Repeated maternal separation: differences in cocaine-induced behavioral sensitization in adult male and female mice.
BACKGROUND
Repeated maternal separations profoundly alter the adult stress response, the development of the hypothalamic-pituitary-adrenal axis, and prominently, the GABAergic and monoaminergic systems. These neural changes are postulated to influence the vulnerability to drugs of abuse implicating glucocortocoids in the behavioral responses to psychomotor stimulants.


OBJECTIVE
To investigate whether repeated brief maternal separation stress increases behavioral sensitization to cocaine in adult male and female mice, and to assess any concurrent changes in hippocampal glucocorticoid receptors and accumbal dopamine transporters.


METHODS
Half of the litters were separated from the nest for 1 h/day from post-natal days 1 to 13. Starting on post-natal day 50, all mice were injected with either cocaine (10.0 mg/kg) or saline for 10 consecutive days. Locomotor activity was assessed in an open field on days 50, 54 and 59 via a tracking system. Approximately 10 and 40 days later, all mice were challenged with 7.5 mg/kg cocaine.


RESULTS
Repeated maternal separation increased the hyperlocomotor response to 10.0 mg/kg cocaine regardless of gender. During expression tests (days 69/71, 99), male, but not female, mice with a history of maternal separation exhibited significant sensitized hyperactivity in response to cocaine. Male mice that were maternally separated and had no history of cocaine sensitization, demonstrated cross-sensitization to 7.5 mg/kg cocaine. Immunohistochemical analysis revealed that the hippocampal CA1 glucocorticoid receptor and nucleus accumbens dopamine transporter proteins were expressed more in females than in males, regardless of maternal separation experience.


CONCLUSIONS
Repeated maternal separation is a stressor that can induce heightened sensitivity to low doses of cocaine, as expressed by hyperactivity. Furthermore, sex differences in glucocorticoid receptor and dopamine transporter expression may be responsible for the sexual dimorphic expression of behavioral sensitization to cocaine.
Department of Psychology, Tufts University, Medford, MA 02155, USA.
Takefumi
T
Kikusui
Sara
S
Faccidomo
Klaus A
KA
Miczek
D000818:Animals; D001143:Arousal / Q000187:drug effects / Q000502:physiology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000503:physiopathology*; D050483:Dopamine Plasma Membrane Transport Proteins; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D008426:Maternal Deprivation; D008562:Membrane Glycoproteins / Q000502:physiology; D026901:Membrane Transport Proteins / Q000502:physiology; D051379:Mice; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000503:physiopathology; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000503:physiopathology; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000502:physiology; D012008:Recurrence; D012307:Risk Factors; D012737:Sex Factors; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011965:Receptors, Glucocorticoid; D005680:gamma-Aminobutyric Acid; D003042:Cocaine