Acquisition session length modulates consolidation effects produced by 5-HT2C ligands in a mouse autoshaping-operant procedure

Abstract

Although the neurotransmitter, 5-hydroxytryptamine (serotonin, 5-HT), has been implicated as a mediator of learning and memory, the specific role of 5-HT receptors in rodents requires further delineation. In this study, 5-HT2C receptor ligands of varying relative intrinsic efficacies were tested in a mouse learning and memory model called autoshaping-operant. On day 1, mice were placed in experimental chambers and presented with a tone on a variable interval schedule. The tone remained on for 6 s or until a nose-poke response occurred to produce a dipper with Ensure solution. Mice were then injected with saline, MK212 (full agonist), m-chlorophenylpiperazine (partial agonist), mianserin, and SB206 553 (inverse agonists), and methysergide and (+)-2-bromo lysergic acid diethylamide (+)-hydrogen tartrate (neutral antagonists). Each compound was injected after either 1 or 2-h acquisition sessions on day 1 to investigate the role of acquisition session length on consolidation. Day 1 injection of the 5-HT2C inverse agonist mianserin produced greater retrieval impairments of the autoshaped operant response on day 2 than any other agent tested. Furthermore, decreasing the length of the acquisition session to 1h significantly increased the difficulty of the autoshaping task further modulating the consolidation effects produced by the 5-HT2C ligands tested.

Fig. 1

Effects of saline and 5–HT_2C ligands on the consolidation of autoshaped-operant reinforced and nonreinforced responding in mice after 1-h (white bars) and 2-h (black bars) acquisitions sessions on day 1. Vertical axis: left panel, mean-adjusted latency defined as the latency to the tenth minus the latency to the first reinforced response; middle panel, rate of overall dipper hole nose-poke responses per second; right panel, rate of left and right nose-poke responding as a measure of nonreinforced activity. Horizonrtal axis: saline, drugs and doses in mg/kg, administered intraperitoneally. 1-h acquisition session: 32 mg/kg mianserin increased day 2 mean latency relative to saline controls (P < 0.001), MK212 (P < 0.01), SB206 553 (P < 0.01), BOL (P < 0.05) and methysergide (P < 0.01) (left panel); reduced rates of reinforced responding relative to saline (P < 0.01) and 10 mg/kg SB206 553 (P < 0.01) (middle panel); MK212 increased nonreinforced response rates relative to 32 mg/kg mianserin (P < 0.05) and methysergide (P < 0.05) (right panel). 2-h acquisition session: 32 mg/kg mianserin increased day 2 mean latency relative to saline controls (P < 0.05) and all other agents tested (P < 0.05) (left panel); reduced rates of reinforced responding compared with saline controls (P < 0.05), m-chlorophenylpiperazine (mCPP) (P < 0.01), 3.2 mg/kg SB206 553 (P < 0.05) and methysergide (P < 0.01) (middle panel); 10 mg/kg SB206 553 significantly altered rates of nonreinforced responding relative to saline controls, (P < 0.05), MK212 (P < 0.01), mCPP (P < 0.05) and 32 mg/kg mianserin (P < 0.05) (right bars). Number of mice tested during the 1- and 2-h acquisition session, respectively: saline (n = 11, 10), MK212 (n = 5, 5), mCPP (n = 11, 12), (10 mg/kg n = 6, 6; 32 mg/kg n = 6, 9), SB206 553 (3.2 mg/kg n = 6, 4; 10 mg/kg n = 11, 5), BOL (n = 5, 7), and methysergide (n = 5, 9). Twelve mice failed to earn five (1 h) or 10 (2 h) reinforcers during the day 1aquisition session. Vertical bars represent SEM *P < 0.05; **P < 0.01; ***P < 0.001.