Different serotonin receptor agonists have distinct effects on sound-evoked responses in inferior colliculus

Abstract

The neuromodulator serotonin has a complex set of effects on the auditory responses of neurons within the inferior colliculus (IC), a midbrain auditory nucleus that integrates a wide range of inputs from auditory and nonauditory sources. To determine whether activation of different types of serotonin receptors is a source of the variability in serotonergic effects, four selective agonists of serotonin receptors in the serotonin (5-HT) 1 and 5-HT2 families were iontophoretically applied to IC neurons, which were monitored for changes in their responses to auditory stimuli. Different agonists had different effects on neural responses. The 5-HT1A agonist had mixed facilitatory and depressive effects, whereas 5-HT1B and 5-HT2C agonists were both largely facilitatory. Different agonists changed threshold and frequency tuning in ways that reflected their effects on spike count. When pairs of agonists were applied sequentially to the same neurons, selective agonists sometimes affected neurons in ways that were similar to serotonin, but not to other selective agonists tested. Different agonists also differentially affected groups of neurons classified by the shapes of their frequency-tuning curves, with serotonin and the 5-HT1 receptors affecting proportionally more non-V-type neurons relative to the other agonists tested. In all, evidence suggests that the diversity of serotonin receptor subtypes in the IC is likely to account for at least some of the variability of the effects of serotonin and that receptor subtypes fulfill specialized roles in auditory processing.

Fig. 1

Effects of the 5-HT1A receptor agonist 8-OH-DPAT agonist applied at different levels of iontophoretic current to a single neuron. Effects of 8-OH-DPAT on spike count approached saturation at higher levels of ejection current and recovered after cessation of iontophoresis.

Fig. 2

Peristimulus time histograms (PSTHs) of the effects of different drugs on spike count and latency in 5 single inferior colliculus (IC) neurons. Examples do not represent the most extreme changes in spike count or latency because neurons were chosen to illustrate both. Control PSTHs were recorded before iontophoretic ejection of drugs, agonist PSTHs were recorded during iontophoresis, and recovery values were recorded after iontophoresis was stopped. Numbers on each plot represent total spike count. Stimulus envelopes are well in advance of the spike trains at the timescales shown; latencies to the start of the control spike train are 15 ms for serotonin, 14 ms for 8-OH-DPAT, 23 ms for CP93129, 12 ms for DOI, and 13 ms for MK212. Stimuli were: for serotonin, a 10-kHz FM sweep centered at 25 kHz at 20 dB SPL; for 8-OH-DPAT, a 10-kHz FM sweep centered at 25 kHz at 40 dB SPL; for CP93129, a 20-kHz tone at 20 dB SPL; for DOI, a 7-kHz FM sweep centered at 21 kHz at 50 dB SPL; for MK212, a 5-kHz FM sweep centered at 19 kHz at 50 dB SPL. All stimuli were 10 ms in duration. 5-HT = serotonin.

Fig. 3

Effects of agonists in the neuron population. A: percentage of neurons showing significant increases or decreases in spike count (filled bars) and latency (open bars). Sample sizes represent all neurons exposed to a given agonist. B: histograms of the numbers of neurons showing agonist-evoked changes of different sizes for the 5 agonists, expressed as (drug-control)/ control spike counts. Dashed line represents no change in spike count.

Fig. 4

Agonist-evoked changes in threshold and frequency tuning. A, top: changes in threshold, in decibels, for neurons with significant changes in spike count in which thresholds were also measured; sample sizes represent this group of neurons. Values are presented as medians and interquartile ranges. Bottom: population values are presented as histograms of the numbers of neurons with agonist-evoked threshold changes of different sizes. Dashed line marks zero change in threshold. B: normalized changes in bandwidth at 10–20 dB above threshold. Top: values for neurons with significant changes in spike count. Bottom: for the neuron population, presented as in A.

Fig. 5

Comparison of the effects of serotonin and 8-OH-DPAT in 2 single neurons. A: for this neuron, sequential application of serotonin and 8-OH-DPAT induced similarly dramatic increases in spike count, but iontophoresis of the carrier vehicle did not. Stimulus envelope is indicated by the dark bar beneath the PSTHs. Stimulus was a 27.7-kHz tone at 20 dB SPL, with a 10-ms duration. B: for this neuron, sequential application of 8-OH-DPAT and serotonin induced similar decreases in spike count and increases in latency, resulting in a similar firing pattern. Stimulus envelope is too far in advance of the PSTHs to indicate in this plot; the latency to the start of the control spike train is 14 ms. Stimulus is a 10-kHz FM sweep centered at 25 kHz at 40 dB SPL.

Fig. 6

Comparison of the effects of serotonin vs. other agonists presented sequentially in the same neurons. Left: cumulative plot of changes in spike count ((drug-control)/control) evoked by serotonin vs. 8-OH-DPAT in 17 neurons. Right: a similar plot for the effects of serotonin and DOI in a different group of 15 neurons.

Fig. 7

Effects of 8-OH-DPAT vs. 2 other agonists, MK212 (A) and CP93129 (B), in the same neurons. A, left: PSTHs of 2 neurons showing effects of either 8-OH-DPAT or MK212, but not both. Stimuli are: a 5-kHz FM sweep centered at 24 kHz at 70 dB SPL for the neuron on the left and a 10-kHz FM sweep centered at 28 kHz at 10 dB SPL on the right. Right: cumulative plot of the effects of both agonists, applied sequentially, on the spike counts of the same 22 neurons. B, left: PSTHs of 2 neurons showing effects of either 8-OH-DPAT or CP93129, but not both. Stimuli are: a 10-kHz FM sweep centered at 15 kHz at 20 dB SPL for the neuron on the left and a 10-kHz FM sweep centered at 25 kHz at 0 dB SPL on the right. Right: cumulative plot of the effects of both agonists, applied sequentially, on the spike counts of the same 14 neurons. For both A and B, the stimulus envelopes are indicated by the dark bar; all stimuli are 10 ms in duration.

Fig. 8

Effects of agonists on neurons with different types of tuning curves. Agonist effects are presented as the relative proportions of V-type and non-V-type neurons with significantly altered spike counts or latencies within the samples for each agonist. These are normalized for the total number of different types of neurons recorded for each agonist.

Fig. 9

Parsimonious model of the placement of serotonin receptor types within the circuitry of the IC. Aspects of the model are described in the text.