Skip to main content
NCBI home page
The Journal of Physiology logoLink to The Journal of Physiology
. 2005 Nov 3;569(Pt 3):715–721. doi: 10.1113/jphysiol.2005.098269

Excitatory effects of serotonin on rat striatal cholinergic interneurones

Craig Blomeley 1, Enrico Bracci 1
PMCID: PMC1464279  PMID: 16269435

Abstract

We investigated the effects of 5-hydroxytryptamine (5-HT, serotonin) in striatal cholinergic interneurones with gramicidin-perforated whole-cell patch recordings. Bath-application of serotonin (30 μm) significantly and reversibly increased the spontaneous firing rate of 37/45 cholinergic interneurones tested. On average, in the presence of serotonin, firing rate was 273 ± 193% of control. Selective agonists of 5-HT1A, 5-HT3, 5-HT4 and 5-HT7 receptors did not affect cholinergic interneurone firing, while the 5-HT2 receptor agonist α-methyl-5-HT (30 μm) mimicked the excitatory effects of serotonin. Consistently, the 5-HT2 receptor antagonist ketanserin (10 μm) fully blocked the excitatory effects of serotonin. Two prominent after-hyperpolarizations (AHPs), one of medium duration that was apamin-sensitive and followed individual spikes, and one that was slower and followed trains of spikes, were both strongly and reversibly reduced by serotonin; these effects were fully blocked by ketanserin. Conversely, the depolarizing sags observed during negative current injections and mediated by hyperpolarization-activated cationic currents were not affected. In the presence of apamin and tetrodotoxin, the slow AHP was strongly reduced by 5-HT, and fully abolished by the calcium channel blocker nickel. These results show that 5-HT exerts a powerful excitatory control on cholinergic interneurones via 5-HT2 receptors, by suppressing the AHPs associated with two distinct calcium-activated potassium currents.

The striatum is the main input region of the basal ganglia, and is crucially involved in motor control and action selection. It displays an extremely high content of choline acetyltransferase (Holt et al. 1997), and striatal projection neurones, interneurones and corticostriatal synapses are subject to cholinergic control (Gabel & Nisenbaum, 1999; Koos & Tepper, 2002; Partridge et al. 2002). Striatal acetylcholine is released by local interneurones, characterized by very large somata and aspiny dendrites (Tepper & Bolam, 2004). There is persuasive evidence that these interneurones correspond to the tonically active neurones recorded in vivo, that briefly stop firing in concomitance to behaviourally salient situations and reward-related events (Apicella, 2002; Morris et al. 2004; Yamada et al. 2004; Reynolds et al. 2004). Cholinergic interneurones are a target for neuromodulators such as dopamine and noradrenaline (Aosaki et al. 1998; Pisani et al. 2003). Serotonin, a crucial neurotransmitter involved in a variety of brain functions (Aghajanian & Sanders-Bush, 2000) and neuropsychiatric disorders, is released in the striatum by dense projections from the raphe (Steinbusch, 1981; Imai et al. 1986; Pickel & Chan, 1999). Serotonin receptors are abundant in the striatum (Ward & Dorsa, 1996; Hoyer et al. 2002), where they affect single-unit responses to drugs of abuse (Ball & Rebec, 2005). To cast light on the cellular action of serotonin in the striatum we therefore investigated its effects on cholinergic interneurones with non-invasive, perforated-patch techniques.

Methods

Wistar rats (16–24 days postnatal) were killed, in accordance with the UK Animals Act 1986, by cervical dislocation; coronal brain slices (300 μm thick) were maintained at 25°C in oxygenated solution (composition, mm: 126 NaCl, 2.5 KCl, 1.3 MgCl2, 1.2 NaH2PO4, 2.4 CaCl2, 10 glucose, 18 NaHCO3). For recordings, slices were submerged, superfused (2–3 ml min−1) at 25°C and visualized with infrared microscopy. Current-clamp recordings were performed in bridge mode using an Axoclamp-2B amplifier. Gramicidin-perforated whole-cell recordings were obtained with patch pipettes (2–5 MΩ) filled with a solution containing (mm): 125 potassium gluconate, 10 NaCl, 1 CaCl2, 2 MgCl2, 1 BAPTA, 19 Hepes, 0.3 guanosine triphosphate, 2 Mg-ATP, and adjusted to pH 7.3 with KOH. Gramicidin was dissolved in dimethylsulfoxide (10 mg ml−1) and then diluted in the intrapipette solution to a final concentration of 10–20 μg ml−1. The tip of the pipette was filled with gramicidin-free intracellular solution. The perforation process was considered complete when (i) the amplitude of the action potentials was steady and > 60 mV, and (ii) electrode resistance (measured with bridge compensation) was steady and < 50 MΩ. Infrequently, an abrupt increase in the amplitude of the action potentials was observed, signalling that the membrane had ruptured, and the experiment was immediately terminated. Spike threshold was defined as the point where the temporal derivative of the membrane potential exceeded 10 mV ms−1. Values are expressed as mean ± standard deviation and statistical comparisons were made (unless otherwise stated) by Student's t test. All drugs were obtained from Tocris UK, apart from 5-HT hydrochloride, Gramicidin and NBQX, which were obtained from Sigma UK.

Results

Effects of serotonin on spontaneous firing

Large-size cholinergic interneurones were visually targeted and electrophysiologically identified based on: (i) the prominent medium AHP (mAHP) following individual spikes; (ii) the slow AHP (sAHP) following positive current injections which increased (or triggered) firing; and (iii) the depolarizing sag which developed during current-induced hyperpolarization (Bennett et al. 2000; Wilson, 2005; see inset of Fig. 1). Gramicidin-perforated techniques were essential to preserve the stability of these cells' properties (Wilson, 2005).

Figure 1. Serotonin increases the spontaneous firing rate of cholinergic interneurones.

Figure 1

Open in a new tab

A and B, bath-application of 30 μm serotonin strongly and reversibly increased spike frequency in two cells which displayed high (A) or low (B) spontaneous firing rates in control solution (note different time scale). Typical responses of a cholinergic interneurone to current injections are shown in the inset below B. C, distribution of 30 μm serotonin effects on firing rate of responsive cells as a function of the spontaneous firing rate in control solution. D, average effects of different serotonin concentrations on spike frequency of cholinergic interneurones.

As previously reported (Bennett et al. 2000), most cholinergic interneurones (63/75) were spontaneously active. In these cells, the average interspike interval (ISI) in control ACSF ranged from 0.095 to 14.86 s, corresponding to a frequency range of 0.067–10.5 Hz. The average ISI across the spontaneously active cells was 2.17 ± 2.10 s (0.46 Hz).

Bath-application of serotonin (30 μm) significantly (P < 0.05) reduced the average ISI in 37/45 (82%) spontaneously active neurones. The effects of serotonin were reversible on washout. In the remaining 8/45 cells, no significant change in ISI was observed. In this subgroup of cells, subsequent application of higher concentrations of serotonin (120–240 μm) also failed to elicit a significant change in ISI. The spontaneous firing rate of these cells was not significantly different from that of the other neurones. We concluded that this subpopulation of cells was not responsive to serotonin.

When data from all 45 cells were pooled together, the average spike frequency in the presence of 30 μm serotonin was 273 ± 193% of that observed in control. Two representative examples of the action of serotonin on two cholinergic interneurones with different levels of spontaneous firing rate in control solution are shown in Fig. 1A and B. Correlation analysis showed that the effects of serotonin did not significantly depend on the level of spontaneous activity in control (correlation coefficient r = −0.13; P > 0.05), as illustrated in the raster plot of Fig. 1C.

The spontaneous activity of cholinergic interneurones and the excitatory effects of serotonin were not significantly affected by application of the ionotropic glutamate receptor antagonists nitro-7-sulfamoyl-[f]-quinoxaline-2,3-dione (NBQX; 20 μm) and d-amino-phosphonovalerate (AP5; 20 μm) (n = 5).

We tested the effects on cholinergic interneurone firing rate of different serotonin concentrations in the range 7.5–240 μm. The average effects on spike frequency for each concentration tested are illustrated in Fig. 1D. This plot was obtained by expressing the frequency observed for each concentration in a given cell as percentage of control, and then pooling together the normalized data from each cell (both responsive and non-responsive cells were included). An analysis of variance (ANOVA) test for multiple groups revealed that there was a significant dependence of the effects on serotonin concentration (P < 0.05). Further paired comparisons revealed that the effects of 7.5 μm were significantly (P < 0.05) smaller than those of 30 μm and higher concentrations, while the differences among other concentrations were not statistically significant.

The use of gramicidin-perforated patch techniques was essential to observe the effects of serotonin. Conventional whole-cell recordings revealed significant (P < 0.05) effects of 30 μm serotonin on the average ISI only in 2/12 cholinergic interneurones, in which the spike frequency was increased by < 20%.

Pharmacology of serotonin effects

In order to identify the serotonin receptors involved in these effects, we used selective ligands of 5-HT receptor classes.

The following selective agonists of postsynaptically located serotonin receptors found in the basal ganglia failed to significantly affect the average ISI of cholinergic interneurones in all cells tested: 8-OH-DPAT (5-HT1A receptor; 100 μm; n = 22); m-chlorophenyl-biguanide (5-HT3 receptor; 10 μm; n = 6); RS 67333 (5-HT4 receptor; 100 μm; n = 4); 5-carboxamidotryptamine (5-HT7 receptor; 10 μm; n = 6).

On the other hand, the excitatory effects of serotonin were mimicked by the broad spectrum 5-HT2 receptor agonist α-methyl-5-HT (30 μm), as shown in the example of Fig. 2A. In 8/10 cells α-methyl-5-HT significantly (P < 0.001) decreased the average ISI. On average, in the 10 cells tested, in the presence of α-methyl-5-HT, spike frequency increased to 564 ± 674% of control.

Figure 2. The 5-HT2 receptor antagonist ketanserin reverses the effects of serotonin on the firing rate of cholinergic interneurones.

Figure 2

Open in a new tab

A, bath-application of the 5-HT2 receptor agonist α-methyl-5-HT (30 μm) strongly increased the spontaneous firing rate of a cholinergic interneurone; subsequent application of ketanserin (10 μm) reduced the firing rate to a level lower than control. B, similarly, bath-application of 30 μm serotonin increased the firing rate of another cholinergic interneurone; subsequent application of ketanserin (10 μm) reduced the firing rate to a level lower than control. C, average effects of serotonin and serotonin plus ketanserin on spike frequency. Data from 5 cells were normalized to average control solution value (100%).

The excitatory effects of serotonin or α-methyl-5-HT were fully reversed by application of the 5-HT2 receptor antagonist ketanserin (10 μm), as shown in the examples of Fig. 2A and B. In a sample of five neurones from different preparations, in which serotonin significantly (P < 0.001) decreased the ISI, further application of ketanserin (in the presence of 5-HT) increased the ISI to a level which was significantly (P < 0.001) larger than those observed either in the presence of serotonin or in control solution (see plot of Fig. 2C). When applied without 5-HT, ketanserin also markedly reduced the spontaneous firing activity of cholinergic interneurones (n = 4). On average, the ISI significantly (P < 0.05) increased to 255 ± 126% of control after ketanserin application.

These results showed that 5-HT2 receptors were responsible for the excitatory effects of serotonin in cholinergic interneurones, and suggested that endogenous serotonin present in the slices was enough to significantly activate 5-HT2 receptors.

Conductances modulated by 5-HT

We then investigated the membrane mechanisms modulated by 5-HT. Cholinergic interneurones display a prominent cationic current activated by hyperpolarization (Ih), which is modulated by other neurotransmitters (Pisani et al. 2003); Ih is also affected by serotonin in other brain areas (Erdemli & Crunelli, 2000). This current gives rise to slow depolarizing sags during negative current injections (Bennett et al. 2000), as apparent in the inset in Fig. 1. The amplitude and time course of the depolarizing sag (measured with 500 ms, 100–200 pA negative current injections delivered from the same membrane potential level) were not significantly affected by serotonin application (n = 6; not shown). We concluded that Ih was not modulated by 5-HT.

Another current which is prominent in cholinergic interneurones is the apamin-sensitive, calcium-activated potassium current, which gives rise to the mAHPs that follow individual spikes (Bennett et al. 2000). The amplitude of the mAHP (measured from spike threshold level to the negative peak following the spike) was on average 10.6 ± 0.5 mV. As previously reported (Bennett et al. 2000), bath-application of apamin (100 nm) strongly reduced the mAHP and induced a bursting behaviour in cholinergic interneurones (n = 4). In control solution, the mAHP was strongly and reversibly reduced by 5-HT, as shown in the example of Fig. 3A. For a better comparison of the mAHPs, in the presence of serotonin a small negative current was injected into the cells to achieve firing rates similar to control. On average, in 10 neurones selected for this analysis, the amplitude of the mAHP was significantly (P < 0.001) reduced by 29.0 ± 2.6% (Fig. 3C). Bath application of ketanserin (in the presence of 5-HT) reversed this effect, and in 6/6 cases increased the mAHP amplitude to levels significantly (P < 0.001) higher than control (Fig. 3B and C). We concluded that one of the cellular effects of 5-HT2 receptor activation is a strong reduction in the apamin-sensitive currents responsible for mAHP.

Figure 3. Serotonin strongly reduces the medium AHP (mAHP) of cholinergic interneurones.

Figure 3

Open in a new tab

A, serotonin application reversibly reduced the mAHP amplitude in a cholinergic interneurone. Traces in A and B (same calibrations) represent the average of 5 events (grey traces) ±s.d. (black traces). B, in a different neurone, serotonin reduced the mAHP amplitude, while subsequent application of ketanserin increased this amplitude to more than control level. C, average effects of serotonin and serotonin plus ketanserin on the mAHP amplitude (data from 10 cells were normalized to average control solution value (100%)).

Positive current injections which elicit or increase firing in cholinergic interneurones are followed by large-amplitude, slow AHPs (sAHPs) which last several seconds, and have not been fully characterized. We tested whether serotonin affected the sAHP. As the amplitude of the sAHP depended on the number of spikes generated, in each pharmacological condition we manually clamped the cell at a membrane potential level similar to that observed in control solution, and injected current steps (1 s) that elicited the same number of spikes as in control. As shown in the example of Fig. 4A, the sAHP was strongly reduced in the presence of 5-HT, and this effect was fully reversed by subsequent application of ketanserin. On average, in four cells, serotonin significantly (P < 0.001) reduced the sAHP amplitude to 52 ± 21% of control. Addition of ketanserin caused the sAHP amplitude to recover to 104 ± 4% of control. For better control of the membrane potential levels in the absence of spikes, we then performed another series of experiments in the presence of the sodium channel blocker tetrodotoxin (TTX; 1 μm). Apamin (100 nm) was also applied during these experiments to block the conductances responsible for the mAHP, and isolate the sAHP. Under these conditions, large amplitude sAHPs (8.9 ± 1.9 mV) were observed after a 2 s positive current injection which depolarized the cell from resting membrane potential (−55 to −65 mV) to a fixed depolarized level (−10 to +5 mV), as illustrated in Fig. 4B. The current-induced depolarizations were characterized by slow negative sags (7.5 ± 4.4 mV; black arrows in Fig. 4B). These sags, and the sAHPs (grey arrows) were not significantly affected by 100 μm barium (n = 5), which selectively blocks a hyperpolarization-activated K+ current that can amplify hyperpolarizations in cholinergic neurones (Wilson, 2005). On the other hand, block of calcium channels by NiCl (1 mm; n = 6) completely abolished negative sags and sAHPs (Fig. 4C), suggesting that these slow waveforms were due to calcium-activated potassium currents.

Figure 4. Serotonin strongly reduces the slow AHP (sAHP) of cholinergic interneurones.

Figure 4

Open in a new tab

A, in control solution, serotonin strongly reduced the sAHPs (arrows) induced by positive current steps, and this effect was reversed by subsequent addition of ketanserin. B, in a different cell, in the presence of TTX (1 μm) and apamin (100 nm), a current injection caused depolarizations followed by negative sags (black arrows); after the end of the step, sAHPs (grey arrows) were present. Serotonin (30 μm) strongly and reversibly reduced both the sag and the sAHP. Calibrations as in C. C, in the same cell as in B, NiCl (1 mm) abolished the sag and the sAHP; in the presence of NiCl serotonin failed to affect the current-induced depolarization. D and E, average serotonin effects (in the presence of TTX and apamin) on the negative sag amplitude (D) and on the sAHP amplitude (E). Data pooled from 11 cells and normalized to control solution average values.

In the presence of apamin and TTX, serotonin did not induce significant changes in the membrane potential of cholinergic interneurones (n = 11). However, serotonin strongly and reversibly reduced both the negative sags and the sAHPs (Fig. 4B). These effects, which were statistically significant (P < 0.001) in all 11 cells tested, are quantified in the plot of Fig. 4D. A small after-depolarization also appeared after serotonin application in 2/11 cells (Fig. 4B). When applied in the presence of NiCl, serotonin did not affect the waveforms elicited by depolarizing current injections (n = 6), as shown in Fig. 4C. We concluded that 5-HT2 receptor activation did not affect leak conductances, but strongly decreased the apamin-insensitive, calcium-activated potassium currents responsible for the sAHPs.

Discussion

These results show that striatal cholinergic interneurones are strongly excited by serotonin, that this action is mediated by 5-HT2 receptors and involves a reversible reduction of two pharmacologically and kinetically distinct AHPs.

In studying these effects, it was crucial not to interfere with the intracellular milieu of the cholinergic interneurones. When performed with conventional whole-cell recordings, serotonin effects were typically absent or very weak, presumably because the metabotropic action of 5-HT2 receptors was disrupted. Gramicidin-perforated recordings allowed us to record from cholinergic interneurones for several hours without any apparent deterioration of their properties (Wilson, 2005). Under these conditions, serotonin strongly increased the spontaneous firing rate of most (> 80%) cholinergic interneurones. The remaining cells did not respond to any concentration of serotonin up to 240 μm; their firing frequency did not differ from average, suggesting that lack of serotonin effects was not due to saturation of 5-HT2 receptors by endogenous serotonin, and that they may belong to a subpopulation that does not express functional 5-HT2 receptors.

Striatal cholinergic interneurones are spontaneously active both in vivo and in vitro, thanks to a dynamic interplay of several voltage-dependent membrane conductances (Wilson, 2005) Among these, the conductances responsible for the medium and slow AHPs are particularly prominent (Bennett et al. 2000; Wilson, 2005), and play an important role in limiting the excitability of cholinergic interneurones. The mAHP sets a lower limit for the interspike interval (Stocker, 2004). The slow AHP provides a powerful negative feedback mechanism which tends to limit the duration of any excitatory input (Wilson, 2005).

The mAHP is due to SK calcium-activated potassium channels and is blocked by apamin (Bennet et al. 2000). The identity of the sAHP in cholinergic interneurones has not been fully characterized; mAHPs can be amplified by a fast, inward rectifier K+ current (KIR) sensitive to 100 μm barium (Wilson, 2005). In our experiments the sAHP observed in the presence of TTX and apamin was insensitive to barium (probably because the threshold for the auto-regenerative activation of KIR was not reached), and was completely abolished by nickel, suggesting that it was due to slow calcium-activated potassium currents similar to those observed in other regions of the brain (Stocker, 2004). Room temperature (25°C) conditions may have accentuated the serotonin effects; at this temperature, cholinergic interneurone spontaneous firing is slower than at 32°C (Bennett & Wilson, 1999), and slow AHPs are enhanced by slower removal of cytosolic calcium (Thompson et al. 1985). On the other hand, the effects of temperature on excitatory synaptic potentials (Vogalshev et al. 2000) are unlikely to have affected the present experiments, as the observed effects persisted in the presence of ionotropic glutamate receptor blockers.

Neuromodulation of the mAHP or sAHP has not been reported so far for cholinergic interneurones. In hippocampal pyramidal neurones, the sAHP has been shown to be suppressed by monoamine neurotransmitters through activation of protein kinase A (Stocker, 2004) and by muscarinic receptor activation (Egorov et al. 1999). Interestingly, 5-HT4 and 5-HT7 receptor activation reduces the sAHP in hippocampal neurones (Torres et al. 1994; Bacon & Beck, 2000). There is evidence that the action of neurotransmitters on the sAHP in hippocampal neurones is exerted directly on the underlying calcium-activated potassium conductances, rather than on calcium channels (Sah & Faber, 2002). In motoneurones, the mAHP is reduced by serotonin through 5-HT1A receptor-mediated inhibition of calcium channels (Bayliss et al. 1995). On the other hand, recent evidence has shown that 5-HT1A receptor activation can also directly affect SK channels that underlie the mAHP (Grunnet et al. 2004). A direct action of serotonin on calcium-dependent potassium conductances, is also consistent with the observation that G-protein-coupled 5-HT2 receptors increase the hydrolysis of inositol phosphates and elevate cytosolic calcium (Hoyer et al. 2002).

Further experiments will be required to determine whether, in cholinergic interneurones, serotonin directly inhibits calcium-dependent potassium channels, or whether its action is due to suppression of calcium channels. Producing evidence will pose serious challenges; calcium-dependent potassium channels are functionally coupled to different subtypes of voltage-activated calcium channels (including L-, N-, P-, R- and T-types) in different neuronal types (Stocker, 2004), and recent work by Goldberg and Wilson (2005) has shown that in striatal cholinergic interneurons Cav2.2 (N-type) calcium channels are functionally associated with the mAHP, while Cav1 (L-type) are selectively associated with the sAHP. Furthermore, studying calcium channel modulation by serotonin will require voltage-clamp experiments, which are difficult to perform with gramicidin-perforated patch techniques, due to the high access resistance of the electrode (Wilson, 2005). High-resolution calcium imaging will perhaps be required to resolve this issue. The absence of effects on membrane potential in the presence of TTX suggests that leak conductances were not modulated by serotonin.

Our pharmacological experiments straightforwardly identified 5-HT2 receptors as responsible for serotonin effects. These G-coupled receptors are abundant in the striatum (Ward & Dorsa, 1996) and modulate neurones in other brain areas, although their ability to affect the AHPs has not been reported so far. The observation that the 5-HT2 receptor antagonist ketanserin (when applied without 5-HT) reduced the spontaneous firing of cholinergic interneurones to levels lower than those observed in control solution suggests that endogenous serotonin in the slice significantly activated 5-HT2 receptors, and this activation was abolished by ketanserin. Alternatively, ketanserin may have acted as an inverse agonist, shifting the balance of 5-HT2 receptors towards the non-active conformational state (Dupre et al. 2004).

Cholinergic interneurones fire tonically in vivo, and changes in their firing activity encode behaviourally relevant information (Yamada et al. 2004; Morris et al. 2004). In the striatum, a host of pre- and postsynaptic membrane mechanisms are controlled by acetylcholine. These membrane mechanisms will undergo phasic changes according to the variations in firing rate of local cholinergic interneurones. The ability of serotonin to strongly increase this firing suggests that the operation of the striatal networks is profoundly affected by serotonin release. Thus, the present data provide a novel cellular explanation for the serotoninergic control of the striatum, which may be relevant for the development of new rational therapies for motor and psychiatric illnesses.

Acknowledgments

This work was supported by the Wellcome Trust Project Grant 071943. We thank Mrs Lidan Christie for excellent technical assistance, and Dr John Turner for critical reading of the manuscript.

References

  1. Aghajanian & Sanders-Bush. Serotonin. In: Davis KL, Charney D, Coyle JT, Nemeroff C, editors. Neuropsychopharmacology, The Fifth Generation of Progress. Philadelphia: Lippincott Williams & Wilkins; 2002. pp. 15–34. [Google Scholar]
  2. Aosaki T, Kiuchi K, Kawaguchi Y. Dopamine D1-like receptor activation excites rat striatal large aspiny neurons in vitro. J Neurosci. 1998;15:5180–5190. doi: 10.1523/JNEUROSCI.18-14-05180.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Apicella P. Tonically active neurons in the primate striatum and their role in the processing of information about motivationally relevant events. Eur J Neurosci. 2002;16:2017–2026. doi: 10.1046/j.1460-9568.2002.02262.x. [DOI] [PubMed] [Google Scholar]
  4. Bacon WL, Beck SG. 5-Hydroxytryptamine7 receptor activation decreases slow afterhyperpolarization amplitude in CA3 hippocampal pyramidal cells. J Pharmacol Exp Ther. 2000;294:672–679. [PubMed] [Google Scholar]
  5. Ball KT, Rebec GV. Role of 5-HT2A and 5-HT2C/B receptors in the acute effects of 3,4-methylene-dioxymethamphetamine (MDMA) on striatal single-unit activity and locomotion in freely moving rats. Psychopharmacology. 2005;6:1–12. doi: 10.1007/s00213-005-0038-z. [DOI] [PubMed] [Google Scholar]
  6. Bayliss DA, Umemiya M, Berger AJ. Inhibition of N- and P-type calcium currents and the after-hyperpolarization in rat motoneurones by serotonin. J Physiol. 1995;15:635–647. doi: 10.1113/jphysiol.1995.sp020758. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bennett BD, Callaway JC, Wilson CJ. Intrinsic membrane properties underlying spontaneous tonic firing in neostriatal cholinergic interneurons. J Neurosci. 2000;15:8493–8503. doi: 10.1523/JNEUROSCI.20-22-08493.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Bennett BD, Wilson CJ. Spontaneous activity of neostriatal cholinergic interneurons in vitro. J Neurosci. 1999;19:5586–5596. doi: 10.1523/JNEUROSCI.19-13-05586.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dupre DJ, Rola-Pleszczynski M, Stankova J. Inverse agonism: more than reverting constitutively active receptor signaling. Biochem Cell Biol. 2004;82:676–680. doi: 10.1139/o04-128. [DOI] [PubMed] [Google Scholar]
  10. Egorov AV, Gloveli T, Muller W. Muscarinic control of dendritic excitability and Ca2+ signaling in CA1 pyramidal neurons in rat hippocampal slice. J Neurophysiol. 1999;82:1909–1915. doi: 10.1152/jn.1999.82.4.1909. [DOI] [PubMed] [Google Scholar]
  11. Erdemli G, Crunelli V. Release of monoamines and nitric oxide is involved in the modulation of hyperpolarization-activated inward current during acute thalamic hypoxia. Neuroscience. 2000;96:565–574. doi: 10.1016/s0306-4522(99)00602-8. [DOI] [PubMed] [Google Scholar]
  12. Gabel LA, Nisenbaum ES. Muscarinic receptors differentially modulate the persistent potassium current in striatal spiny projection neurons. J Neurophysiol. 1999;81:1418–1423. doi: 10.1152/jn.1999.81.3.1418. [DOI] [PubMed] [Google Scholar]
  13. Goldberg JA, Wilson CJ. Control of spontaneous firing patients by the selective coupling of calcium currents to calcium-activated potassium currents in striatal cholinergic interneurons. J Neurosci. 2005;44:10230–8. doi: 10.1523/JNEUROSCI.2734-05.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Grunnet M, Jespersen T, Perrier JF. 5-HT1A receptors modulate small-conductance Ca2+-activated K+ channels. J Neurosci Res. 2004;15:845–854. doi: 10.1002/jnr.20318. [DOI] [PubMed] [Google Scholar]
  15. Holt DJ, Graybiel AM, Saper CB. Neurochemical architecture of the human striatum. J Comp Neurol. 1997;21:1–25. doi: 10.1002/(sici)1096-9861(19970721)384:1<1::aid-cne1>3.0.co;2-5. [DOI] [PubMed] [Google Scholar]
  16. Hoyer D, Hannon JP, Martin GR. Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav. 2002;71:533–554. doi: 10.1016/s0091-3057(01)00746-8. [DOI] [PubMed] [Google Scholar]
  17. Imai H, Steindler DA, Kitai ST. The organization of divergent axonal projections from the midbrain raphe nuclei in the rat. J Comp Neurol. 1986;15:363–380. doi: 10.1002/cne.902430307. [DOI] [PubMed] [Google Scholar]
  18. Koos T, Tepper JM. Dual cholinergic control of fast-spiking interneurons in the neostriatum. J Neurosci. 2002;15:529–535. doi: 10.1523/JNEUROSCI.22-02-00529.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Morris G, Arkadir D, Nevet A, Vaadia E, Bergman H. Coincident but distinct messages of midbrain dopamine and striatal tonically active neurons. Neuron. 2004;8:133–143. doi: 10.1016/j.neuron.2004.06.012. [DOI] [PubMed] [Google Scholar]
  20. Partridge JG, Apparsundaram S, Gerhardt GA, Ronesi J, Lovinger DM. Nicotinic acetylcholine receptors interact with dopamine in induction of striatal long-term depression. J Neurosci. 2002;1:2541–2549. doi: 10.1523/JNEUROSCI.22-07-02541.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Pickel VM, Chan J. Ultrastructural localization of the serotonin transporter in limbic and motor compartments of the nucleus accumbens. J Neurosci. 1999;1:7356–7366. doi: 10.1523/JNEUROSCI.19-17-07356.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Pisani A, Bonsi P, Centonze D, Martorana A, Fusco F, Sancesario G, et al. Activation of β1-adrenoceptors excites striatal cholinergic interneurons through a cAMP-dependent, protein kinase-independent pathway. J Neurosci. 2003;15:5272–5282. doi: 10.1523/JNEUROSCI.23-12-05272.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Reynolds JN, Hyland BI, Wickens JR. Modulation of an afterhyperpolarization by the substantia nigra induces pauses in the tonic firing of striatal cholinergic interneurons. J Neurosci. 2004;3:9870–9877. doi: 10.1523/JNEUROSCI.3225-04.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Sah P, Faber ES. Channels underlying neuronal calcium-activated potassium currents. Prog Neurobiol. 2002;66:345–353. doi: 10.1016/s0301-0082(02)00004-7. [DOI] [PubMed] [Google Scholar]
  25. Steinbusch HW. Distribution of serotonin-immunoreactivity in the central nervous system of the rat-cell bodies and terminals. Neuroscience. 1981;6:557–618. doi: 10.1016/0306-4522(81)90146-9. [DOI] [PubMed] [Google Scholar]
  26. Stocker M. Ca2+-activated K+ channels: molecular determinants and function of the SK family. Nat Rev Neurosci. 2004;5:758–770. doi: 10.1038/nrn1516. [DOI] [PubMed] [Google Scholar]
  27. Tepper JM, Bolam JP. Functional diversity and specificity of neostriatal interneurons. Curr Opin Neurobiol. 2004;14:685–692. doi: 10.1016/j.conb.2004.10.003. [DOI] [PubMed] [Google Scholar]
  28. Thompson SM, Masukawa LM, Prince DA. Temperature dependence of intrinsic membrane properties and synaptic potentials in hippocampal CA1 neurons in vitro. J Neurosci. 1985;5:817–824. doi: 10.1523/JNEUROSCI.05-03-00817.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Torres GE, Holt IL, Andrade R. Antagonists of 5-HT4 receptor-mediated responses in adult hippocampal neurons. J Pharmacol Exp Ther. 1994;271:255–261. [PubMed] [Google Scholar]
  30. Vogalshev M, Vidyasagar TR, Christiakova M, Eysel UT. Synaptic transmission in the neocortex during reversible cooling. Neuroscience. 2000;98:9–22. doi: 10.1016/s0306-4522(00)00109-3. [DOI] [PubMed] [Google Scholar]
  31. Ward RP, Dorsa DM. Colocalization of serotonin receptor subtypes 5-HT2A, 5-HT2C, and 5-HT6 with neuropeptides in rat striatum. J Comp Neurol. 1996;1:405–414. doi: 10.1002/(SICI)1096-9861(19960701)370:3<405::AID-CNE10>3.0.CO;2-R. [DOI] [PubMed] [Google Scholar]
  32. Wilson CJ. The mechanism of intrinsic amplification of hyperpolarizations and spontaneous bursting in striatal cholinergic interneurons. Neuron. 2005;17:575–585. doi: 10.1016/j.neuron.2004.12.053. [DOI] [PubMed] [Google Scholar]
  33. Yamada H, Matsumoto N, Kimura M. Tonically active neurons in the primate caudate nucleus and putamen differentially encode instructed motivational outcomes of action. J Neurosci. 2004;7:3500–3510. doi: 10.1523/JNEUROSCI.0068-04.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The Journal of Physiology are provided here courtesy of The Physiological Society

RESOURCES