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Perinatal caffeine, acting on maternal adenosine A(1) receptors, causes long-lasting behavioral changes in mouse offspring.

Björklund O, Kahlström J, Salmi P, Fredholm BB - PLoS ONE (2008)

Bottom Line: This indicates that long-term behavioral alterations in the offspring result from the maternal effect of caffeine, and not a direct effect on fetus.WT offspring from WT mother but having a A(1)R Hz grandmother preserved higher locomotor response to cocaine.We suggest that perinatal caffeine, by acting on adenosine A(1) receptors in the mother, causes long-lasting behavioral changes in the offspring that even manifest themselves in the second generation.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. Olga.Bjorklund@gmail.com

ABSTRACT

Background: There are lingering concerns about caffeine consumption during pregnancy or the early postnatal period, partly because there may be long-lasting behavioral changes after caffeine exposure early in life.

Methodology/principal findings: We show that pregnant wild type (WT) mice given modest doses of caffeine (0.3 g/l in drinking water) gave birth to offspring that as adults exhibited increased locomotor activity in an open field. The offspring also responded to cocaine challenge with greater locomotor activity than mice not perinatally exposed to caffeine. We performed the same behavioral experiments on mice heterozygous for adenosine A(1) receptor gene (A(1)RHz). In these mice signaling via adenosine A(1) receptors is reduced to about the same degree as after modest consumption of caffeine. A(1)RHz mice had a behavioral profile similar to WT mice perinatally exposed to caffeine. Furthermore, it appeared that the mother's genotype, not offspring's, was critical for behavioral changes in adult offspring. Thus, if the mother partially lacked A(1) receptors the offspring displayed more hyperactivity and responded more strongly to cocaine stimulation as adults than did mice of a WT mother, regardless of their genotype. This indicates that long-term behavioral alterations in the offspring result from the maternal effect of caffeine, and not a direct effect on fetus. WT offspring from WT mother but having a A(1)R Hz grandmother preserved higher locomotor response to cocaine.

Conclusions/significance: We suggest that perinatal caffeine, by acting on adenosine A(1) receptors in the mother, causes long-lasting behavioral changes in the offspring that even manifest themselves in the second generation.

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Effect of mother's genotype on cocaine responce.A1R Hz mice are similar to mice exposed to perinatal caffeine in locomotor response to cocaine and this response seems to be dependent on mother's genotype, not offspring's (A,B). Closed circle represents WT mice born to a WT mother (M∶WT,O∶WT, males n = 11, females n = 12), open circle WT are mice born to an A1R Hz mother (M∶WT,O∶A1R Hz, males n = 6, females n = 6), closed square stand for A1R Hz mice born to a WT mother (M∶A1R Hz,O∶WT, males n = 6, females n = 3) and open square A1R Hz mice born to a A1R Hz mother (M∶A1R Hz,O∶ A1R Hz, males n = 12, females n = 10). Mice were habituated to the open-field arena for 45 min before administration of cocaine (10 mg/kg, i.p.), immediately followed by a 90-min test session. Arrow indicates time of injection of cocaine or vehicle. Results are shown as means±S.E.M.. The enhanced response to cocaine was only present in offspring born to a mother heterozygous for the adenosine A1 receptor gene. Statistical analysis was performed with Two-Way ANOVA with factors offspring's genotype and factor mother's genotype (**p<0.01; ***p<0.001 significantly different from WT mother WT offspring). (C) Response to cocaine in the second generation. Open circle grandmother WT, mother WT, offspring WT (G∶WT,M∶WT,O∶WT, n = 9) and closed circle: grandmother A1R Hz, mother WT, offspring WT (G∶A1R Hz,M∶WT,O∶WT n = 4). After 45 min of habituatain mice were injected cocaine and analysed for the next 90 min. Each point represents the mean±S.E.M of the beam breaks recorded during 15 minute intervals for habituation 3 and cocaine challenge. Arrows indicate the time of cocaine injection. Statistical analysis was performed with Student's t-test (*p<0.05).
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pone-0003977-g006: Effect of mother's genotype on cocaine responce.A1R Hz mice are similar to mice exposed to perinatal caffeine in locomotor response to cocaine and this response seems to be dependent on mother's genotype, not offspring's (A,B). Closed circle represents WT mice born to a WT mother (M∶WT,O∶WT, males n = 11, females n = 12), open circle WT are mice born to an A1R Hz mother (M∶WT,O∶A1R Hz, males n = 6, females n = 6), closed square stand for A1R Hz mice born to a WT mother (M∶A1R Hz,O∶WT, males n = 6, females n = 3) and open square A1R Hz mice born to a A1R Hz mother (M∶A1R Hz,O∶ A1R Hz, males n = 12, females n = 10). Mice were habituated to the open-field arena for 45 min before administration of cocaine (10 mg/kg, i.p.), immediately followed by a 90-min test session. Arrow indicates time of injection of cocaine or vehicle. Results are shown as means±S.E.M.. The enhanced response to cocaine was only present in offspring born to a mother heterozygous for the adenosine A1 receptor gene. Statistical analysis was performed with Two-Way ANOVA with factors offspring's genotype and factor mother's genotype (**p<0.01; ***p<0.001 significantly different from WT mother WT offspring). (C) Response to cocaine in the second generation. Open circle grandmother WT, mother WT, offspring WT (G∶WT,M∶WT,O∶WT, n = 9) and closed circle: grandmother A1R Hz, mother WT, offspring WT (G∶A1R Hz,M∶WT,O∶WT n = 4). After 45 min of habituatain mice were injected cocaine and analysed for the next 90 min. Each point represents the mean±S.E.M of the beam breaks recorded during 15 minute intervals for habituation 3 and cocaine challenge. Arrows indicate the time of cocaine injection. Statistical analysis was performed with Student's t-test (*p<0.05).

Mentions: As shown in Figure 6A, there was a statistically significant increase in locomotor activity in male mice (regardless of their genotype) to the response to cocaine injection only when born to a mother that partially lacked adenosine A1 receptors (significant interaction being mother's genotype p<0.0001, F(1,31) = 23.8, Two Way ANOVA with factors offspring and mother's genotype). The same phenomenon was also found in the female offspring of the A1R Hz mothers after the cocaine stimulation (interaction mother's genotype p = 0.0014, F(1,27) = 12.6, Two Way ANOVA) (Figure 6B).


Perinatal caffeine, acting on maternal adenosine A(1) receptors, causes long-lasting behavioral changes in mouse offspring.

Björklund O, Kahlström J, Salmi P, Fredholm BB - PLoS ONE (2008)

Effect of mother's genotype on cocaine responce.A1R Hz mice are similar to mice exposed to perinatal caffeine in locomotor response to cocaine and this response seems to be dependent on mother's genotype, not offspring's (A,B). Closed circle represents WT mice born to a WT mother (M∶WT,O∶WT, males n = 11, females n = 12), open circle WT are mice born to an A1R Hz mother (M∶WT,O∶A1R Hz, males n = 6, females n = 6), closed square stand for A1R Hz mice born to a WT mother (M∶A1R Hz,O∶WT, males n = 6, females n = 3) and open square A1R Hz mice born to a A1R Hz mother (M∶A1R Hz,O∶ A1R Hz, males n = 12, females n = 10). Mice were habituated to the open-field arena for 45 min before administration of cocaine (10 mg/kg, i.p.), immediately followed by a 90-min test session. Arrow indicates time of injection of cocaine or vehicle. Results are shown as means±S.E.M.. The enhanced response to cocaine was only present in offspring born to a mother heterozygous for the adenosine A1 receptor gene. Statistical analysis was performed with Two-Way ANOVA with factors offspring's genotype and factor mother's genotype (**p<0.01; ***p<0.001 significantly different from WT mother WT offspring). (C) Response to cocaine in the second generation. Open circle grandmother WT, mother WT, offspring WT (G∶WT,M∶WT,O∶WT, n = 9) and closed circle: grandmother A1R Hz, mother WT, offspring WT (G∶A1R Hz,M∶WT,O∶WT n = 4). After 45 min of habituatain mice were injected cocaine and analysed for the next 90 min. Each point represents the mean±S.E.M of the beam breaks recorded during 15 minute intervals for habituation 3 and cocaine challenge. Arrows indicate the time of cocaine injection. Statistical analysis was performed with Student's t-test (*p<0.05).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2597749&req=5

pone-0003977-g006: Effect of mother's genotype on cocaine responce.A1R Hz mice are similar to mice exposed to perinatal caffeine in locomotor response to cocaine and this response seems to be dependent on mother's genotype, not offspring's (A,B). Closed circle represents WT mice born to a WT mother (M∶WT,O∶WT, males n = 11, females n = 12), open circle WT are mice born to an A1R Hz mother (M∶WT,O∶A1R Hz, males n = 6, females n = 6), closed square stand for A1R Hz mice born to a WT mother (M∶A1R Hz,O∶WT, males n = 6, females n = 3) and open square A1R Hz mice born to a A1R Hz mother (M∶A1R Hz,O∶ A1R Hz, males n = 12, females n = 10). Mice were habituated to the open-field arena for 45 min before administration of cocaine (10 mg/kg, i.p.), immediately followed by a 90-min test session. Arrow indicates time of injection of cocaine or vehicle. Results are shown as means±S.E.M.. The enhanced response to cocaine was only present in offspring born to a mother heterozygous for the adenosine A1 receptor gene. Statistical analysis was performed with Two-Way ANOVA with factors offspring's genotype and factor mother's genotype (**p<0.01; ***p<0.001 significantly different from WT mother WT offspring). (C) Response to cocaine in the second generation. Open circle grandmother WT, mother WT, offspring WT (G∶WT,M∶WT,O∶WT, n = 9) and closed circle: grandmother A1R Hz, mother WT, offspring WT (G∶A1R Hz,M∶WT,O∶WT n = 4). After 45 min of habituatain mice were injected cocaine and analysed for the next 90 min. Each point represents the mean±S.E.M of the beam breaks recorded during 15 minute intervals for habituation 3 and cocaine challenge. Arrows indicate the time of cocaine injection. Statistical analysis was performed with Student's t-test (*p<0.05).
Mentions: As shown in Figure 6A, there was a statistically significant increase in locomotor activity in male mice (regardless of their genotype) to the response to cocaine injection only when born to a mother that partially lacked adenosine A1 receptors (significant interaction being mother's genotype p<0.0001, F(1,31) = 23.8, Two Way ANOVA with factors offspring and mother's genotype). The same phenomenon was also found in the female offspring of the A1R Hz mothers after the cocaine stimulation (interaction mother's genotype p = 0.0014, F(1,27) = 12.6, Two Way ANOVA) (Figure 6B).

Bottom Line: This indicates that long-term behavioral alterations in the offspring result from the maternal effect of caffeine, and not a direct effect on fetus.WT offspring from WT mother but having a A(1)R Hz grandmother preserved higher locomotor response to cocaine.We suggest that perinatal caffeine, by acting on adenosine A(1) receptors in the mother, causes long-lasting behavioral changes in the offspring that even manifest themselves in the second generation.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. Olga.Bjorklund@gmail.com

ABSTRACT

Background: There are lingering concerns about caffeine consumption during pregnancy or the early postnatal period, partly because there may be long-lasting behavioral changes after caffeine exposure early in life.

Methodology/principal findings: We show that pregnant wild type (WT) mice given modest doses of caffeine (0.3 g/l in drinking water) gave birth to offspring that as adults exhibited increased locomotor activity in an open field. The offspring also responded to cocaine challenge with greater locomotor activity than mice not perinatally exposed to caffeine. We performed the same behavioral experiments on mice heterozygous for adenosine A(1) receptor gene (A(1)RHz). In these mice signaling via adenosine A(1) receptors is reduced to about the same degree as after modest consumption of caffeine. A(1)RHz mice had a behavioral profile similar to WT mice perinatally exposed to caffeine. Furthermore, it appeared that the mother's genotype, not offspring's, was critical for behavioral changes in adult offspring. Thus, if the mother partially lacked A(1) receptors the offspring displayed more hyperactivity and responded more strongly to cocaine stimulation as adults than did mice of a WT mother, regardless of their genotype. This indicates that long-term behavioral alterations in the offspring result from the maternal effect of caffeine, and not a direct effect on fetus. WT offspring from WT mother but having a A(1)R Hz grandmother preserved higher locomotor response to cocaine.

Conclusions/significance: We suggest that perinatal caffeine, by acting on adenosine A(1) receptors in the mother, causes long-lasting behavioral changes in the offspring that even manifest themselves in the second generation.

Show MeSH
Related in: MedlinePlus