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Acquisition Deficit and Time-Dependent Retrograde Beha¨ioural Pharmacology 2000; 11:93᎐97 SHORT REPORT Acquisition de®cit and time-dependent retrograde amnesia for contextual fear conditioning in agmatine-treated rats L.S. Stewart and B.E. McKay Neurochemistry and Neuroanatomy Laboratory, Department of Biology, Laurentian University, Sudbury, Ontario, Canada Correspondence to Lee S. Stewart, Departments of Physiology and Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada N6A 5A5. E-mail: ly᎐ [email protected] Received 25 October 1999; accepted as revised 29 November 1999 Cumulative evidence indicates that the hippocampus plays a time-limited role in contextual learning paradigms. Pharmacological studies have indicated that acquisition of background contextual cues during Pavlovian fear condition- ing is dependent upon hippocampal function, whereas early inactivation of the hippocampus after training produces retrograde amnesia. When administered prior to contextual fear conditioning, agmatine() 5 and 10 mgrkg, i.p. , an endogenous polyamine and N-methyl-D-aspartate() NMDA receptor ligand found at excitatory synapses in the hippocam- pus, impaired the acquisition of contextual fear() measured as defensive freezing 26 hours later without a reduction in baseline motor activity during training. Furthermore, ascending doses of agmatine were found not to exert analgesic effects on response thresholds to peripheral shock. This negated the possibility that the observed learning de®cit resulted from a difference in perceived shock intensity. Post-training agmatine treatment produced a time-dependent impairment of consolidation, with subjects approaching a level of fear equivalent to that of a reference group as the delay of treatment increased() up to 6 hours . Since physiologically high levels of agmatine are able to inhibit NMDA receptor activity, these results suggest that polyamine modulation of NMDA receptors, most likely within the hippocampus, is required for the acquisition and consolidation of contextual fear stimuli. ᮊ 2000 Lippincott Williams & Wilkins. Keywords: agmatine; fear conditioning; hippocampus; learning; NMDA receptor; rat INTRODUCTION de®cits in CF if made shortly after trainingŽ Anag- nostaras et al., 1999. and data obtained from addi- Pavlovian fear conditioning is a rapid form of learn- tional experiments suggest that NMDA receptor ac- ing whereby the polymodal, or contextual, stimulus tivity within the hippocampal formation is critical for elements of a novel environment are placed into the consolidation of emotional learning tasks that association with an aversive engram following a stressful eventŽ. i.e. footshock . Cumulative evidence possess a strong contextual element, although such implicating the hippocampal formation in this form activity appears to have a limited, or time-depen- Ž of learningŽ. Maren et al., 1998 also points to a role dent, role in post-training memory processing Fer- for hippocampal N-methyl-D-aspartateŽ. NMDA - reira et al., 1992; Izquierdo et al., 1997; Roesler et . dependent long-term potentiationŽ. LTP , a cellular al., 1998 . analog of behavioral memoryŽ Bliss and Collingridge, The polyamine agmatine is an upstream precursor 1993. , in the acquisition of contextual information for the synthesis of spermine and is localized to Ž.Maren et al., 1994 . The inhibitory effects of sys- numerous cortical and subcortical regionsŽ Otake et temic NMDA receptor antagonists on contextual al., 1998. Endogenous agmatine interacts with a fear conditioningŽ. CF suggests that activity at these number of receptor subtypes, including imidazoline, receptors is a necessary component of associative ␣ 2-adrenergic and NMDAŽ Reis and Regunatham, plasticityŽ. acquisition required for the subsequent 1999. Available data suggest that agmatine is found expression of punishment-suppressed behavior in hippocampal pyramidal cellsŽ. Reis et al., 1998 Ž.Young et al., 1994 . Lesions of the hippocampal and functions as a modulator of the NMDA recep- formation have been shown to produce retrograde tor channel pore, but high systemic levels display a 0955-8810 ᮊ 2000 Lippincott Williams & Wilkins Behavioural Pharmacology 2000, Vol 11 No 1 93 STEWART AND MCKAY pharmacological pro®le similar to that of systemi- PlexiglassŽ. front, back and hinged ceiling door cally administered NMDA receptor antagonists chamber with a raised ¯oor composed of 18 steel Ž.Kolesnikov et al., 1996; Gilad et al., 1995 . Further- rods spaced 1.5 cm apart. The intensity of electric more, high concentrations of agmatine Ž.)100 nM current was controlled by an A-615-C Master have been shown to displace binding of spermine, a ShockerŽ Lafayette Instruments, Lafayette, Indiana, local NMDA polyamine site agonist, to the receptor USA. After the subject had been placed in the channel in hippocampal slicesŽ Rock and McDonald, chamber, the intensity of electric current was slowly 1995. Interestingly, in-vivo experiments have impli- increased by increments of 0.01 mA until the subject cated spermine in the formation of LTP in the displayed a qualitatively distinct ¯inch. After 30 s the dentate gyrusŽ. Chida et al., 1992 . amount of current required to evoke the initial To examine the possible effects of agmatine on ¯inch response was increased by 0.05 mA and then CF, we administered agmatine prior to, or at speci®c quickly decreased until no ¯inch was observed. The intervals following, trainingŽ acquisition versus con- threshold was then recorded in milliamperes. solidation. Peripherally, the effects of agmatine in- clude the ability to decrease blood pressure and Experiment 2a: Acquisition Ž sympathetic neuronal activity Forsang and Kapocsi, Both conditioning and CF testing were performed . ␣ 1999 . Agonists of imidazoline and 2-adrenergic using the footshock apparatus described above. The receptors have been reported to decrease spinal chamber was cleaned with a 10% acetic acid solu- nociceptive processing and induce thermal antinoci- tion between conditioning trials. On the day of con- Ž ception, respectively Diaz et al., 1997; Graham et ditioning, subjects were randomly allocated to treat- . al., 1997 . To discern possible non-speci®c drug ef- ment groups Ž.ns6 each and received one of the fects on learning related to either decreases in three doses of agmatineŽ. intraperitoneally 20 min arousal or differences in perceived shock intensity, prior to conditioning. An additional six animals re- additional measures were employed that monitored ceived a saline vehicle and were assigned to a refer- the exploratory activity of subjects in the presence of ence group. Ž. contextual conditioned stimuli CSs prior to uncon- CF was accomplished by placing each subject in Ž. ditional stimulus UCS delivery, and response the chamber for 3 min, after which three unsignaled thresholds to peripheral shock. We hypothesized footshocksŽ. 2-s, 0.5 mA, 60-s interstimulus interval that if the pharmacological effects of systemic agma- were delivered. Sixty seconds following the last foot- tine are comparable to that of traditional NMDA shock, the subjects were returned to their home antagonists, then an impairment in acquisition and cages. BaselineŽ. pre-shock locomotor activity was early consolidation would be expected. This hy- measured by conditioning chamber crossovers and pothesis was consistent with the results of previous was de®ned as forward movement over the chamber Ž work Ferreira et al., 1992; Young et al., 1994; midline. Subjects were then returned to the original . Izquierdo et al., 1997; Roesler et al., 1998 . conditioning chamber 26 hours later and scored for defensive freezing, a behavioral index of fearŽ Bolles, Methods 1970.Ž. , by an experimenter B.E.M. blind to treat- Subjects ment conditions. Freezing was assessed every 8 s In total, 68 male Wistar strain ratsŽ Charles River, during an 8-min extinction test, for a total of 60 Quebec, Canada. , approximately 80᎐90 days of age observations per subject. To satisfy parametric re- and weighing between 310 and 360 g served as sub- quirements, freezing measures were converted to a jects. All animals were group housed in plastic percentage of total observations. shoebox cages and maintained under a 20 " 1ЊC ambient temperature and 12 : 12 light᎐dark cycle Experiment 2b: Consolidation Ž.lights on at 07.30 hours . Food and water were A second experiment was performed using the same freely available throughout the experiment. conditioning parameters outlined above. Subjects were administered 10 mgrkg agmatineŽ. i.p. at Experiment 1: Effects of agmatine on response thresh- 30 min, 2 h, or 6 h Ž.ns6 each following condition- olds to peripheral shock ing. This single dose was chosen following the results Subjects were randomly assigned to receive one of of experiment 1 but has been shown to produce the three ascending doses of agmatineŽ 1, 5, or 10 mgrkg, behavioral effects of systemically administered i.p..Ž. 20 min prior to testing ns5 each . Response NMDA receptor antagonistsŽ Kolesnikov et al., thresholds to peripheralŽ. foot shock were assessed 1996. An additional six animals served as a refer- using a 28 = 20 = 20 cm aluminumŽ. side walls and ence group. Context testing was performed 26 h later. 94 Behavioural Pharmacology 2000, Vol 11 No 1 AGMATINE EFFECTS ON CONDITIONED FEAR Results Footshock response() ¯inch thresholds Analysis of variance revealed no signi®cant differ- ence in mean footshock ¯inch thresholds in re- sponse to ascending doses of agmatine w FŽ.3, 19 s 0.63, NSx Ž. Table 1 . This observation
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