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HIV-1 infection affects approximately 37 million individuals, and approximately 50% of seropositive individuals will develop symptoms of clinical depression and/or apathy. Dysfunctions of both serotonergic and dopaminergic neurotransmission have been implicated in the pathogenesis of motivational alterations. The present study evaluated the efficacy of a SSRI (escitalopram) in the HIV-1 transgenic (Tg) rat. Behavioral, neurochemical, and neuroanatomical outcomes with respect to HIV-1 and sex were evaluated to determine the efficacy of chronic escitalopram treatment. Escitalopram treatment restored function in each of the behavioral tasks that were sensitive to HIV-1-induced impairments. Further, escitalopram treatment restored HIV-1-mediated synaptodendritic damage in the nucleus accumbens; treatment with escitalopram significantly increased dendritic proliferation in HIV-1 Tg rats. However, restoration did not consistently occur with the neurochemical analysis in the HIV-1 rat. Taken together, these results suggest a role for SSRI therapies in repairing long-term HIV-1 protein-mediated neuronal damage and restoring function. [ABSTRACT FROM AUTHOR]

HIV-1 and addictive drugs, such as cocaine (COC), may act in combination to produce serious neurological complications. In the present experiments, striatal brain slices from HIV-1 transgenic (Tg) and F344 control female rats were studied. First, we examined dopamine (DA) reuptake in control, HIV-1, COC-treated (5µM) and HIV-1+COC-treated, striatal slices using fast scan cyclic voltammetry. COC-treated striatal slices from F344 control animals significantly increased DA reuptake time (T80), relative to untreated control slices. In contrast, in HIV-1 Tg striatal slices, DA reuptake time was extended by HIV-1, which was not further altered by COC treatment. Second, analysis of medium spiny neuronal populations from striatal brain slices found that controls treated with cocaine displayed increases in spine length, whereas cocaine treated HIV-1 slices displayed decreased spine length. Taken together, the current study provides evidence for dysfunction of the dopamine transporter (DAT) in mediating DA reuptake in HIV-1 Tg rats and limited responses to acute COC exposure. Collectively, dysfunction of the DAT reuptake and altered dendritic spine morphology of the MSNs, suggest a functional disruption of the dopamine system within the HIV-1 Tg rat. [ABSTRACT FROM AUTHOR]

Understanding the variability caused by uterine position effects in polytocus species, such as rats, may enhance prenatal animal models for the study of drug and environmental agents. The primiparous litters of 42 intact female Sprague-Dawley rats were studied. Uterine position, fetal body weight, and fetal brain (wet) weight were recorded on gestation day (GD) 20 (GD 0 = sperm positive). Uterine position effect for brain and body weight varied depending upon horn size. Furthermore, an inverse relationship between horn size (and, to a lesser extent, litter size) and fetal weight applied to both body and brain weight measures. There were no statistical differences in brain and body weights between the left and right uterine horns. The position of the uterine horn (left vs. right) and litter size did not influence the uterine position effect in the rat. Collectively, the present data suggest the presence of a significant uterine position effect. Prenatal differences based on uterine position provide an untapped opportunity to increase our understanding of developmental neurotoxicological and teratological studies that employ a polytocus species as an animal model. [ABSTRACT FROM AUTHOR]

Abstract: Long-term consequences of early developmental exposure to drugs of abuse may have deleterious effects on the proliferative plasticity of the brain. The purpose of this study was to examine the long-term effects of prenatal exposure to cocaine, using the IV route of administration and doses that mimic the peak arterial levels of cocaine use in humans, on the proliferative cell types of the subventricular zones (SVZ) in the adult (180 days-old) rat brain. Employing immunocytochemistry, the expression of GFAP+ (type B cells) and nestin+(GFAP−) (type C and A cells) staining was quantified in the subcallosal area of the SVZ. GFAP+ expression was significantly different between the prenatal cocaine treated group and the vehicle (saline) control group. The prenatal cocaine treated group possessed significantly lower GFAP+ expression relative to the vehicle control group, suggesting that prenatal cocaine exposure significantly reduced the expression of type B neural stem cells of the SVZ. In addition, there was a significant sex difference in nestin+ expression with females showing approximately 8–13% higher nestin+ expression compared to the males. More importantly, a significant prenatal treatment condition (prenatal cocaine, control) by sex interaction in nestin+ expression was confirmed, indicating different effects of cocaine based on sex of the animal. Specifically, prenatal cocaine exposure eliminated the basal difference between the sexes. Collectively, the present findings suggest that prenatal exposure to cocaine, when delivered via a protocol designed to capture prominent features of recreational usage, can selectively alter the major proliferative cell types in the subcallosal area of the SVZ in an adult rat brain, and does so differently for males and females. [Copyright &y& Elsevier]

Abstract: The purpose of the present experiment was to examine the effects of acute and repeated intravenous (IV) cocaine on rat behavior in the home cage environment. An observational sampling method was used. Pair-housed, male, female, castrated (CAST), and ovariectomized (OVX) rats were administered daily IV cocaine injections (3.0 mg/kg/injection) in the home cage for 13 consecutive days, and observations occurred after the 1st and 13th injections. The incidence, i.e., occurrence or nonoccurrence of a behavior, was recorded according to a behavioral profile comprised of 11 behaviors. Data were analyzed as locomotor composite and orofacial composite scores. Behaviors not amenable for combination into a composite incidence score were evaluated independently (e.g., still behavior). Females exhibited more locomotor incidence scores than males following acute injection and more still behavior after repeated cocaine administration. Females exhibited more locomotor activity than OVX rats following acute, but not repeated, cocaine injection. There were no differences between the male and CAST rats on days 1 or 13. CAST rats exhibited more still behavior than OVX following only acute cocaine administration. This study indicates that IV cocaine-induced sex differences and the effects of gonadectomy can be measured in the home cage, and furthermore, describes a simple method to screen changes in cocaine-induced locomotor behaviors in the absence of automated equipment. [Copyright &y& Elsevier]

Attentional dysfunction is a persistent behavioral abnormality that is emerging as one of the cardinal features in the investigations of the teratogenic effects of cocaine in humans and rodents. The present study sought to extend this work by using a dose–response design with an alternate strain of rat. Virgin Long–Evans female rats, implanted with an IV access port prior to breeding were administered saline, 0.5, 1.0, or 3.0 mg/kg of cocaine HCl from gestational day (GD) GD8–21 (1× per day-GD8–14, 2× per day-GD15–21). Cocaine had no significant effect on maternal or litter parameters. At 14–15 days of age, 1 male and 1 female from each litter were tested to evaluate the heart rate orienting response (HR-OR). Following 20 min for acclimation, pups were presented an olfactory stimulus for 20 s per trial, across four trials, and with an intertrial interval of 2 min. The initial baseline HR was not significantly different across the treatment groups, although cocaine did alter the stability of the QRS complex duration. The magnitude of the HR-OR averaged across trials increased as a linear function of dosage of cocaine. A more complex (quadratic) interaction between cocaine dose and sex of the offspring was also noted. When examined across trials, the controls failed to display any significant within-session variation in the HR-OR; in contrast all of the prenatal cocaine treated groups displayed either sensitization (low and high dose) or habituation of the response (middle dose). Analysis of the peak HR-OR confirmed that the controls were indeed displaying the response on at least one trial of the session, albeit not consistently on any specific trial. The more vigorous HR-OR of the prenatal cocaine groups, relative to vehicle controls, most likely reflects an alteration in development of the neural basis of response; as previously shown, the most vigorous response to the olfactory stimulus is seen early (12 days of age) and progressively decreases across the preweaning period. In sum, prenatal exposure to cocaine, at least when administered by the IV route, provides reproducible alterations in attentional processes, as indexed by the noradrenergically-mediated HR-OR. The documentation of a linear dose–response function suggests that there is likely no threshold for the drug-induced alteration. Moreover, the sex of the animal also appears to play some role in the nature of the expression of the altered HR-OR. [Copyright &y& Elsevier]

The present study was designed to examine retention of spatial information in the immature, Fischer-344N rat using a savings paradigm. Following training to locate a hidden platform using extramaze cues, preweanling animals (17 days of age) were immediately probed by testing in the tank with the platform removed. One week later, pups (26 days of age) were given an additional four training trials immediately followed by a second probe test to examine the animals' memory for the location of the platform. Animals that received initial training at 17 days of age demonstrated significant savings of information when tested after the retention interval. These data replicate our recent report of spatial navigation capabilities in the preweanling rat, and extend those findings by demonstrating that preweanling spatial navigation performance permits more rapid and accurate navigation following a 7-day retention interval after a “reinstatement” insufficient to produce accurate navigation in maturation controls. © 2002 John Wiley & Sons, Inc. Dev Psychobiol 40: 68–77, 2002 [ABSTRACT FROM AUTHOR]

Abstract: Previous research demonstrates that repeated intravenous (IV) nicotine injection resulted in increased locomotor sensitization in female relative to male rats. In order to determine if increased nicotine levels are detected in females compared to males the present experiment examined the plasma nicotine levels of male, female, castrated (CAST), and ovariectomized (OVX) rats (n =7–11 rats/group) following repeated IV nicotine injection (50 μg/kg/injection). All rats received 14 IV nicotine injections, one/day. Approximately 1 min after the 14th nicotine injection, rats were rapidly decapitated and trunk blood was collected immediately. Gas chromatography revealed a sex difference in nicotine content: higher plasma nicotine levels were measured from female rats (>10 × increase) relative to males, and the sex difference was attenuated by gonadectomy. These data suggest that the sex difference in plasma nicotine levels is due to alteration in distribution or nicotine metabolism as a function of circulating gonadal hormones. These findings indicate that gonadal hormones may influence nicotine pharmacokinetics and therefore nicotine-induced sex differences in behavior. [Copyright &y& Elsevier]

The present study was designed to assess working memory in adult rats exposed to intravenous cocaine in utero, as part of an examination of various cognitive and affective functions. The study included four groups: a saline control and three groups exposed to ascending doses of cocaine from gestational days 8 to 21 (0.5, 1.0, or 3.0 mg/kg). This exposure regimen (route of administration and dose) has been shown to accurately reproduce the pharmacokinetic profile and physiological effects of human recreational cocaine use. This report describes the results of a series of automated alternation tasks, in which the animals were rewarded for alternating their responses between two response ports on successive trials. In the final task, the delay between trials varied randomly between 0, 20, 40, and 80 s, thereby varying the retention interval. Although performance declined dramatically as the retention interval increased, the rate of this decline did not differ across treatment groups. These results suggest that prenatal cocaine exposure, at doses that model recreational use, does not produce lasting changes in explicit memory or working memory. However, subtle, sex-specific effects of prenatal cocaine exposure were seen on measures that indicate impairments in sustained attention and “readiness”, as well as altered reactivity to task-related stressors such as waiting for long and unpredictable delays. [Copyright &y& Elsevier]

Abstract: Neurotoxic viral proteins released from HIV-infected cells are believed to play a major role in the pathogenesis of the dementia displayed in a significant number of AIDS patients. HIV-1 associated neuropathology severely affects dopaminergic regions of the brain. Growing evidence indicates that HIV-1 neurotoxic proteins, such as Tat may affect the function of the dopamine transmission system. In turn, molecular components of dopamine neurotransmission may participate in a complex network of Tat-induced cell responses which result in neurodegeneration. In this study we investigated whether D1 dopamine receptors are involved in the mechanism of Tat neurotoxicity in primary rat neuronal cell cultures. We found that in rat midbrain cell cultures, which express significant levels of D1 dopamine receptors, the specific D1 antagonist SCH 23390 attenuates the cell death caused by HIV-1 Tat. In rat hippocampal cell cultures, where the expression of D1 receptors is low, SCH 23390 did not change the toxicity of Tat. Thus, the protective effect of SCH 23390 in rat primary neuronal cell cultures is a function of the level of D1 receptor protein expression. Our results provide further evidence for the involvement of the dopaminergic transmission system in the mechanism of HIV-1 Tat neurotoxicity. [Copyright &y& Elsevier]

Abstract: The present experiment examined the effects of sex and gonadectomy on cocaine-induced locomotor activity via intravenous (IV) cocaine. Male, female, castrated (CAST), and ovariectomized (OVX) rats received daily IV cocaine injections (3.0 mg/kg/injection) for 13 consecutive days. Locomotor activity was measured in automated activity chambers for 60 min following the baseline-saline administration and after the 1st and 13th cocaine injections. Observational time sampling was also performed, and the observational data were grouped into locomotor and orofacial composite incidence scores. Females exhibited more cocaine-induced locomotor activity, rearing, and locomotor incidence compared to males. The orofacial data revealed a sex difference in the expression of behavioral sensitization: females exhibited more orofacial behaviors than males after repeated, but not acute, cocaine injection. Females exhibited more cocaine-induced locomotor activity, rearing, and locomotor incidence compared to OVX rats, but exhibited less orofacial incidence following acute cocaine administration. There were no differences between male and CAST rats. CAST rats showed more locomotor incidence than OVX after repeated, but not acute, cocaine injection. CAST rats exhibited behavioral sensitization, whereas OVX rats'' locomotor incidence did not change with repeated cocaine injection. CAST rats showed less orofacial incidence than OVX after acute, but not repeated, cocaine injection. These findings demonstrate sex differences in response to IV cocaine and replicate earlier findings which show that OVX attenuates increased locomotor activity in females. Furthermore, these findings suggest that IV cocaine administration produces behavioral differences between male and female rats in the absence of circulating gonadal hormones. [Copyright &y& Elsevier]

Adult Long-Evans rats, exposed prenatally to 1 of 4 doses of cocaine (0.0, 0.5, 1.0, or 3.0 mg/kg iv), were tested on a 3-choice visual attention task with an olfactory distracter presented unpredictably on one third of the trials. The performance of all 3 cocaine-exposed groups was significantly more disrupted than that of controls by the presentation of distracters. Results demonstrate that prenatal cocaine exposure increases susceptibility to distracters, using a task specifically designed to measure this function. In addition, the present study revealed that individuals exposed to cocaine in utero exhibit greater performance disruption after an error than controls, in certain types of tasks. Both areas of dysfunction, impaired selective attention and impaired arousal regulation, have important functional consequences in humans, possibly affecting the school performance and social development of cocaine-exposed children. [ABSTRACT FROM AUTHOR]