at 200 μg/kg, iv) did not modify neuronal firing when injected alone, but reverted the bidirectional effects of Ro 60‐0175 orTCB‐2, respectively. 5‐HT_2CRs and 5‐HT_2ARs are expressed in less than the 20% of theLHb neurons, and they neither colocalize nor make heterodimers. Strikingly, only 5‐HT_2ARs are expressed by the majority ofLHb astrocyte cells.Conclusions: Peripheral administration of 5‐HT_2AR agonist promotes a heterogeneous pattern of neuronal responses in theLHb, and these effects are more prominent than those induced by the 5‐HT_2CR activation.

Nicotine addiction is a serious public health problem causing millions of deaths worldwide. Serotonin (5-hydroxytryptamine; 5-HT) is involved in central nervous system (CNS) nicotine effects, and it has been suggested as a promising pharmacological target for smoking cessation. In this regard, what is particularly interesting are the 5-HT_2A receptors (5-HT_2ARs) and the lateral habenula (LHb), a central area in nicotine addiction that we showed to be under a strong 5-HT_2AR-modulation. Single-cell extracellular recording of LHb neurons was used to study the 5-HT_2AR function by intravenously administrating the potent agonist TCB-2. Acute nicotine (2 mg/kg, intraperitoneal, i.p.) and chronic nicotine (6 mg/kg/day for 14 days) differently affected both the 5-HT_2AR-immuno reactive (IR) neuron number and the 5-HT_2AR immunostaining area in the different brain areas studied. After acute nicotine, TCB-2 cumulative doses (5–640 µg/kg, intravenous, i.v.) bidirectionally affected the activity of 74% of LHb recorded neurons. After chronic nicotine treatment, TCB-2 was only capable of decreasing the LHb firing rate. The expression of 5-HT_2AR under acute and chronic nicotine exposure was studied in the LHb and in other brain areas involved in nicotine effects in rats by using immunohistochemistry. These data reveal that acute and chronic nicotine differentially affect the 5-HT_2AR function in different brain areas and this might be relevant in nicotine addiction and its treatment.

Locus coeruleus (LC) neurons, with their extensive innervations throughout the brain, control a broad range of physiological processes. Several ion channels have been characterized in LC neurons that control intrinsic membrane properties and excitability. However, ERG (ether-à-go-go–related gene) K⁺ channels that are particularly important in setting neuronal firing rhythms and automaticity have not as yet been discovered in the LC. Moreover, the neurophysiological and pathophysiological roles of ERG channels in the brain remain unclear despite their expression in several structures. By performing immunohistochemical investigations, we found that ERG-1A, ERG-1B, ERG-2 and ERG-3 are highly expressed in the LC neurons of mice. To examine the functional role of ERG channels, current-clamp recordings were performed on mouse LC neurons in brain slices under visual control. ERG channel blockade by WAY-123,398, a class III anti-arrhythmic agent, increased the spontaneous firing activity and discharge irregularity of LC neurons. Here, we have shown the presence of distinct ERG channel subunits in the LC which play an imperative role in modulating neuronal discharge patterns. Thus, we propose that ERG channels are important players behind the changes in, and/or maintenance of, LC firing patterns that are implicated in the generation of different behaviors and in several disorders.

Serotonin (5-HT) is important in some nicotine actions in the CNS. Among all the 5-HT receptors (5-HTRs), the 5-HT_2CR has emerged as a promising drug target for smoking cessation. The 5-HT_2CRs within the lateral habenula (LHb) may be crucial for nicotine addiction. Here we showed that after acute nicotine tartrate (2 mg/kg, i.p.) exposure, the 5-HT_2CR agonist Ro 60-0175 (5–640 µg/kg, i.v.) increased the electrical activity of 42% of the LHb recorded neurons in vivo in rats. Conversely, after chronic nicotine treatment (6 mg/kg/day, i.p., for 14 days), Ro 60-0175 was incapable of affecting the LHb neuronal discharge. Moreover, acute nicotine exposure increased the 5-HT_2CR-immunoreactive (IR) area while decreasing the number of 5-HT_2CR-IR neurons in the LHb. On the other hand, chronic nicotine increased both the 5-HT_2CR-IR area and 5-HT_2CR-IR LHb neurons in the LHb. Western blot analysis confirmed these findings and further revealed an increase of 5-HT_2CR expression in the medial prefrontal cortex after chronic nicotine exposure not detected by the immunohistochemistry. Altogether, these data show that acute and chronic nicotine exposure differentially affect the central 5-HT_2CR function mainly in the LHb and this may be relevant in nicotine addiction and its treatment.