ABSTRACT
Cocaine sensitization is a marker for some facets of addiction, is greater in female rats, and may be influenced by their sex hormones. We compared the modulatory effects of endogenous or exogenous estradiol and progesterone on cocaine-induced behavioral sensitization in 106 female rats. Ovariectomized female rats received progesterone (0.5 mg/mL), estradiol (0.05 mg/mL), progesterone plus estradiol, or the oil vehicle. Sham-operated control females received oil. Control and acute subgroups received injections of saline, while the repeated group received cocaine (15 mg/kg, ip) for 8 days. After 10 days, the acute and repeated groups received a challenge dose of cocaine, after which locomotion and stereotypy were monitored. The estrous cycle phase was evaluated and blood was collected to verify hormone levels. Repeated cocaine treatment induced overall behavioral sensitization in female rats, with increased locomotion and stereotypies. In detailed analysis, ovariectomized rats showed no locomotor sensitization; however, the sensitization of stereotypies was maintained. Only females with endogenous estradiol and progesterone demonstrated increased locomotor activity after cocaine challenge. Estradiol replacement enhanced stereotyped behaviors after repeated cocaine administration. Cocaine sensitization of stereotyped behaviors in female rats was reduced after progesterone replacement, either alone or concomitant with estradiol. The behavioral responses (locomotion and stereotypy) to cocaine were affected differently, depending on whether the female hormones were of an endogenous or exogenous origin. Therefore, hormonal cycling appears to be an important factor in the sensitization of females. Although estradiol increases the risk of cocaine sensitization, progesterone warrants further study as a pharmacological treatment in the prevention of psychostimulant abuse.
Subject(s)
Central Nervous System Sensitization/drug effects , Cocaine/pharmacology , Estradiol/blood , Motor Activity/drug effects , Progesterone/blood , Stereotyped Behavior/drug effects , Analysis of Variance , Animals , Cocaine/administration & dosage , Estradiol/pharmacology , Estrous Cycle/blood , Female , Hormone Replacement Therapy , Ovariectomy , Progesterone/pharmacology , Rats, Wistar , Sex FactorsABSTRACT
Cocaine sensitization is a marker for some facets of addiction, is greater in female rats, and may be influenced by their sex hormones. We compared the modulatory effects of endogenous or exogenous estradiol and progesterone on cocaine-induced behavioral sensitization in 106 female rats. Ovariectomized female rats received progesterone (0.5 mg/mL), estradiol (0.05 mg/mL), progesterone plus estradiol, or the oil vehicle. Sham-operated control females received oil. Control and acute subgroups received injections of saline, while the repeated group received cocaine (15 mg/kg, ip) for 8 days. After 10 days, the acute and repeated groups received a challenge dose of cocaine, after which locomotion and stereotypy were monitored. The estrous cycle phase was evaluated and blood was collected to verify hormone levels. Repeated cocaine treatment induced overall behavioral sensitization in female rats, with increased locomotion and stereotypies. In detailed analysis, ovariectomized rats showed no locomotor sensitization; however, the sensitization of stereotypies was maintained. Only females with endogenous estradiol and progesterone demonstrated increased locomotor activity after cocaine challenge. Estradiol replacement enhanced stereotyped behaviors after repeated cocaine administration. Cocaine sensitization of stereotyped behaviors in female rats was reduced after progesterone replacement, either alone or concomitant with estradiol. The behavioral responses (locomotion and stereotypy) to cocaine were affected differently, depending on whether the female hormones were of an endogenous or exogenous origin. Therefore, hormonal cycling appears to be an important factor in the sensitization of females. Although estradiol increases the risk of cocaine sensitization, progesterone warrants further study as a pharmacological treatment in the prevention of psychostimulant abuse.
Subject(s)
Animals , Female , Central Nervous System Sensitization/drug effects , Cocaine/pharmacology , Estradiol/blood , Motor Activity/drug effects , Progesterone/blood , Stereotyped Behavior/drug effects , Analysis of Variance , Cocaine/administration & dosage , Estradiol/pharmacology , Estrous Cycle/blood , Hormone Replacement Therapy , Ovariectomy , Progesterone/pharmacology , Rats, Wistar , Sex FactorsABSTRACT
The present study aimed to verify the effect of bilateral intra-hippocampus administration of the neurosteroid allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one; 3alpha, 5alpha-THP) in the forced swimming test (FST) and in the alpha4 and gamma2 GABA(A) receptor subunits gene expression. Results showed that bilateral intra-hippocampal allopregnanolone administration of 2.5 microg/rat ( P<0.05) reduced immobile behavior and increased climbing behavior in the FST. Overall, for all doses of allopregnanolone tested (1.25, 2.5, 5.0 microg/rat), an increase of gamma2 (P<0.05) GABA(A) subunit mRNA was observed. There was a higher increase in the gamma2 gene expression in the right hemisphere than in the left hemisphere (P<0.01) after allopregnanolone treatment. Intra-hippocampal allopregnanolone did not change the expression of the alpha4 subunits. In conclusion, intra-hippocampal administration of allopregnanolone produces an antidepressant-like effect in the FST at an intermediate dose, confirming the potential of neurosteroids as a new class of antidepressant drugs. Our findings suggest that the gamma2, but not the alpha4 GABA(A) subunit, needs further evaluation to be involved in the antidepressant effect of allopregnanolone in the hippocampus and that there is a hemispheric diversity in the biochemical effect of the drug.
