Genetic Inactivation of the 5-HT2CR and Egocentric Reversal Learning
5-HT2CR KO mice showed impaired egocentric spatial discrimination learning and, contrary to the effect of SB242084, they showed selective deficits in the subsequent perseverance test, observed as increased attrition rates, trials to criterion and incorrect responses to criterion, that could not be accounted for by the initial learning deficit. A recent study also reported opposing effects of SB242084 and constitutive loss of the 5-HT2CR in the 5-choice serial reaction time task [43].
Targeted mutations causing constitutive loss of specific components in 5-HT systems often cause adaptations additional to the mutation, leading to behavioural effects which differ from those of acute pharmacological blockade [44]. For example, the 5-HT2CR KO mutant show markedly elevated levels of dialysate DA in the dorsal striatum [32] while pharmacological inactivation is without effect on DA levels in this area [31], [45], [46]. Importantly, it has been speculated that perseverative responding can be produced by dorsal striatal DA elevations [47]. In a probabilistic reversal task, dopamine-agonist treated Parkinson patients show impaired performance compared to unmedicated patients [48] and increased dopamine activity at the D2R and D3R in the caudate nucleus, observed as an increase in methylphenidate induced [11C]-raclopride displacement in human volunteers, correlates negatively with reversal performance [49]. The selective increase in perseverative responding following genetic but not pharmacological inactivation could therefore be explained by the selective increase in dorsal striatal DA levels in the 5-HT2CR KO mouse.
Moreover, rodent egocentric spatial learning has repeatedly been shown to selectively depend upon the integrity of the dorsal striatum. For example, lesioning or local inactivation of the dorsal striatum impairs egocentric spatial but not allocentric visuospatial discrimination learning [25], [50] and working memory [26], [28] and dorsal striatal inactivation also impairs egocentric reversal learning [51]. Thus, the discrepant effects of 5-HT2CR inactivation across visuospatial [15], [16] and egocentric tasks could be explained by a greater involvement of the dorsal striatum in egocentric relative to allocentric spatial learning.
Alternatively, it is possible that both the impaired discrimination learning and perseverative responding seen in 5-HT2CR KO mice could be explained by altered functioning within the hippocampus. Aberrant spatial learning has previously been observed in 5-HT2CR KO mice using a water maze task [52]. Within the perforant path of the dentate gyrus, LTP-formation is suppressed both in the 5-HT2CR KO mouse [52] and by intraventricular 5,7-dihydroxytryptamine induced 5-HT depletions [53]. Since LTP-formation within the perforant path of the dentate gyrus correlate with spatial learning in the water maze [54] and blocking LTP-formation in the medial perforant path retards water maze performance [55], the observed retardation of discrimination learning could be related to the suppressed hippocampal LTP. However, there is no direct evidence to confirm that acute modulation of hippocampal 5-HT2CR function modulates either egocentric learning or the regulation of hippocampal LTP.
It should be recognised that the dichotomy that we have used between ‘visuospatial’ and ‘egocentric’ tasks may not fully reflect the differences between the types of task employed in rodent studies; particular task differences are also likely to be important. Specifically, impaired two-choice operant reversal learning has been observed in the 5-HT2CR KO mouse [43]. The reversal task described by Pennanen et al [43] is based on that described by Boulougouris et al [15], as is the one used in our earlier ‘visuospatial’ study [16]. However animals had to initiate individual trials in the two earlier studies by nosepoking into the magazine [15], [16], whereas trials were automatically initiated after a very short ITI in the recent report [43]. This is likely to have led to different behavioural strategies being used to ‘solve’ the task which themselves may be differentially sensitive to serotonergic manipulations. It may be that the perseverative impairments of 5-HT2CR KO mice in some task variants, including that used here and the one described in [43] are related to elevated dopamine dysregulation in the dorsal striatum or elsewhere.