Effect of 5-HT2A and 5-HT2C receptors on temporal discrimination by mice

Abstract

Timing deficits are observed in patients with schizophrenia. Serotonergic hallucinogens can also alter the subjective experience of time. Characterizing the mechanism through which the serotonergic system regulates timing will increase our understanding of the linkage between serotonin (5-HT) and schizophrenia, and will provide insight into the mechanism of action of hallucinogens. We investigated whether interval timing in mice is altered by hallucinogens and other 5-HT2 receptor ligands. C57BL/6J mice were trained to perform a discrete-trials temporal discrimination task. In the discrete-trials task, mice were presented with two levers after a variable interval. Responding on lever A was reinforced if the interval was <6.5 s, and responding on lever B was reinforced if the interval was >6.5 s. A 2-parameter logistic function was fitted to the proportional choice for lever B (%B responding), yielding estimates of the indifference point (T50) and the Weber fraction (a measure of timing precision). The 5-HT2A antagonist M100907 increased T50, whereas the 5-HT2C antagonist SB-242,084 reduced T50. The results indicate that 5-HT2A and 5-HT2C receptors have countervailing effects on the speed of the internal pacemaker. The hallucinogen 2,5-dimethoxy-4-iodoamphetamine (DOI; 3 mg/kg IP), a 5-HT2 agonist, flattened the response curve at long stimulus intervals and shifted it to the right, causing both T50 and the Weber fraction to increase. The effect of DOI was antagonized by M100907 (0.03 mg/kg SC) but was unaffected by SB-242,084 (0.1 mg/kg SC). Similar to DOI, the selective 5-HT2A agonist 25CN-NBOH (6 mg/kg SC) reduced %B responding at long stimulus intervals, and increased T50 and the Weber fraction. These results demonstrate that hallucinogens alter temporal perception in mice, effects that are mediated by the 5-HT2A receptor. It appears that 5-HT regulates temporal perception, suggesting that altered serotonergic signaling may contribute to the timing deficits observed in schizophrenia and other psychiatric disorders.

Keywords: Discrete-trials; Hallucinogen; Interval timing; Mice; Psychedelic.

Figure 1

(A) Format of the discrete-trials task. (B) Change in proportional choice of lever B (%B responding) for the two extreme stimulus durations (2.5 and 10.5 s) over the first 50 training sessions. The dotted lines show criterion (≥85% correct responding). Data shown are group means±SEM, (C) Number of animals responding at criterion over the first 50 training sessions.

Figure 2

Proportional choice of lever B (%B responding) in 38 mice injected with saline. Data shown are group means±SEM,

Figure 3

Effects of M100907 (A) and SB-242,084 (B) on temporal discrimination. The data shown (group means±SEM) are the proportional choice of lever B (%B responding) as a function of stimulus duration. *Significant difference from the control group, p<0.05. **Significant difference from the control group, p<0.01.

Figure 4

Effect of DOI on temporal discrimination. The data shown (group means±SEM) are the proportional choice of lever B (%B responding) as a function of stimulus duration. *Significant difference from the control group, p<0.05. **Significant difference from the control group, p<0.01.

Figure 5

Effect of pretreatment with 0.03 mg/kg M100907 (A) or 0.1 mg/kg SB-242,084 (B) on the response to 3 mg/kg DOI on temporal discrimination. Vehicle pretreated mice are shown in the left panel, and antagonist pretreated mice are shown in the right panel. The data shown (group means±SEM) are the proportional choice of lever B (%B responding) as a function of stimulus duration. *Significant difference from the control group, p<0.05. ^#Significant difference from DOI alone, p<0.05.

Figure 6

(A) Effect of 25CN-NBOH on the head twitch response (HTR). Mice were treated with 25CN-NBOH and HTR was assessed for 30 minutes. Data shown are group means±SEM for the entire 30 min session. (B) Effect of 25CN-NBOH on temporal discrimination. The data shown (group means±SEM) are the proportional choice of lever B (%B responding) as a function of stimulus duration. *Significant difference from the control group, p<0.05. **Significant difference from the control group, p<0.01.