Novel Object Recognition

Rodents naturally tend to approach and explore novel objects, which lack of significance for the animals and which have never been paired with a reinforcing stimulus; thus, they show innate preference for novel objects over familiar objects. The rodents approach novel objects and investigate them by touching and sniffing them (Aggleton et al. 1995). The novel object exploration can be evaluated experimentally by testing recognition memory. Briefly, animals are exposed to two identical objects placed in two opposite corners of an apparatus and exploration of the objects is allowed during a period of 2 min. Twenty-four hours later the animals are submitted to an exploration session with a known and a novel object, and the time employed in exploring each object is recorded (Ennaceur and Delacour 1988).

Recognition memory tests are dependent on normal hippocampal functioning when they are tested after longer delays (10 min, 1 h, and 24 h), as shown by the impairment of object recognition after lesions of the hippocampus (Clark et al. 2000). Likewise, inactivation of the dorsal hippocampus through locally infused lidocaine application impairs one-trial object recognition testing with 24 h delay in C57BL/6 mice (Hammond et al. 2004).

Acute tryptophan depletion is a pharmacological procedure to decrease cerebral serotonin levels (Lieben et al. 2004a). Early studies found that serotonin depletion caused by tryptophan depletion impairs object recognition (Lieben et al. 2004b; van Donkelaar et al. 2008). Moreover, dorsal raphe lesion with 5,7-DHT produced a pronounced impairment in object recognition (Lieben et al. 2006). However, chronic administration of fluoxetine also causes object recognition impairment in the rat (Valluzzi and Chan 2007).

Pitsikas and Sakellaridis (2005) evaluated the effect of the administration of 3.0 mg/kg Ro 60-0491, a 5-HT2C receptor antagonist, just after the training trial and evaluated the retention 24 h later, suggesting that the 5-HT2C receptor antagonist modulates the storage and retrieval of information because the drug-treated rats spent more time exploring the novel object than did the saline-treated animals. Moreover, effects on motor activity or exploration were not observed in the drug-treated animals. Siuciak et al. (2007) evaluated the effect of 2-(3-chlorobenzyloxy)-6-(piperazin-1-yl)pyrazine (CP-809101), a potent selective 5-HT2C receptor agonist, in a novel object recognition task and observed an enhancing effect of the drug compared with vehicle-treated mice, because mice treated with CP-809101 (1 mg/kg SC) spent significantly more time exploring novel objects. In this work, the authors applied the drug before the first exposure to the objects, in a manner such that the effects could influence the acquisition process, consolidation, or both.

At present, few works address the participation of 5-HT2C receptors in recognition memory and data from the previous studies presented here were obtained from experimental animals of different species and several schedules of drug administration; hence, well-supported proposals about the nature of 5-HT2C receptor participation in these cognitive phenomena could not easily be done.

In summary, experimental data from pharmacological studies concerning 5-HT2C receptor participation in the hippocampal-related learning process have not yielded consistent evidence. Few studies have suggested a role for 5-HT2C receptors in the modulation of place learning ability, and most of the obtained results indicate a hypolocomotion influence on escape latency, a parameter that has been used as the index of learning in the Morris water maze. It seems that path lengths must be analyzed in place learning evaluations under the actions of 5-HT2C agonist or antagonist compounds in order to discard the influence of drug-induced locomotor alterations. With regard to tests with spatial components such as DNMTP, compounds with affinity for 5-HT2C receptors have not elicited effects. Finally, inconsistent results have been obtained in object recognition memory tests in which antagonists or agonists improve recognition memory (see Table 24.2).

In view of the influence of 5-HT2C receptors on hippocampal physiology, we believe that exhaustive analysis at behavioral, biochemical, and electrophysiologi-cal levels addressing the role of 5-HT2C receptors must be conducted.

Table 24.2 Hippocampal dependent learning modulation by 5-HT2C receptors

Approach

Dose, Via

Task

Effect

Main result (Reference)

Mutant mice

WM

Impairment

Used no hippocampal

(no functional

strategy (Tecott et al.

5-HT2C

1998)

receptors)

TFMPP

5.0 mg/kg, i.p.

WM: RM/

No effect

Latencies increased by

5-HT2C agonist

WM

hypolocomotion (Kant et al. 1996)

DOI

0.1 and

WM: RM/

No effect

Latencies increased by

1.p.

WM

hypolocomotion (Kant et al. 1998)

mCPP

1.0, 3.0, 5.0 mg/

WM

Impairment

Latencies increased.

5-HT1B/2A/2C agonist

kg, i.p.

Possibly due to hypolocomotion (Khaliq et al. 2008)

DOI

100 and 300 mg/

DNMTP

No effect

Affect only reversal

5-HT2A/2B/2C agonist

kg, i.p.

learning (Ruotsalainen et al. 1998)

Ro 60-0491

3.0 mg/kg, i.p.

OR

Improvement

More time exploring novel

5-HT2C antagonist

object (Pitsikas and Sakellaridis 2005)

CP-809,101

1.0 mg/kg, s.c.

OR

Improvement

More time exploring the

5-HT2C agonist

novel object (Siuciak et al. 2007)

DNMTP delayed not matching to place task, WM water maze, RM reference memory, WM working memory, OR object recognition task

DNMTP delayed not matching to place task, WM water maze, RM reference memory, WM working memory, OR object recognition task

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