Both selleck bio the hippocampus and amygdala are involved in contextual fear conditioning, whereas only the amygdala is involved in cued fear conditioning (Frankland, Cestari, Filipkowski, McDonald, & Silva, 1998; Maren, Aharonov, & Fanselow, 1997; Phillips & LeDoux, 1992; Rudy, Huff, & Matus-Amat, 2004; Wehner & Radcliffe, 2004). Thus, amygdala-dependent learning was likely impaired in ��4 knockout mice to a larger extent than hippocampus-dependent learning. ��4-Containing nAChRs in Affective Behaviors Our results showed that ��4?/? mice tended to exhibit less anxiety-like behavior compared with ��4+/+ mice in the light�Cdark box as measured by the number of transitions but not time spent in the light compartment.

Similarly, previous findings indicated that ��4?/? mice exhibited less anxiety-like behavior compared with ��4+/+ mice on the elevated plus and staircase mazes, with no differences between genotypes in the light�Cdark box, open field, or mirrored chamber (Salas et al., 2003). Compulsive-like behavior measured in the marble burying test did not differ between ��4?/? and ��4+/+ mice. Depression-like behavior was measured in the tail suspension and forced swim tests, and conflicting results were obtained in these two tests. In the forced swim test, ��4?/? mice exhibited increased immobility compared with ��4+/+ mice, indicating a tendency for increased depression-like behavior. In contrast, in the tail suspension test, antidepressant-like behavior was evident in ��4?/? mice. It is postulated that the biological substrates that underlie the depression-like behavior measured in these tests are different (Bai, Li, Clay, Lindstrom, & Skolnick, 2001).

In the forced swim test, climbing behavior is indicative of norepinephrine neurotransmitter function (Cryan, Markou, & Lucki, 2002), whereas swimming behavior is indicative of serotonin neurotransmitter function (Cryan et al., 2002). Swimming was significantly decreased in ��4?/? mice compared with ��4+/+ mice. This finding suggests that the lack of the nAChR ��4 subunit alters serotonin but not norepinephrine transmission. On the other hand, ��4-containing nAChRs in the medial habenula and interpeduncular nucleus pathway may regulate glutamate release (Girod & Role, 2001; McGehee & Role, 1995) involved in both depression and anxiety (Krystal et al., 2002; Skolnick, 2002; Stewart & Reid, 2002).

Therefore, the lack of the ��4 subunit may alter glutamatergic tone in the habenulo�Craphe pathway and mediate affective behavior in mice lacking ��4-containing nAChRs. Finally, potential developmental compensatory changes in ��4 nAChR knockout mice cannot be ruled out in the expression of depression-like behavior. Specifically, the ��2 subunit of nAChRs, which is involved in Cilengitide depression-like behavior, may partially substitute for the loss of the ��4 subunit as it has been shown in the autonomic ganglia (Xu et al., 1999).