Role of the serotonin 5-HT(2A) receptor in learning

Abstract

This study reviews the role of the serotonin 5-HT2A receptor in learning as measured by the acquisition of the rabbit's classically conditioning nictitating membrane response, a component of the eyeblink response. Agonists at the 5-HT2A receptor including LSD (d-lysergic acid diethylamide) enhanced associative learning at doses that produce cognitive effects in humans. Some antagonists such as BOL (d-bromolysergic acid diethylamide), LY53,857, and ketanserin acted as neutral antagonists in that they had no effect on learning, whereas others (MDL11,939, ritanserin, and mianserin) acted as inverse agonists in that they retarded learning through an action at the 5-HT2A receptor. These results were placed in the context of what is known concerning the anatomical distribution and electrophysiological effects of 5-HT2A receptor activation in frontal cortex and hippocampus, as well as the role of cortical 5-HT2A receptors in schizophrenia. It was concluded that the 5-HT2A receptor demonstrates constitutive activity, and that variations in this activity can produce profound alterations in cognitive states.

Figure 1

Enhancement of associative learning produced by the 5-HT_2A agonist LSD under different experimental conditions. The ordinate presents the mean percent conditioned responses (CRs) during each of 10 conditioning days derived from a minimum of 10 animals per group. (A,B,C,D) The dose of LSD was 13 μg/kg (0.030 μmole/kg) administered intravenously into the marginal ear vein of the rabbit. Conditioning of the NM response was based on a delay procedure using an 800-msec CS, whose offset occurred simultaneously with the onset of a 100-msec unconditioned stimulus (US). (A) Acquisition of the conditioned nictitating membrane (NM) response (a component of the eyeblink) during tone CS and corneal airpuff US conditioning (Schindler et al. 1985a); (B) acquisition of the NM response during tone CS and paraorbital shock US conditioning (Gimpl et al. 1979); (C) Acquisition of the appetitive jaw movement (JM) response during pairings of tone CS and water US in water-deprived rabbits. Jaw movements are produced during the ingestion of water, and during conditioning, these movements begin to be initiated to the tone CS prior to water presentation (Gormezano et al. 1980); (D) acquisition of the NM response to tone or light CSs paired with a shock US. The intensity of the tone CS had been adjusted so as to support the same rate of conditioning as the light CS (Schindler et al. 1985b).

Figure 2

Enhancement of associative learning produced by the 5-HT_2A agonist LSD (13 μg/kg) at different CS–US intervals. Acquisition of the NM response during the pairing of a tone CS and paraorbital shock US. A trace procedure was employed using a 100-msec tone and shock US. Thus, the 0-msec CS–US interval indicates the simultaneous presentation of the stimuli and the 100 msec CS–US interval represents a delay procedure (0 trace). The 200-, 400-, and 800-msec CS–US intervals represent trace conditioning of 100, 300, and 500 msec, respectively. Data are taken from Harvey et al. (1988).

Figure 3

The relationship between the mean percentage of CRs generated by various NM conditioning procedures in control animals (abscissa) and the degree of enhancement of learning produced by LSD (13 μg/kg). The effects of LSD are expressed as an acquisition ratio, calculated as the mean percentage of CRs for animals injected with LSD divided by the mean percentage of CRs for their respective controls. Data were taken from Gimpl et al. (1979), Harvey et al. (1982, 1988), Schindler et al. (1985a,b), and Welsh et al. (1998a,b).

Figure 4

Retardant effect of MDL11,939, ritanserin, and mianserin on acquisition of NM response as a function of dose. Drugs were injected subcutaneously 1 h prior to each conditioning session. Conditioning used the pairing of a tone CS with an air puff US. Drug effects are expressed as the percentage of vehicle controls. Data are taken from Welsh et al. (1998b) and Romano et al. (2000).

Figure 5

Antagonism by ritanserin (1 μmole/kg) of the enhancement of CR acquisition produced by LSD (0.030 μmole/kg). Ritanserin was injected subcutaneously 60 min prior and LSD intravenously 20 min prior to each acquisition session. Acquisition of the NM response was measured during the pairing of a tone CS and air puff US. Data are taken from Welsh et al. (1998a).

Figure 6

Antagonism by BOL (5.8 μmole/kg) of the retardant effects of mianserin (10 μmole/kg) on acquisition of the NM response. Mianserin was injected 1 h and BOL 20 min prior to each conditioning session by use of the pairing of a tone CS and air puff US. All injections were subcutaneous. Data are taken from Romano et al. (2000).