Gender and the behavioral manifestations of neuropathic pain

A model of peripheral nerve injury was used to study gender differences in the development and progression of chronic constriction injury (CCI)-induced hyperalgesia and allodynia in male and female Fischer 344 FBNF1 hybrid rats. Rats were randomly assigned to one of the following treatment groups: (1) gonadally intact unligated males (male); (2) gonadally intact ligated males (male (CCI)); (3) castrated ligated males (male (CAS/CCI)); (4) gonadally intact unligated females (female); (5) gonadally intact ligated females (female (CCI)); and (6) ovariectomized ligated females (female (OVX/CCI)). A plantar analgesia meter and calibrated von Frey pressure filaments were used as the analgesiometric assays. In the absence of nerve injury, gonadally intact males responded significantly faster than females to a thermal nociceptive stimulus. The onset of the behavioral manifestations of unilateral ligation of the sciatic nerve did not differ as a function of sex or hormonal status (e.g., gonadally intact and gonadectomized male and female rats developed thermal hyperalgesia within 14 days post-CCI). Paw withdrawal latency (PWL) values of gonadally intact males returned to baseline control values after postligation day 14, whereas gonadally intact females, ovariectomized females and castrated males continued to elicit robust thermal hyperalgesic symptoms throughout the 35-day duration of the experiment. Allodynic responses to peripheral nerve injury were less variable across genders. These data suggest that the mechanisms underlying chronic nociceptive processing differ as a function of gender and gonadal hormone status.     

Sex differences in locomotor effects of morphine in the rat

Sex differences in reinforcing, analgesic and other effects of opioids have been demonstrated; however, the extent to which sex differences in motoric effects of opioids contribute to apparent sex differences in their primary effects is not known. The goal of this study was to compare the effects of the prototypic mu opioid agonist morphine on locomotor activity in male vs. female rats. Saline or morphine (1-10 mg/kg) was administered s.c. to adult Sprague-Dawley rats, which were placed into a photobeam apparatus for 3-5 h to measure activity. Modulation of morphine's effects by gonadal hormones and by handling (either during the test session or for 4 days before the test session) were examined. Morphine initially suppressed and later increased locomotor activity in both sexes relative to their saline-injected controls, but males were more sensitive than females to the initial locomotor suppressant effect of morphine. Intermittent, brief handling during the 3-h test session blunted morphine-induced locomotor activation in both sexes. Females in proestrus were the most sensitive to morphine's locomotor-stimulant effect, with females in estrus showing the least response to morphine. Gonadectomized (GDX) males with or without testosterone were equally sensitive to morphine's effects, whereas GDX females treated with estradiol showed a blunted response to morphine's effects, similar to intact females in estrus. Brief handling on each of 4 consecutive days pre-test attenuated morphine's locomotor suppressant effect in males but had no effect in females, thereby eliminating the sex difference. These data suggest that sex differences in morphine's effects on locomotor activity can be attributed to gonadal hormones in females, and to differential stress-induced modulation of morphine's effects in males vs. females.     

Expression of proopiomelanocortin and proenkephalin mRNA in sexually dimorphic brain regions are altered in adult male and female rats treated prenatally with morphine

Abstract: The present study demonstrates that prenatal morphine exposure on gestation days 11–18 differentially alters proopiomelanocortin (POMC) and proenkephalin (pENK) mRNA in the hypothalamus and limbic system of adult male and female rats. In adult, prenatally morphine‐exposed male rats POMC mRNA levels are decreased in the arcuate nucleus of the hypothalamus (ARC), while the pENK mRNA levels are increased in the paraventricular nucleus of the hypothalamus (PVN) and in the ventrolateral subdivision of the ventromedial nucleus of the hypothalamus (VMH), specifically in the ventrolateral subdivision of the VMH. In adult, prenatally morphine‐exposed female rats, POMC mRNA levels in the ARC are increased in ovariectomized (OVX) but not in OVX, estradiol benzoate‐ (EB) or EB‐ and progesterone‐ (P) treated females. In contrast, pENK mRNA levels are decreased in the VMH of morphine‐exposed, OVX females and increased in EB‐treated females. Further, prenatal morphine exposure decreases pENK mRNA in the ARC and increases it in the medial pre‐optic area independently of female gonadal hormones. Finally, POMC mRNA levels are increased in the ARC of saline‐exposed, EB‐ or EB‐ and P‐treated females but not in OVX females. Thus, the present study suggests that prenatal morphine exposure sex and brain region specifically alters the level of POMC and pENK mRNA.     

Gonadal hormone modulation of the behavioral effects of Delta9-tetrahydrocannabinol in male and female rats

Female rats are more sensitive than males to many behavioral effects of cannabinoids. The purpose of the present study was to determine if sex differences in the antinociceptive and motoric effects of Delta(9)-tetrahydrocannabinol (THC) are due to activational effects of gonadal steroid hormones. THC-induced antinociception (tail withdrawal, paw pressure tests) and motoric effects (horizontal locomotion, catalepsy) were compared in male and female gonadectomized rats that were chronically treated with hormone (testosterone in males, estradiol in females) vs. those that were gonadectomized and had no hormone replacement. THC's effects were also compared between gonadally intact females tested during vaginal estrus vs. diestrus. THC (5 and 10 mg/kg i.p.) produced very similar antinociceptive effects in no-hormone vs. testosterone-treated males, but significantly less locomotor suppression in testosterone-treated males than those with no hormone replacement. In gonadectomized females, estradiol enhanced THC's antinociceptive but not motoric effects. In gonadally intact, cycling females, 5 mg/kg THC produced slightly to significantly greater behavioral effects in estrous than in diestrous females. These results suggest that sex differences in THC-induced behavioral effects in the adult rat can be attributed to activational effects of testosterone in males and/or estradiol in females.     

Sex differences in locomotor effects of morphine in the rat

Sex differences in reinforcing, analgesic and other effects of opioids have been demonstrated; however, the extent to which sex differences in motoric effects of opioids contribute to apparent sex differences in their primary effects is not known. The goal of this study was to compare the effects of the prototypic mu opioid agonist morphine on locomotor activity in male vs. female rats. Saline or morphine (1–10 mg/kg) was administered s.c. to adult Sprague–Dawley rats, which were placed into a photobeam apparatus for 3–5 h to measure activity. Modulation of morphine's effects by gonadal hormones and by handling (either during the test session or for 4 days before the test session) were examined. Morphine initially suppressed and later increased locomotor activity in both sexes relative to their saline-injected controls, but males were more sensitive than females to the initial locomotor suppressant effect of morphine. Intermittent, brief handling during the 3-h test session blunted morphine-induced locomotor activation in both sexes. Females in proestrus were the most sensitive to morphine's locomotor-stimulant effect, with females in estrus showing the least response to morphine. Gonadectomized (GDX) males with or without testosterone were equally sensitive to morphine's effects, whereas GDX females treated with estradiol showed a blunted response to morphine's effects, similar to intact females in estrus. Brief handling on each of 4 consecutive days pre-test attenuated morphine's locomotor suppressant effect in males but had no effect in females, thereby eliminating the sex difference. These data suggest that sex differences in morphine's effects on locomotor activity can be attributed to gonadal hormones in females, and to differential stress-induced modulation of morphine's effects in males vs. females.     

Estrogen differentially alters NMDA- and kainate-induced seizures in prenatally morphine- and saline-exposed adult female rats

The purpose of the present study was to investigate the effects of prenatal exposure to morphine on seizure susceptibility in adult female rats. Adult female rats, exposed to saline or morphine on prenatal days 11-18, were ovariectomized (OVX) and some were injected 48 h prior to seizure testing with estradiol benzoate (EB). To assess the latency to onset of stereotypy and seizures, females received systemic injections of N-methyl-D-aspartate (NMDA; 150, 175, 200 mg/kg) or kainic acid (KA; 10 or 15 mg/kg). Prenatal morphine exposure increased the latency to onset of wet-dog-shakes (WDS) in both OVX and OVX, EB-injected females after the higher dose of KA. However, prenatal morphine exposure increased the latency to onset of stereotypy only in OVX, EB-injected females after the highest dose of NMDA. Prenatal morphine exposure also increased the latency to onset of seizures after the lower dose of KA, but did not change the latency to onset of NMDA-induced seizures. Additionally, an EB injection increased the latency to onset of seizures in both saline- and morphine-exposed females after the lowest dose of NMDA, but decreased the latency to onset of seizures after the lower dose of KA. Thus, the present study demonstrates that prenatal morphine exposure has different effects on the estrogen regulation of the onset of seizures and stereotypy induced by NMDA or KA in adult, OVX female rats.     

Gender and gonadal hormone effects in the olfactory bulbectomy animal model of depression

Major depressive disorder (MDD) affects women to a greater extent then men; however, the few studies that have examined the role of gender in an animal model of depression have shown inconsistent results. The purpose of the present study was to determine if the gonadal hormone milieu of the animal modulated behavioral changes following olfactory bulbectomy (OBX), a well-documented animal model of depression. Body weight, sucrose preference levels and open-field activity levels were measured once a week for a period of 2 weeks in gonadally intact and gonadectomized male and female rats. Following these baseline measurements, animals underwent either OBX or sham surgery. Body weight, sucrose preference and activity levels were assessed for 4 weeks post-OBX surgery. OBX-gonadectomized animals exhibited higher activity levels than OBX gonadally intact and control animals. This effect of gonadectomy was more robust in males. OBX-females (both intact and gonadectomized) exhibited significantly lower sucrose preference levels than OBX-males (both intact and gonadectomized) and control animals. These results suggest that the gonadal hormone milieu of the animal plays a role in modulating sucrose preference and activity levels following OBX.     

Effect of gonadectomy on discriminative stimulus effects of morphine in female versus male rats

In a previous study, we found sex differences in the potency of morphine as a discriminative stimulus; the present study was designed to determine whether sex differences in gonadal hormones contribute to sex differences in morphine's discriminative effects. Adult female and male rats were gonadectomized (GNDZ) or sham-gonadectomized (SHAM), and then trained to discriminate 3.0 mg/kg morphine from saline. The ED50 for morphine discrimination was significantly lower in females than in males (0.66 +/- 0.12 vs. 1.25 +/- 0.16 mg/kg, respectively); ED50 values in GNDZ rats were slightly higher than in SHAM rats. The time course of morphine discrimination was not significantly different in females and males, whether GNDZ or not. The micro agonist fentanyl completely substituted for morphine in all rats, with no group differences in ED50 value. The micro agonists buprenorphine and nalbuphine substituted for morphine in nearly all females and in all SHAM males, but in only four of seven GNDZ males. The kappa agonist U69,593 did not substitute for morphine in rats of any group. Most opioid agonists were significantly more potent in decreasing response rate in males than females, and in GNDZ than SHAM rats; morphine and nalbuphine also increased response rate above control in some females. A pA2 analysis of naltrexone in combination with morphine suggested that there were no significant differences among groups in receptors at which morphine produced its discriminative stimulus effects. Although hormone replacement in GNDZ female rats at the end of the study reinstated estrous cycling, it did not substantially alter the ED50 for morphine discrimination. Thus, sex differences in potency of morphine as a discriminative stimulus may not be due to sex differences in gonadal hormone milieu. The possibility that sex differences in reinforcement frequency on morphine versus saline levers caused the sex differences in morphine discrimination is discussed.     

Methylphenidate potentiates morphine-induced antinociception, hyperthermia, and locomotor activity in young adult rats

The goal of this study was to determine if the exaggerated morphine-induced conditioned place preference (CPP) response seen in adult rats after preweanling methylphenidate exposure is unique to reward-mediated behaviors or is indicative of generalized changes in opioid-mediated behaviors. Rats were exposed to saline or methylphenidate (2.0 or 5.0 mg/kg) for 10 consecutive days starting on postnatal (PD) 11 with testing beginning on PD 60. In Experiment 1, morphine-induced (0, 2.5, 5.0 or 10.0 mg/kg) antinociception was assessed using the tail immersion and hot plate tasks. In Experiment 2, morphine-induced (0, 2.5, 5.0, or 10.0 mg/kg) hyperthermia and locomotor activity were measured. Morphine caused an increase in antinociception, with early methylphenidate (5.0 mg/kg) exposure potentiating the effects of 5.0 mg/kg morphine. Rectal temperatures were elevated after morphine, with the greatest increase occurring in male rats. Methylphenidate potentiated the hyperthermic effects of morphine (10.0 mg/kg) but only in males. Moderate doses (2.5 and 5.0 mg/kg) of morphine increased the locomotor activity of adult rats, while a higher dose (10.0 mg/kg) decreased locomotion. Interestingly, methylphenidate-pretreated females showed increased locomotor activity relative to controls. These results suggest that early methylphenidate exposure induces general changes in opioid system functioning that are not specific to reward-mediated behaviors.     

Facilitation of sexual behaviors in the male rat in the presence of stimuli previously paired with systemic injections of morphine

Male rats were tested for sexual behaviors in an environment previously associated with injections of morphine. Both gonadally intact and castrated males displayed more frequent female-directed behavior, such as pursuit of the female, anogenital exploration, and partial mounts, and gonadally intact animals had shorter latencies to initiate copulation when tested for sexual behaviors in the environment previously associated with morphine. These results suggest that a conditioned state induced by stimuli previously paired with the positive incentive effects of an opiate drug can facilitate or modulate behaviors under the control of other primary positive incentives.     

Neonatal stress alters habituation of exploratory behavior in adult male but not female rats

The effect of monosodium-L-glutamate (MSG) administration in the neonatal period on habituation of exploratory behavior related to gender differences was investigated. Rats of both sexes were intraperitoneally treated with MSG (4 mg/g) or hypertonic saline (10% NaCl) on postnatal days 2, 4, 6, 8, and 10. On postnatal day 65, the animals were tested in an open-field test during 4 consecutive days, once daily in 6-min sessions. The rapidity of habituation of exploratory behavior during repeated exposure to the open field (interrupted habituation) and over individual sessions (uninterrupted habituation) was evaluated by using the method of linear regression. Compared to intact controls, there were no significant differences found in interrupted habituation, neither in males nor in females. Uninterrupted habituation in neonatally treated males was slowed down in the first 2 days of testing. No differences in adult behavior between treated groups (MSG and hypertonic saline) were observed, i.e., there were no late effects specific for neonatal MSG administration. In females, uninterrupted habituation was not affected. Males proved to be more sensitive to neonatal stress associated with injections of MSG or hypertonic saline than females, and showed feminine-like habituation in the new environment.     

Long-lasting changes in stress-induced corticosterone response and anxiety-like behaviors as a consequence of neonatal maternal separation in Long-Evans rats

Early neonatal environmental factors appear to have powerful and long-lasting influences on an organism's physiology and behavior. Long-Evans male rats separated from their dam for 3 h daily over the first 2 weeks of life (maternally separated, MS rats) when tested as adults exhibit exaggerated behavioral and neuroendocrine responses to stress compared to 15-min separated (handled, H) animals. The purpose of this study was to compare male and female adult rats that were MS, H or were undisturbed (nonhandled, NH) as neonates in anxiety-like behaviors, in the elevated plus-maze, and in response to startle-inducing auditory stimuli. We confirmed that MS males oversecrete corticosterone (CORT; 2.5-5 times) in response to mild handling stress. MS males and females were less likely to explore open arms of the plus-maze. MS males exhibited 35% higher startle amplitudes compared to controls. Furthermore, MS males were more likely to emit ultrasonic vocalizations in response to startle than were H controls. However, MS and control females did not differ in auditory startle response or in startle-induced ultrasonic vocalizations. Therefore, experiencing maternal separation results in a long-lasting increase in anxiety-like behaviors that occurs in a sex-dependent manner.     

Ovarian hormones and chronic administration during adolescence modify the discriminative stimulus effects of delta-9-tetrahydrocannabinol (Δ⁹-THC) in adult female rats

Marijuana abuse during adolescence may alter its abuse liability during adulthood by modifying the interoceptive (discriminative) stimuli produced, especially in females due to an interaction with ovarian hormones. To examine this possibility, either gonadally intact or ovariectomized (OVX) female rats received 40 intraperitoneal injections of saline or 5.6 mg/kg of Δ⁹-THC daily during adolescence, yielding 4 experimental groups (intact/saline, intact/Δ⁹-THC, OVX/saline, and OVX/Δ⁹-THC). These groups were then trained to discriminate Δ⁹-THC (0.32-3.2 mg/kg) from saline under a fixed-ratio (FR) 20 schedule of food presentation. After a training dose was established for the subjects in each group, varying doses of Δ⁹-THC were substituted for the training dose to obtain dose-effect (generalization) curves for drug-lever responding and response rate. The results showed that: 1) the OVX/saline group had a substantially higher mean response rate under control conditions than the other three groups, 2) both OVX groups had higher percentages of THC-lever responding than the intact groups at doses of Δ⁹-THC lower than the training dose, and 3) the OVX/Δ⁹-THC group was significantly less sensitive to the rate-decreasing effects of Δ⁹-THC compared to other groups. Furthermore, at sacrifice, western blot analyses indicated that chronic Δ⁹-THC in OVX and intact females decreased cannabinoid type-1 receptor (CB1R) levels in the striatum, and decreased phosphorylation of cyclic adenosine monophosphate response element binding protein (p-CREB) in the hippocampus. In contrast to the hippocampus, chronic Δ⁹-THC selectively increased p-CREB in the OVX/saline group in the striatum. Extracellular signal-regulated kinase (ERK) was not significantly affected by either hormone status or chronic Δ⁹-THC. In summary, these data in female rats suggest that cannabinoid abuse by adolescent human females could alter their subsequent responsiveness to cannabinoids as adults and have serious consequences for brain development.     

Neonatal naltrindole and handling differently affect morphine antinociception in male and female rats

The effects of a daily injection of the delta selective opioid antagonist naltrindole (1 mg/kg), from birth to postnatal day 19, on antinociceptive responses to morphine (2 mg/kg) in 20-day-old rats of both sexes were investigated. The effects of postnatal handling were studied by including two control groups--one group receiving daily injections of saline, and a naive unhandled group. Antinociception was assessed using the tail-immersion test and time-response curves (5, 10, 15, and 30 min) were carried out for all experimental groups. In all treatment groups females showed greater sensitivity to the noxious stimuli compared to males. No significant effect of naltrindole treatment on baseline latencies was found. Postnatal handling increased sensitivity to thermal pain in both sexes, and reduced the effect of morphine in males. No significant effect of chronic naltrindole administration on morphine antinociception was found in this sex. Naltrindole-treated females showed an increased antinociception when compared to unhandled animals of the same gender. The results indicate that preweanling handling stress and chronic naltrindole treatment differentially affected morphine antinociception in male and female neonatal rats.     

Sex differences in discriminative stimulus effects of morphine in the rat

Nine female and ten male rats were trained to discriminate 3.0mg/kg s.c. morphine from saline. The six female rats that acquired and maintained the morphine discrimination did so in significantly fewer sessions than the eight males did (28 +/- 5 vs 51 +/- 9 sessions, respectively), and the ED(50) for morphine substitution was significantly lower in females (0.69 +/- 0.15 vs 1.28 +/- 0.20mg/kg). The time course of morphine substitution was approximately equivalent in females and males. The μ agonist fentanyl completely substituted for morphine in both sexes, with no sex difference in potency to substitute for morphine. The μ agonist buprenorphine partially or completely substituted for morphine in all females and five of six males, but at a lower dose in females (ED(50) 0.009 +/- 0.002 vs 0.019 +/- 0.006mg/kg). The delta agonist BW373U86 partially substituted for morphine in both sexes, with no potency differences; the kappa agonist U69,593 and the non-opioid cocaine did not substitute for morphine in either sex. On a test of spontaneous locomotor activity, morphine increased locomotion to a slightly but not significantly greater extent in males than in females. Morphine also produced significantly greater hotplate antinociception in males than in females. Further drug discrimination training with a lower dose of morphine, 1.0mg/kg, decreased the ED(50) for morphine substitution in females and males to 0.26 +/- 0.06 vs 0.45 +/- 0.11mg/kg, respectively (not significant). In a separate group of age-matched rats, there was no sex difference in brain or plasma levels of morphine measured via HPLC 20min post-injection, the pretreatment time used to examine behavioral effects of morphine. The HPLC results, plus the fact that sex differences were not the same for all behavioral effects of morphine, suggest that sex differences in discriminative stimulus effects of morphine are not due to differential pharmacokinetics. The possibility that sex differences in morphine discrimination reflect sex differences in opioid receptor pharmacology, or differential reinforcement between morphine and saline levers for males but not females, is discussed.     

Anxiety- and depression-like behaviors are accompanied by an increase in oxidative stress in a rat model of fetal alcohol spectrum disorders: Protective effects of voluntary physical exercise

Prenatal ethanol exposure can damage the developing nervous system, producing long-lasting impairments in both brain structure and function. In this study we analyzed how exposure to this teratogen during the period of brain development affects the intracellular redox state in the brain as well as the development of anxiety- and depressive-like phenotypes. Furthermore, we also tested whether aerobic exercise might have therapeutic potential for fetal alcohol spectrum disorders (FASD) by increasing neuronal antioxidant capacity and/or by alleviating ethanol-induced behavioral deficits. Sprague-Dawley rats were administered ethanol across all three-trimester equivalents (i.e., throughout gestation and during the first 10 days of postnatal life). Ethanol-exposed and control animals were assigned to either sedentary or running groups at postnatal day (PND) 48. Runners had free access to a running wheel for 12 days and at PND 60 anxiety- and depressive-like behaviors were assessed. Perinatal ethanol exposure resulted in the occurrence of depressive and anxiety-like behaviors in adult rats without affecting their locomotor activity. Voluntary wheel running reversed the depressive-like behaviors in ethanol-exposed males, but not in ethanol-exposed females. Levels of lipid peroxidation and protein oxidation were significantly increased in the hippocampus and cerebellum of ethanol-exposed rats, and there was a concomitant reduction in the levels of the endogenous antioxidant glutathione. Voluntary exercise was able to reverse the deficits in glutathione both in ethanol-exposed males and females. Thus, while voluntary physical exercise increased glutathione levels in both sexes, its effects at the behavioral level were sex dependent, with only ethanol-exposed male runners showing a decrease in depressive-like behaviors.     

Dietary ethinyl estradiol exposure during development causes increased voluntary sodium intake and mild maternal and offspring toxicity in rats

Exogenous estrogen exposure during development often results in behavioral masculinization and/or defeminization of genetic females. Genetic males may be defeminized, hypermasculinized or even demasculinized after similar treatment. Here, pregnant Sprague-Dawley rats consumed phytoestrogen-free diets containing 0, 1, 5 or 200 ppb EE(2) beginning on gestational day (GD) 7. Offspring were weaned to the same maternal diet and maintained gonadally intact. There were mild effects on body weight and food consumption in dams of the 200 ppb group and their offspring weighed less at birth than those of the control group; however, gross assessments of nursing behavior were normal in all dietary groups. Postweaning, offspring of the 200 ppb group weighed less and consumed less food than controls. There were no EE(2)-related effects on open-field activity (tested at postnatal days (PND) 22-24, 43-45 and 64-66), play behavior (tested at PND 35), running wheel activity (PND 63-77) or intake of a 0.3% saccharin-flavored solution (PND 69-71). Intake of a 3.0% sodium chloride-flavored solution on PND 73-75 was increased in both male and female offspring of the 200 ppb group relative to same-sex controls, an effect that is reportedly estrogen mediated. Sodium chloride-flavored solution intake is a sexually dimorphic behavior for which female rats consume more than males. Here, while EE(2) exposure had few effects on the conventional tests of sexually dimorphic behaviors, exposure to 200 ppb in the diet appeared to feminize genetic males and hyperfeminize genetic females with regard to sodium intake.     

Cocaine-induced behavioral sensitization in preweanling and adult rats: effects of a single drug–environment pairing

Rationale Adult rats typically exhibit more robust behavioral sensitization than do preweanling rats. A possible explanation for this age-dependent difference is that environmental context may have relatively less impact on the psychostimulant-induced behaviors of preweanling rats. Objective The purpose of this study was to assess the importance of environmental context for the development of cocaine-induced sensitization in preweanling and adult rats. Materials and methods On postnatal day (PD) 19 or PD 79, rats in the context-dependent condition were injected with 30 mg/kg cocaine immediately before being placed in a novel test chamber for 30 min. The same rats were then injected with saline 30 min after being returned to the home cage. Rats in the context-independent condition were injected with saline before being placed in the novel chamber and cocaine in the home age. Control rats were injected with saline at both time points. One day later, adult and preweanling rats were challenged with saline or 10 mg/kg cocaine (experiment 1), or preweanling rats were challenged with 5, 20, or 30 mg/kg cocaine (experiment 2). After being injected, rats were placed in the test chamber, and behavior was measured for 60 min. Results Adult rats showed context-dependent locomotor sensitization and conditioned activity, with females exhibiting more locomotor activity than males. Preweanling rats did not exhibit conditioned activity, but they showed robust context-dependent and context-independent sensitization when challenged with 10–30 mg/kg cocaine. Conclusions Context did not influence the expression of behavioral sensitization in preweanling rats, suggesting that deficits in associative or memory processes may be responsible for age-dependent differences in behavioral sensitization and conditioned activity.     

Gonadal steroids mediate the opposite changes in cocaine-induced locomotion across adolescence in male and female rats

Evidence from both human studies and animal models indicates that cocaine elicits more behavioral stimulation in females than males. The present study sought to determine whether sex-specific responses to cocaine emerge during adolescence and to determine if gonadal steroid action during puberty affects adult responsiveness to cocaine. We administered cocaine using an escalating dose model in male and female rats at ages postnatal (PN) 28, 42, and 65 days. To assess the effects of pubertal gonadal steroid action, we compared the effects of binge cocaine administration on intact and prepubertally gonadectomized male and female rats in adulthood. Cocaine responses changed in opposite directions in males and females as they progressed through adolescence. At most doses, adolescent males were more responsive than adult males whereas adult females were more responsive than adolescent females. Ambulatory activity was age-dependent in males whereas non-ambulatory activity was age-dependent in females. Prepubertal gonadectomy increased behavioral responsiveness to the highest dose of cocaine in males whereas it decreased behavioral responsiveness to lower doses of cocaine in females. We conclude that sex differences in behavioral responses to cocaine arise during adolescence from a concurrent decrease in male responsiveness and increase in female responsiveness. Our results suggest that gonadal steroids exert lasting and opposing effects on the sensitivity of males and females to psychostimulants during development.     

AMPA/kainate receptors in the ventromedial hypothalamus mediate the effects of glutamate on estrus termination in the rat

Infusions of glutamate or its selective receptor agonists to the VMH of ovariectomized (OVX) female rats primed with estradiol benzoate (EB) and progesterone (P) inhibit both appetitive and consummatory aspects of sexual behavior whereas selective glutamate receptor antagonists facilitate these measures in females primed with EB alone. Because vaginocervical stimulation (VCS) activates glutamate neurons in the VMH, and induces a faster termination of estros behavior, the present study examined the effects of the AMPA/kainate receptor antagonist DNQX on the induction of estrus termination by manual VCS. Ovx, sexually-experienced rats were primed with EB and P and subsequently received either 1 or 50 distributed VCSs, over the course of an hour, 12 h before a test with sexually vigorous males. Half of the females in each stimulus group received bilateral infusions of 1 μl/side of either DNQX (19.8 mmol/μl) or saline aimed at the VMH immediately prior to VCS or sham stimulation. Saline-infused females given VCS had lower lordosis quotients compared to females given sham stimulation. In contrast, females infused with DNQX prior to VCS displayed more appetitive behaviors and higher lordosis quotients and magnitudes compared to females infused with saline. These data indicate that activation of AMPA/kainate receptors in the VMH by increased glutamate transmission induced by VCS mediates estrus termination.