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Spontaneous individual differences in cognitive performances of young adult rats predict locomotor response to amphetamine
Neurobiology of Learning and Memory 83 (2005) 43–47 www.elsevier.com/locate/ynlme
Spontaneous individual differences in cognitive performances of young adult rats predict locomotor response to amphetamine F. Dellu-Hagedorn* Laboratoire de Neuropsychobiologie des De´sadaptations, CNRS UMR 5541, Universite´ Victor Segalen Bordeaux 2, BP. 31, 146 rue Le´o Saignat, 33076 Bordeaux cedex, France Received 2 April 2004; revised 8 June 2004; accepted 13 July 2004 Available online 11 September 2004
Abstract Inter-individual differences in cognitive capacities of young adult rats have largely been ignored. To explore this variability and its neurobiological bases, the relationships between individual differences in working memory and locomotor responses to novelty and to amphetamine were investigated in SD rats. Groups of good and poor learners were isolated, the latter demonstrating a markedly slower learning of the task compared to performant rats, with more perseverations independently to motivational state. They also presented a much higher increase in amphetamine-induced locomotion that remained significant for more than 1 h after the injection. These results provide evidence that variability in cognitive capacities can be used to reveal their neurobiological substrates. They open new perspectives to study a possible cognitive origin of addictive behaviors and to investigate the involvement of these inter-individual differences on those observed later in life. 2004 Elsevier Inc. All rights reserved. Keywords: Working memory; Inter-individual differences; Locomotor activity; Predictive factor; Amphetamine; Eight arm radial-arm maze; Rats
1. Introduction Most animal models use cognitive capacities of individuals as a pooled control group from which one assumes that they have an optimal level of performance. Surprisingly, individual differences in cognition of young animals are much neglected whereas in the aging domain, comparisons between aged cognitively impaired vs cognitively unimpaired individuals were successfully used to clarify the role of neurobiological markers that discriminate between them (for review, see Hedden & Gabrieli, 2004). Working memory, a system of operations for processing information in real time or over short periods of time (Baddeley, 1986) should demonstrate important individual differences in youth since it is particularly sensitive: even subtle *
Fax: +33 556986182. E-mail address: [email protected].
1074-7427/$ - see front matter 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.nlm.2004.07.002
deficiencies in this process reveal substantial deficits in ideation, reasoning, and planning (Goldman-Rakic, 1991). Impaired working memory and dopamine dysfunction are closely related in the natural aging process as well as in a wide variety of pathologies (Nieoullon, 2002). To explore the neurobiological bases of such variability, and more specifically the role of the dopaminergic system, the relationships between individual differences in working memory and locomotor responses to novelty and amphetamine, which are considered as good indexes of dopaminergic transmission level in the mesolimbic system, were investigated in rats.
2. Materials and methods Forty-two-month-old male Sprague–Dawley rats were housed in groups of four on a 12 h light–dark (08:00–20:00) schedule. After a week of daily gentle
44
F. Dellu-Hagedorn / Neurobiology of Learning and Memory 83 (2005) 43–47
handling, locomotor activities were measured in a circular corridor (Dellu et al., 1996). The locomotor response to novelty was recorded over a period of 2 h between 16:00 and 18:00 h. Then, locomotor response to vehicle (1 ml/kg i.p.) was measured during 30 min followed by locomotor response to amphetamine (1 mg/kg/i.p.) during 2.5 h. Working memory was measured by the ability to visit eight baited arms of a eight arm radial maze without reentry (error) (Olton & Samuelson, 1976) over six consecutive days (see Dellu-Hagedorn, Trunet, & Simon, 2004). Mean total number of errors and errors during the eight first choices from day two to day six were considered as well as perseverations (returns in the previously visited arm), and mean time to reach the extremity of the arm after opening of the doors. All experiments were performed in accordance with the European Communities Council Directive of November 24, 1986 (86/609/EEC). Comparisons of scores were made using StudentÕs t test or analysis of variance (ANOVA) with repeated measures, followed by analyses of simple main effects (SME) and by post hoc comparisons using the Newman–Keuls (NK) test, when appropriate. Correlations between scores were evaluated using Bravais–PearsonÕs correlation test. The normality of the variable distribution was verified using Shapiro–WilkÕs test.
3. Results Eight arm radial maze. After habituation, all animals explored the radial maze freely without apparent signs of anxiety and readily consumed the pellets available except one highly reactive rat that was eliminated. The number of errors during the eight-first choices was chosen to classify the animals. Large individual differences were observed in learning capacities, following a normal distribution (w = 0.98, p = 0.66) (Fig. 1A). Groups of poor (WM , n = 9), and good (WM+, n = 10) learners were selected in the superior and inferior quartiles, a third group with intermediate scores (INT, n = 20) contained the remainder. One rat in the WM group, presenting an identical score to that of the following six INT rats (see Fig. 1A) was included in this latter group. While WM+ and WM scores were similar on the first day of training, they were significantly different on each of the remaining five days (F(1, 17) = 85.6, p < .001; SME for days 2–5: p < .001, and last day: p < .01) (Fig. 1B). Only WM+ improved their scores with practice (F(5, 45) = 4.1, days 1–5, NK p < .01, day 1–day 6, NK p < .05). Total number of errors was also significantly higher for WM (F(1, 17) = 56.94, p < .001) from days 2 to 5 but not day 6 (SME for days 2–5: p < .001). Perseverations were also more frequent for WM during the two first
Fig. 1. Inter-individual differences in learning performances in a eight arm radial maze of a group of young adult rats. (A) Distribution of individual scores of rats during the learning phase of the task (mean of the number of errors during the eight-first choices of the five last sessions) and selection of good learners (WM+, scores below 1.5) and poor learners (WM , scores above 2). (B) Comparisons of the time course of working memory performances of the two groups. Number of errors during the eight-first choices and perseverative errors (C) were significantly higher in WM compared to WM+.
F. Dellu-Hagedorn / Neurobiology of Learning and Memory 83 (2005) 43–47
days of the task (F(1, 17) = 8.1, p < .02, SME, day 1, p = .05 and day 2, p < .001) (Fig. 1C). The mean time to reach the end of an arm was lower for WM (F(1, 17) = 12.13, p < .01), from days 1 to 5 (SME, day 1, p < .001 ; days 2–5, p < .05). Locomotor responses to novelty and amphetamine. No significant difference was observed between groups in response to novelty or after saline injection (total activity in response to novelty over 2 h: WM = 408 ± 51; WM+ = 468 ± 35; INT = 463 ± 33; F(2, 36) = 0.58, ns). Strikingly, the amphetamine injection produced a greater increase in locomotor activity of WM compared to the other groups, being almost double that of WM+ (total activity over 2 h 30 min: WM = 852 ± 111; WM+ = 495 ± 46; INT = 560 ± 81; F(2, 36) = 3.53, p < .05). SME analysis showed that differences between groups remained significant for 70 min after the injection. The time-course of this effect also differed between groups: WM+ and INT returned to basal levels faster than WM (interaction group · time: F(28, 504) = 2.49, p < .001). NK post hoc analysis revealed that locomotor activity returned to basal levels 50 min after the amphetamine injection for WM+, after 60 min for INT, whereas it only returned to baseline after 80 min for WM (Fig. 2). Positive correlations were found between scores of learning in the eight arm radial maze and locomotor response to amphetamine (activity scores over 2 h and errors during the eight-first choices: r = 0.40, n = 39, p < .02 (Fig. 2, inset); and total number of errors: r = 0.37, n = 39, p < .05).
45
4. Discussion The present study focuses on a well-known but largely neglected observation: substantial inter-individual differences are observed in cognitive abilities of young adult outbred rats. Individual differences in working memory in a eight arm radial maze were evidenced of which specificity was ensured by reduction of nonspecific parameters like anxiety, motivation or motricity. For this purpose, a strict criterion of habituation to the procedure (maze, opening, and closing of the doors) and a control for motivation (eating of pellets, time to explore eight arms) were applied for each individual. The learning of the rule (reference memory) of this task was also facilitated by closing each arm previously visited during the habituation phase thus eliciting the measure of working memory. To investigate these individual differences, a typological approach was used consisting in grouping individuals into two extreme subgroups. Reduced ability of WM to perform the task compared to WM+ may be due in part to a slower win-shift strategy acquisition given that they returned more frequently in the previously visited arm (perseverations) at the beginning of the task. Reduced working memory capacities of WM can neither be attributed to a decrease in motivation given that they reached the end of the arm even more rapidly than WM+, nor to a greater impulsivity, as we have recently shown that there is no relationship between working memory capacities and impulsivity, measured in three
Fig. 2. Comparisons of the scores of WM+, INT, and WM in response to saline and to amphetamine injections (1 mg/kg i.p.). No difference in locomotor response to a saline injection was observed between groups whereas WM had a higher locomotor response to amphetamine compared to INT and WM+. Inset: This result is confirmed by a positive correlation between total locomotor response to amphetamine during 2.5 h and mean number of errors in the eight-first choices.
46
F. Dellu-Hagedorn / Neurobiology of Learning and Memory 83 (2005) 43–47
different experimental paradigms (Dellu-Hagedorn et al., 2004 and data not shown). A prime candidate for a brain substrate that might contribute to such individual differences in working memory is dopaminergic activity in the prefrontal cortex, a brain area associated with cognition, motivation, memory response inhibition, and decision making (Goldman-Rakic, 1990). The antagonism between performances in working memory and locomotor response to amphetamine evidenced here corroborates the hypothesis of a balance between prefrontal and mesolimbic dopamine transmissions (Le Moal & Simon, 1991; Pycock, Kerwin, & Carter, 1980; Tzschentke, 2001). It has been proposed that working memory requires an optimal level of dopaminergic receptor stimulation in the prefrontal cortex (PFC) (Goldman-Rakic, Muly 3rd, & Williams, 2000) and a reduced DA transmission in this area, which has been related to the physiopathology of schizophrenia, may be concurrent with increased subcortical transmission (Deutch, 1992; Weinberger et al., 2001). Thus, reduced prefrontal dopamine transmission, reflected by lower working memory capacities, could enhance behavioral effects associated with stimulation of mesolimbic dopaminergic activity, reflected here by the locomotor response to amphetamine. It has been shown that a higher locomotor response to amphetamine is a characteristic of rats predisposed to amphetamine self-administration. These subjects also have a reduced dopaminergic activity in the PFC and an increased activity in the nucleus accumbens (Piazza, Deminiere, Le Moal, & Simon, 1989; Piazza et al., 1991). Given WM rats, that may be at risk to develop self-administration, have lower working memory performances before any contact with drug, these results may open new perspectives on a possible cognitive origin of predisposition to drug addiction. This new experimental approach provides evidence that variability in cognitive abilities of young adult rats is relevant and can be used to investigate their neurobiological substrates. It presents the advantage to be only based on spontaneous individual differences in the cognitive dimension of interest. Separation of the population into two groups can magnify differences and can be sensitive to individual differences not captured by overall correlations. This approach will need to be broaden to other cognitive functions, especially attentional capacities, which have also been shown to vary among individuals (Puumala et al., 1996). Finally, these results may have major interest from a life-span perspective by adding information about factors underlying individual differences later in life: will these individual differences in cognition and dopaminergic activity become magnified with time? (for review, see Hedden & Gabrieli, 2004). This hypothesis is supported by a recent longitudinal birth cohort study in human showing that cognitive abilities in childhood can protect
against cognitive decline in mid-life and beyond (Richards, Shipley, Fuhrer, & Wadsworth, 2004). Because cohorts of laboratory rodents can be maintained under relatively controlled conditions and their life-span is short, this new approach may help isolating factors contributing to such individual differences.
Acknowledgments This work was supported by grants from CNRS, Universite´ de Bordeaux 2, Conseil Re´gional dÕAquitaine and Fondation pour la Recherche Me´dicale. I thank Dr. Serge Ahmed for helpful comments, Dr Glyn Goodall for English corrections, Lydie Gouttie`re for animal care and Pierre Gonzalez for technical assistance.
References Baddeley, A. D. (1986). Working memory. Oxford: Oxford University Press. Dellu, F., Mayo, W., Vallee, M., Maccari, S., Piazza, P. V., Le Moal, M., et al. (1996). Behavioral reactivity to novelty during youth as a predictive factor of stress-induced corticosterone secretion in the elderly—A life-span study in rats. Psychoneuroendocrinology, 21, 441–453. Dellu-Hagedorn, F., Trunet, S., & Simon, H. (2004). Impulsivity in youth predicts early age-related cognitive deficits in rats. Neurobiology of Aging, 25, 525–537. Deutch, A. Y. (1992). The regulation of subcortical dopamine systems by the prefrontal cortex: Interactions of central dopamine systems and the pathogenesis of schizophrenia. Journam of Neural Transmission Supplementum, 36, 61–89. Goldman-Rakic, P. S. (1990). Cellular and circuit basis of working memory in prefrontal cortex of nonhuman primates. Progress in Brain Research, 85, 325–335 discussion 335–326. Goldman-Rakic, P. S. (1991). Prefrontal cortical dysfunction in schizophrenia: The relevance of working memory. In B. J. Carroll & J. E. Barrett (Eds.), Psychopathology and the brain (pp. 1–23). New York: Raven Press. Goldman-Rakic, P. S., Muly 3rd, E. C., & Williams, G. V. (2000). D(1) receptors in prefrontal cells and circuits. Brain Research Review, 31, 295–301. Hedden, T., & Gabrieli, J. D. (2004). Insights into the ageing mind: A view from cognitive neuroscience. Nature Review Neurosciences, 5, 87–96. Le Moal, M., & Simon, H. (1991). Mesocorticolimbic dopaminergic network: Functional and regulatory roles. Physiological Review, 71, 155–234. Nieoullon, A. (2002). Dopamine and the regulation of cognition and attention. Progress in Neurobiology, 67, 53–83. Olton, D. S., & Samuelson, R. J. (1976). Remenbrance of place passed: Spatial memory in rats. Journal of Experimental Psychology, 2, 97–116. Piazza, P. V., Deminiere, J. M., Le Moal, M., & Simon, H. (1989). Factors that predict individual vulnerability to amphetamine selfadministration. Science, 245, 1511–1513. Piazza, P. V., Rouge-Pont, F., Deminiere, J. M., Kharoubi, M., Le Moal, M., & Simon, H. (1991). Dopaminergic activity is reduced in the prefrontal cortex and increased in the nucleus accumbens of rats predisposed to develop amphetamine self-administration. Brain Research, 567, 169–174.
F. Dellu-Hagedorn / Neurobiology of Learning and Memory 83 (2005) 43–47 Puumala, T., Ruotsalainen, S., Jakala, P., Koivisto, E., Riekkinen, P., Jr., & Sirvio, J. (1996). Behavioral and pharmacological studies on the validation of a new animal model for attention deficit hyperactivity disorder. Neurobiology of Learning and Memory, 66, 198–211. Pycock, C. J., Kerwin, R. W., & Carter, C. J. (1980). Effect of lesion of cortical dopamine terminals on subcortical dopamine receptors in rats. Nature, 286, 74–76. Richards, M., Shipley, B., Fuhrer, R., & Wadsworth, M. E. (2004). Cognitive ability in childhood and cognitive decline in mid-life:
47
Longitudinal birth cohort study. British Medical Journal, 328, 552. Tzschentke, T. M. (2001). Pharmacology and behavioral pharmacology of the mesocortical dopamine system. Progress in Neurobiology, 63, 241–320. Weinberger, D. R., Egan, M. F., Bertolino, A., Callicott, J. H., Mattay, V. S., Lipska, B. K., et al. (2001). Prefrontal neurons and the genetics of schizophrenia. Biological Psychiatry, 50, 825–844.
Spontaneous individual differences in cognitive performances of young adult rats predict locomotor response to amphetamine F. Dellu-Hagedorn* Laboratoire de Neuropsychobiologie des De´sadaptations, CNRS UMR 5541, Universite´ Victor Segalen Bordeaux 2, BP. 31, 146 rue Le´o Saignat, 33076 Bordeaux cedex, France Received 2 April 2004; revised 8 June 2004; accepted 13 July 2004 Available online 11 September 2004
Abstract Inter-individual differences in cognitive capacities of young adult rats have largely been ignored. To explore this variability and its neurobiological bases, the relationships between individual differences in working memory and locomotor responses to novelty and to amphetamine were investigated in SD rats. Groups of good and poor learners were isolated, the latter demonstrating a markedly slower learning of the task compared to performant rats, with more perseverations independently to motivational state. They also presented a much higher increase in amphetamine-induced locomotion that remained significant for more than 1 h after the injection. These results provide evidence that variability in cognitive capacities can be used to reveal their neurobiological substrates. They open new perspectives to study a possible cognitive origin of addictive behaviors and to investigate the involvement of these inter-individual differences on those observed later in life. 2004 Elsevier Inc. All rights reserved. Keywords: Working memory; Inter-individual differences; Locomotor activity; Predictive factor; Amphetamine; Eight arm radial-arm maze; Rats
1. Introduction Most animal models use cognitive capacities of individuals as a pooled control group from which one assumes that they have an optimal level of performance. Surprisingly, individual differences in cognition of young animals are much neglected whereas in the aging domain, comparisons between aged cognitively impaired vs cognitively unimpaired individuals were successfully used to clarify the role of neurobiological markers that discriminate between them (for review, see Hedden & Gabrieli, 2004). Working memory, a system of operations for processing information in real time or over short periods of time (Baddeley, 1986) should demonstrate important individual differences in youth since it is particularly sensitive: even subtle *
Fax: +33 556986182. E-mail address: [email protected].
1074-7427/$ - see front matter 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.nlm.2004.07.002
deficiencies in this process reveal substantial deficits in ideation, reasoning, and planning (Goldman-Rakic, 1991). Impaired working memory and dopamine dysfunction are closely related in the natural aging process as well as in a wide variety of pathologies (Nieoullon, 2002). To explore the neurobiological bases of such variability, and more specifically the role of the dopaminergic system, the relationships between individual differences in working memory and locomotor responses to novelty and amphetamine, which are considered as good indexes of dopaminergic transmission level in the mesolimbic system, were investigated in rats.
2. Materials and methods Forty-two-month-old male Sprague–Dawley rats were housed in groups of four on a 12 h light–dark (08:00–20:00) schedule. After a week of daily gentle
44
F. Dellu-Hagedorn / Neurobiology of Learning and Memory 83 (2005) 43–47
handling, locomotor activities were measured in a circular corridor (Dellu et al., 1996). The locomotor response to novelty was recorded over a period of 2 h between 16:00 and 18:00 h. Then, locomotor response to vehicle (1 ml/kg i.p.) was measured during 30 min followed by locomotor response to amphetamine (1 mg/kg/i.p.) during 2.5 h. Working memory was measured by the ability to visit eight baited arms of a eight arm radial maze without reentry (error) (Olton & Samuelson, 1976) over six consecutive days (see Dellu-Hagedorn, Trunet, & Simon, 2004). Mean total number of errors and errors during the eight first choices from day two to day six were considered as well as perseverations (returns in the previously visited arm), and mean time to reach the extremity of the arm after opening of the doors. All experiments were performed in accordance with the European Communities Council Directive of November 24, 1986 (86/609/EEC). Comparisons of scores were made using StudentÕs t test or analysis of variance (ANOVA) with repeated measures, followed by analyses of simple main effects (SME) and by post hoc comparisons using the Newman–Keuls (NK) test, when appropriate. Correlations between scores were evaluated using Bravais–PearsonÕs correlation test. The normality of the variable distribution was verified using Shapiro–WilkÕs test.
3. Results Eight arm radial maze. After habituation, all animals explored the radial maze freely without apparent signs of anxiety and readily consumed the pellets available except one highly reactive rat that was eliminated. The number of errors during the eight-first choices was chosen to classify the animals. Large individual differences were observed in learning capacities, following a normal distribution (w = 0.98, p = 0.66) (Fig. 1A). Groups of poor (WM , n = 9), and good (WM+, n = 10) learners were selected in the superior and inferior quartiles, a third group with intermediate scores (INT, n = 20) contained the remainder. One rat in the WM group, presenting an identical score to that of the following six INT rats (see Fig. 1A) was included in this latter group. While WM+ and WM scores were similar on the first day of training, they were significantly different on each of the remaining five days (F(1, 17) = 85.6, p < .001; SME for days 2–5: p < .001, and last day: p < .01) (Fig. 1B). Only WM+ improved their scores with practice (F(5, 45) = 4.1, days 1–5, NK p < .01, day 1–day 6, NK p < .05). Total number of errors was also significantly higher for WM (F(1, 17) = 56.94, p < .001) from days 2 to 5 but not day 6 (SME for days 2–5: p < .001). Perseverations were also more frequent for WM during the two first
Fig. 1. Inter-individual differences in learning performances in a eight arm radial maze of a group of young adult rats. (A) Distribution of individual scores of rats during the learning phase of the task (mean of the number of errors during the eight-first choices of the five last sessions) and selection of good learners (WM+, scores below 1.5) and poor learners (WM , scores above 2). (B) Comparisons of the time course of working memory performances of the two groups. Number of errors during the eight-first choices and perseverative errors (C) were significantly higher in WM compared to WM+.
F. Dellu-Hagedorn / Neurobiology of Learning and Memory 83 (2005) 43–47
days of the task (F(1, 17) = 8.1, p < .02, SME, day 1, p = .05 and day 2, p < .001) (Fig. 1C). The mean time to reach the end of an arm was lower for WM (F(1, 17) = 12.13, p < .01), from days 1 to 5 (SME, day 1, p < .001 ; days 2–5, p < .05). Locomotor responses to novelty and amphetamine. No significant difference was observed between groups in response to novelty or after saline injection (total activity in response to novelty over 2 h: WM = 408 ± 51; WM+ = 468 ± 35; INT = 463 ± 33; F(2, 36) = 0.58, ns). Strikingly, the amphetamine injection produced a greater increase in locomotor activity of WM compared to the other groups, being almost double that of WM+ (total activity over 2 h 30 min: WM = 852 ± 111; WM+ = 495 ± 46; INT = 560 ± 81; F(2, 36) = 3.53, p < .05). SME analysis showed that differences between groups remained significant for 70 min after the injection. The time-course of this effect also differed between groups: WM+ and INT returned to basal levels faster than WM (interaction group · time: F(28, 504) = 2.49, p < .001). NK post hoc analysis revealed that locomotor activity returned to basal levels 50 min after the amphetamine injection for WM+, after 60 min for INT, whereas it only returned to baseline after 80 min for WM (Fig. 2). Positive correlations were found between scores of learning in the eight arm radial maze and locomotor response to amphetamine (activity scores over 2 h and errors during the eight-first choices: r = 0.40, n = 39, p < .02 (Fig. 2, inset); and total number of errors: r = 0.37, n = 39, p < .05).
45
4. Discussion The present study focuses on a well-known but largely neglected observation: substantial inter-individual differences are observed in cognitive abilities of young adult outbred rats. Individual differences in working memory in a eight arm radial maze were evidenced of which specificity was ensured by reduction of nonspecific parameters like anxiety, motivation or motricity. For this purpose, a strict criterion of habituation to the procedure (maze, opening, and closing of the doors) and a control for motivation (eating of pellets, time to explore eight arms) were applied for each individual. The learning of the rule (reference memory) of this task was also facilitated by closing each arm previously visited during the habituation phase thus eliciting the measure of working memory. To investigate these individual differences, a typological approach was used consisting in grouping individuals into two extreme subgroups. Reduced ability of WM to perform the task compared to WM+ may be due in part to a slower win-shift strategy acquisition given that they returned more frequently in the previously visited arm (perseverations) at the beginning of the task. Reduced working memory capacities of WM can neither be attributed to a decrease in motivation given that they reached the end of the arm even more rapidly than WM+, nor to a greater impulsivity, as we have recently shown that there is no relationship between working memory capacities and impulsivity, measured in three
Fig. 2. Comparisons of the scores of WM+, INT, and WM in response to saline and to amphetamine injections (1 mg/kg i.p.). No difference in locomotor response to a saline injection was observed between groups whereas WM had a higher locomotor response to amphetamine compared to INT and WM+. Inset: This result is confirmed by a positive correlation between total locomotor response to amphetamine during 2.5 h and mean number of errors in the eight-first choices.
46
F. Dellu-Hagedorn / Neurobiology of Learning and Memory 83 (2005) 43–47
different experimental paradigms (Dellu-Hagedorn et al., 2004 and data not shown). A prime candidate for a brain substrate that might contribute to such individual differences in working memory is dopaminergic activity in the prefrontal cortex, a brain area associated with cognition, motivation, memory response inhibition, and decision making (Goldman-Rakic, 1990). The antagonism between performances in working memory and locomotor response to amphetamine evidenced here corroborates the hypothesis of a balance between prefrontal and mesolimbic dopamine transmissions (Le Moal & Simon, 1991; Pycock, Kerwin, & Carter, 1980; Tzschentke, 2001). It has been proposed that working memory requires an optimal level of dopaminergic receptor stimulation in the prefrontal cortex (PFC) (Goldman-Rakic, Muly 3rd, & Williams, 2000) and a reduced DA transmission in this area, which has been related to the physiopathology of schizophrenia, may be concurrent with increased subcortical transmission (Deutch, 1992; Weinberger et al., 2001). Thus, reduced prefrontal dopamine transmission, reflected by lower working memory capacities, could enhance behavioral effects associated with stimulation of mesolimbic dopaminergic activity, reflected here by the locomotor response to amphetamine. It has been shown that a higher locomotor response to amphetamine is a characteristic of rats predisposed to amphetamine self-administration. These subjects also have a reduced dopaminergic activity in the PFC and an increased activity in the nucleus accumbens (Piazza, Deminiere, Le Moal, & Simon, 1989; Piazza et al., 1991). Given WM rats, that may be at risk to develop self-administration, have lower working memory performances before any contact with drug, these results may open new perspectives on a possible cognitive origin of predisposition to drug addiction. This new experimental approach provides evidence that variability in cognitive abilities of young adult rats is relevant and can be used to investigate their neurobiological substrates. It presents the advantage to be only based on spontaneous individual differences in the cognitive dimension of interest. Separation of the population into two groups can magnify differences and can be sensitive to individual differences not captured by overall correlations. This approach will need to be broaden to other cognitive functions, especially attentional capacities, which have also been shown to vary among individuals (Puumala et al., 1996). Finally, these results may have major interest from a life-span perspective by adding information about factors underlying individual differences later in life: will these individual differences in cognition and dopaminergic activity become magnified with time? (for review, see Hedden & Gabrieli, 2004). This hypothesis is supported by a recent longitudinal birth cohort study in human showing that cognitive abilities in childhood can protect
against cognitive decline in mid-life and beyond (Richards, Shipley, Fuhrer, & Wadsworth, 2004). Because cohorts of laboratory rodents can be maintained under relatively controlled conditions and their life-span is short, this new approach may help isolating factors contributing to such individual differences.
Acknowledgments This work was supported by grants from CNRS, Universite´ de Bordeaux 2, Conseil Re´gional dÕAquitaine and Fondation pour la Recherche Me´dicale. I thank Dr. Serge Ahmed for helpful comments, Dr Glyn Goodall for English corrections, Lydie Gouttie`re for animal care and Pierre Gonzalez for technical assistance.
References Baddeley, A. D. (1986). Working memory. Oxford: Oxford University Press. Dellu, F., Mayo, W., Vallee, M., Maccari, S., Piazza, P. V., Le Moal, M., et al. (1996). Behavioral reactivity to novelty during youth as a predictive factor of stress-induced corticosterone secretion in the elderly—A life-span study in rats. Psychoneuroendocrinology, 21, 441–453. Dellu-Hagedorn, F., Trunet, S., & Simon, H. (2004). Impulsivity in youth predicts early age-related cognitive deficits in rats. Neurobiology of Aging, 25, 525–537. Deutch, A. Y. (1992). The regulation of subcortical dopamine systems by the prefrontal cortex: Interactions of central dopamine systems and the pathogenesis of schizophrenia. Journam of Neural Transmission Supplementum, 36, 61–89. Goldman-Rakic, P. S. (1990). Cellular and circuit basis of working memory in prefrontal cortex of nonhuman primates. Progress in Brain Research, 85, 325–335 discussion 335–326. Goldman-Rakic, P. S. (1991). Prefrontal cortical dysfunction in schizophrenia: The relevance of working memory. In B. J. Carroll & J. E. Barrett (Eds.), Psychopathology and the brain (pp. 1–23). New York: Raven Press. Goldman-Rakic, P. S., Muly 3rd, E. C., & Williams, G. V. (2000). D(1) receptors in prefrontal cells and circuits. Brain Research Review, 31, 295–301. Hedden, T., & Gabrieli, J. D. (2004). Insights into the ageing mind: A view from cognitive neuroscience. Nature Review Neurosciences, 5, 87–96. Le Moal, M., & Simon, H. (1991). Mesocorticolimbic dopaminergic network: Functional and regulatory roles. Physiological Review, 71, 155–234. Nieoullon, A. (2002). Dopamine and the regulation of cognition and attention. Progress in Neurobiology, 67, 53–83. Olton, D. S., & Samuelson, R. J. (1976). Remenbrance of place passed: Spatial memory in rats. Journal of Experimental Psychology, 2, 97–116. Piazza, P. V., Deminiere, J. M., Le Moal, M., & Simon, H. (1989). Factors that predict individual vulnerability to amphetamine selfadministration. Science, 245, 1511–1513. Piazza, P. V., Rouge-Pont, F., Deminiere, J. M., Kharoubi, M., Le Moal, M., & Simon, H. (1991). Dopaminergic activity is reduced in the prefrontal cortex and increased in the nucleus accumbens of rats predisposed to develop amphetamine self-administration. Brain Research, 567, 169–174.
F. Dellu-Hagedorn / Neurobiology of Learning and Memory 83 (2005) 43–47 Puumala, T., Ruotsalainen, S., Jakala, P., Koivisto, E., Riekkinen, P., Jr., & Sirvio, J. (1996). Behavioral and pharmacological studies on the validation of a new animal model for attention deficit hyperactivity disorder. Neurobiology of Learning and Memory, 66, 198–211. Pycock, C. J., Kerwin, R. W., & Carter, C. J. (1980). Effect of lesion of cortical dopamine terminals on subcortical dopamine receptors in rats. Nature, 286, 74–76. Richards, M., Shipley, B., Fuhrer, R., & Wadsworth, M. E. (2004). Cognitive ability in childhood and cognitive decline in mid-life:
47
Longitudinal birth cohort study. British Medical Journal, 328, 552. Tzschentke, T. M. (2001). Pharmacology and behavioral pharmacology of the mesocortical dopamine system. Progress in Neurobiology, 63, 241–320. Weinberger, D. R., Egan, M. F., Bertolino, A., Callicott, J. H., Mattay, V. S., Lipska, B. K., et al. (2001). Prefrontal neurons and the genetics of schizophrenia. Biological Psychiatry, 50, 825–844.