Effects of brain-derived neurotrophic factor on dopaminergic function and motor behavior during aging.

Brain-derived neurotrophic factor (BDNF) is critical in synaptic plasticity and in the survival and function of midbrain dopamine neurons. In this study, we assessed the effects of a partial genetic deletion of BDNF on motor function and dopamine (DA) neurotransmitter measures by comparing Bdnf(+/-) with wildtype mice (WT) at different ages. Bdnf(+/-) and WT mice had similar body weights until 12 months of age; however, at 21 months, Bdnf(+/-) mice were significantly heavier than WT mice. Horizontal and vertical motor activity was reduced for Bdnf(+/-) compared to WT mice, but was not influenced by age. Performance on an accelerating rotarod declined with age for both genotypes and was exacerbated for Bdnf(+/-) mice. Body weight did not correlate with any of the three behavioral measures studied. Dopamine neurotransmitter markers indicated no genotypic difference in striatal tyrosine hydroxylase, DA transporter (DAT) or vesicular monoamine transporter 2 (VMAT2) immunoreactivity at any age. However, DA transport via DAT (starting at 12 months) and VMAT2 (starting at 3 months) as well as KCl-stimulated DA release were reduced in Bdnf(+/-) mice and declined with age suggesting an increasingly important role for BDNF in the release and uptake of DA with the aging process. These findings suggest that a BDNF expression deficit becomes more critical to dopaminergic dynamics and related behavioral activities with increasing age.

Intravenous cocaine self-administration: individual differences in male and female C57BL/6J mice.

This study examined individual differences in male and female C57BL/6J (C57) mice responding for intravenous cocaine reinforcement. The experiment used 4 groups of mice, distinguished by sex and cocaine unit dose (0.3 or 1 mg/kg/infusion). Mice trained to lever respond for IV cocaine were given the drug initially on an FR2 schedule and then on a Progressive Ratio 2(PR2) schedule. Hierarchical linear modeling (HLM) techniques were used to examine data generated across four FR2 and four PR2 sessions, as well as within session data when cocaine was delivered on the PR2 schedule. HLM techniques, although uncommon in the animal literature, characterize individual differences in human studies and are likely to be useful in more complex preclinical studies. Analysis established distinct patterns of self-administration both across and within sessions. Responses for cocaine delivered on the FR2 schedule was dose-dependent, but did not differ according to sex. Response output was greater when either dose of cocaine was delivered on the PR2 than the FR2 schedule. Although response output for the more rewarding 1 mg/kg unit dose was similar for the two sexes, males responded more and had greater cocaine intake than females when the less reinforcing 0.3 mg/kg dose was delivered at the more behaviorally challenging PR2 schedule. HLM analysis of response patterns and cocaine intake within the PR2 sessions corroborated this sex difference and also indicated that trajectories differed for individual mice after accounting for the sex and dose factors. The reduced response output by females for cocaine in the present experiment is consistent with previous reports that sex differences in the rewarding effects of either alcohol or food reinforcement were revealed for C57 mice only when delivered on more behaviorally demanding schedules (e.g. PR2 or FR100).

Chronic cocaine exposure in the SCID mouse model of HIV encephalitis.

Clinical and preclinical evidence suggests that cocaine exposure hastens progression of the HIV disease process. An established active, euphoric dose of cocaine (20 mg/kg) was administered to SCID mice according to a regimen consistent with exposure to the drug by cocaine-abusing HIV-infected patients to determine the effects of cocaine on four previously established pathological characteristics of HIV encephalitis: cognitive deficits, fatigue, astrogliosis, and microgliosis. Mice were intracranially inoculated with either HIV-infected, or uninfected macrophages and then injected with either cocaine or saline in a 2 (Infection)x2 (Cocaine) factorial design. Cognition was assessed by acquisition and retention of a spatially cued learning task. Fatigue was assessed by monitoring motor activity following a 2 min forced swim. Mice were then sacrificed to determine the extent of astrogliosis and microgliosis in the four groups. Results indicated that in comparison to uninfected controls, HIV positive mice had increased astrogliosis and microgliosis, cognitive deficits, and recovered more slowly from fatigue. However, despite evidence that the cocaine exposure regimen activated the central nervous system and had long-term CNS effects, the drug did not alter the behavioral or the neuropathological deficits noted in HIV-infected SCID mice.

A partial GDNF depletion leads to earlier age-related deterioration of motor function and tyrosine hydroxylase expression in the substantia nigra.

Glial cell line-derived neurotrophic factor (GDNF) is a trophic factor for peripheral organs, spinal cord, and midbrain dopamine (DA) neurons. Levels of GDNF deteriorate in the substantia nigra in Parkinson's disease (PD). A heterozygous mouse model was created to assess whether chronic reductions in this neurotrophic factor impact motor function and the nigrostriatal dopamine system during the aging process. Due to the important role GDNF plays in kidney development, kidney function and histology were assessed and were found to be normal in both wild-type (WT) and GDNF+/- mice up to 22 months of age. Further, the animals of both genotypes had similar weights throughout the experiment. Locomotor activity was assessed for male WT and GDNF+/- mice at 4-month intervals from 4 to 20 months of age. Both GDNF+/- and WT mice exhibited an age-related decline in horizontal activity, although this was found 4 months earlier in GDNF+/- mice, at 12 months of age. Comparison of young (8 month old) and aged (20 month old) GDNF+/- and WT mice on an accelerating rotarod apparatus established a deficiency for aged but not young GDNF+/- mice, while aged WT mice performed as well as young WT mice on this task. Finally, both WT and GDNF+/- mice exhibited an age-related decrease in substantia nigra TH immunostaining, which was accelerated in the GDNF+/- mice. These behavioral and histological alterations suggest that GDNF may be an important factor for maintenance of motor coordination and spontaneous activity as well as DA neuronal function during aging, and further suggest that GDNF+/- mice may serve as a model for neuroprotective or rescue studies.

Partial deletion of glial cell line-derived neurotrophic factor (GDNF) in mice: Effects on sucrose reward and striatal GDNF concentrations.

Glial cell line derived neurotrophic factor (GDNF) has been reported to alter the reward value of abused substances such as alcohol and cocaine as well as neural circuitry underlying reward. The role of GDNF in reward was further characterized in the present study using operant procedures to determine the value of a natural reward, sucrose, in GDNF heterozygous (GDNF+/-) mice versus wild-type (WT) mice. Female mice were tested for 2 h daily for 10 days in operant chambers with 2 levers. Responses on the correct lever allowed 5-s access to a dipper cup containing 15% sucrose. GDNF+/- and WT mice did not differ with acquisition or accuracy of responding. GDNF+/- mice emitted more responses than WT mice for sucrose, suggesting enhanced reward value of sucrose in these mice. In a separate experiment, concentrations of GDNF protein in striatal tissue were determined at 4, 8, and 12 months of age and found to be 38%-68% lower in GDNF+/- than WT mice at all three ages. Together, the results are consistent with an emerging literature indicating that reduced GDNF levels augment reward and increased GDNF levels attenuate reward, suggesting that GDNF plays an important role in neural systems mediating reward.

The influence of sex on extracellular dopamine and locomotor activity in C57BL/6J mice before and after acute cocaine challenge.

C57BL6/J (C57) mice serve as a useful animal model of cocaine abuse because they self-administer cocaine, exhibit place conditioning to cocaine, discriminate the interoceptive cues of cocaine, and are used for backcrossing strains of genetically modified mice. The present study was to examine the influence of sex on extracellular DA and locomotor activity in C57 mice in response to acute cocaine challenge. In the first experiment, male and female mice were implanted with guide cannulae aimed at the dorsal striatum. Microdialysates were collected in three consecutive phases: baseline, post-saline injection, and post-cocaine injection. Sex did not influence DA measurements during baseline or after intraperitoneal (i.p.) saline injection. Cocaine (20 mg/kg) injections increased peak extracellular DA of both sexes, and the increase was greater for males (278%+/-14.0%) than females (182.5%+/-10.8%) (P<0.05). In the second experiment, under conditions similar to the microdialysis experiment, locomotor activity of male and female mice was assessed during baseline, after saline injection, and after cocaine injection (5, 10, 20, or 40 mg/kg). Cocaine dose-dependently increased activity; however, sex did not influence locomotor activity during baseline, after saline, or after any cocaine dose. Results of the experiments established that cocaine (20 mg/kg) increased extracellular DA in the dorsal striatum to a greater extent in male than in female mice; however, when cocaine was administered under similar experimental conditions, sex did not influence cocaine stimulation of locomotor activity over a wide range of doses.

Genetic variation in heroin-induced changes in behaviour: effects of B6 strain dose on conditioned reward and locomotor sensitization in 129-B6 hybrid mice.

Substantial interindividual variability exists in the propensity to develop opiate addiction. Genetic variation in opiate reward may contribute to this variability. A large body of evidence indicates genetic variation in mice for several effects of opiate drugs. The present study examined heroin-induced place conditioning and locomotor sensitization in the two strains of mice employed most frequently in the generation of transgenic animals, C57BL/6J (B6) and 129X1/sVJ (129), as well as in groups of B6-129 hybrid mice, differing in their amount of B6 genetic background. Four pairings of 100 microg/kg of heroin elicited robust place conditioning and locomotor sensitization in B6 controls and in N(10) congenic B6-129 hybrid mice. In comparison, the identical treatment produced no locomotor sensitization and induced place aversion in 129 controls. No heroin-induced changes in the behaviour of N(3) congenic B6-129 hybrid mice or F5-8 non-congenic B6-129 hybrid mice were observed. The expression of place conditioning was not facilitated in any group by the administration of a heroin-priming injection prior to testing. These data indicate that genetic variation exists in mice for the rewarding and locomotor-sensitizing effects of heroin and that the capacity of heroin to induce conditioned reward and locomotor sensitization can be modulated in a B6 strain dose-dependent manner in B6-129 hybrid mice. Thus, strain differences in heroin responsiveness should be considered when examining transgenic lines on B6-129 backgrounds for opiate-induced changes in behaviour that may be relevant for addiction.

Acquisition of lever pressing for cocaine in C57BL/6J mice: effects of prior Pavlovian conditioning.

The purpose of this study was to determine (1) if C57BL/6J (C57) mice would lever-press for intravenous cocaine infusions in a limited-access paradigm without previously establishing the instrumental response with natural reinforcers and (2) if prior Pavlovian conditioning of cocaine to the response contingent stimulus complex used in the cocaine self-administration sessions would facilitate acquisition of lever responding for cocaine. After implanting jugular catheters, some mice received Pavlovian conditioning during which 12 passive cocaine infusions (0.1 or 1 mg/kg unit doses) were paired with the tone/light/pump sound stimulus complex used in the self-administration sessions. The remaining mice simply began the cocaine self-administration sessions for 0.1 or 1 mg/kg unit doses of cocaine. Twenty-seven of the 33 mice with patent catheters acquired stable lever responding within an average of 5 to 6 days without previously establishing the instrumental response with natural rewards. Prior Pavlovian pairing of cocaine with the response contingent stimulus complex used in the self-administration sessions did not influence the acquisition of cocaine self-administration at the highest cocaine dose (1 mg/kg). This conditioning procedure using the low cocaine dose (0.1 mg/kg/infusion) reduced the number of mice acquiring cocaine self-administration to 50%, and the number of mice developing stable response patterns was only 25%. The results establish that C57 mice can acquire cocaine self-administration over several unit doses in a limited-access paradigm without previously establishing the instrumental response with natural reinforcers. Furthermore, prior pairing of response contingent cues with cocaine via Pavlovian conditioning did not facilitate the acquisition of cocaine self-administration.

The noradrenergic system of aged GDNF heterozygous mice.

Glial cell line-derived neurotrophic factor (GDNF) is a trophic factor for noradrenergic (NE) neurons of the pontine nucleus locus coeruleus (LC). Decreased function of the LC-NE neurons has been found during normal aging and in neurodegenerative disorders. We have previously shown that GDNF participates in the differentiation of LC-NE neurons during development. However, the continued role of GDNF for LC-NE neurons during maturation and aging has not been addressed. We examined alterations in aged mice that were heterozygous for the GDNF gene (Gdnf+/-). Wild-type (Gdnf+/+) and Gdnf+/- mice (18 months old) were tested for locomotor activity and brain tissues were collected for measuring norepinephrine levels and uptake, as well as for morphological analysis. Spontaneous locomotion was reduced in Gdnf+/- mice in comparison with Gdnf+/+ mice. The reduced locomotor activity of Gdnf+/- mice was accompanied by reductions in NE transporter activity in the cerebellum and brain stem as well as decreased norepinephrine tissue levels in the LC. Tyrosine hydroxylase (TH) immunostaining demonstrated morphological alterations of LC-NE cell bodies and abnormal TH-positive fibers in the hippocampus, cerebellum, and frontal cortex of Gdnf+/- mice. These findings suggest that the LC-NE system of Gdnf+/- mice is impaired and suggest that GDNF plays an important role in continued maintenance of this neuronal system throughout life.

The Noradrenergic System of Aged GDNF Heterozygous Mice.

Glial cell line-derived neurotrophic factor (GDNF) is a trophic factor for noradrenergic (NE) neurons of the pontine nucleus locus coeruleus (LC). Decreased function of the LC-NE neurons has been found during normal aging and in neurodegenerative disorders. We have previously shown that GDNF participates in the differentiation of LC-NE neurons during development. However, the continued role of GDNF for LC-NE neurons during maturation and aging has not been addressed. We examined alterations in aged mice that were heterozygous for the GDNF gene (Gdnf+/-). Wild-type (Gdnf+/+) and Gdnf+/- mice (18 months old) were tested for locomotor activity and brain tissues were collected for measuring norepinephrine levels and uptake, as well as for morphological analysis. Spontaneous locomotion was reduced in Gdnf+/- mice in comparison with Gdnf+/+ mice. The reduced locomotor activity of Gdnf +/- mice was accompanied by reductions in NE transporter activity in the cerebellum and brain stem as well as decreased norepinephrine tissue levels in the LC. Tyrosine hydroxylase (TH) immunostaining demonstrated morphological alterations of LC-NE cell bodies and abnormal TH-positive fibers in the hippocampus, cerebellum, and frontal cortex of Gdnf+/- mice. These findings suggest that the LC-NE system of Gdnf+/- mice is impaired and suggest that GDNF plays an important role in continued maintenance of this neuronal system throughout life.

Naltrexone effects on ethanol consumption and response to ethanol conditioned cues in C57BL/6 mice.

RATIONALE: The conditions under which naltrexone reduces ethanol consumption and its effect on behavior controlled by ethanol conditioned stimuli remain unclear. OBJECTIVES: The objectives were to determine the effects of naltrexone on ethanol consumption by C57BL/6 (B6) mice when injected subcutaneously (expt 1) or delivered by osmotic minipump (expt 2), and on ethanol conditioned cues (expt 3). METHODS: Naltrexone effects on ethanol consumption and preference were measured in a continuous access two-bottle choice paradigm in groups of mice implanted with osmotic minipumps delivering 0-3.0 mg/kg per day or injected subcutaneously with 0-6.0 mg/kg doses. Naltrexone's (0-3.0 mg/kg) effect on ethanol-conditioned cues was indexed by its effect on the expression of ethanol place conditioning (expt 3). RESULTS: Naltrexone produced a transient reduction in ethanol consumption and a consistent reduction in preference when injected; however, it had no effect on ethanol consumption or preference when delivered continuously by osmotic minipump. Naltrexone attenuated the expression of ethanol place conditioning in a U-shaped dose-response function. CONCLUSIONS: The transient reduction in ethanol consumption produced by injected naltrexone and the absence of an effect when continuously delivered confirms a report that maintaining naltrexone at steady state levels may antagonize its attenuation of ethanol consumption. The reduced expression of ethanol place conditioning in naltrexone-injected mice suggests that the drug can attenuate the reinforcing effects of ethanol conditioned stimuli as was recently reported for lever responding maintained by ethanol conditioned stimuli in rats. These effects were observed at naltrexone doses with no readily apparent adverse side-effects, supporting its usefulness for treating alcoholism.

Ethanol reinforcement in nondeprived mice: effects of abstinence and naltrexone.

BACKGROUND: Operant experiments which indicate that ethanol can serve as a reinforcer to maintain lever responding during limited periods of access have not been conducted on non-food-deprived mice, as they have for rats and monkeys. Furthermore, there are no reports of the effects of chronic ethanol and subsequent abstinence on ethanol reward in mice. Finally, although naltrexone reduces responding for ethanol in food-deprived mice, the effects of the drug on ethanol reward for non-food-deprived mice have not been reported. METHODS: In three experiments, lever responding for ethanol (10-12%) was established in C57BL/6 (B6) mice by using either sucrose or saccharin fading procedures commonly used for rats. Experiment 1 examined both appetitive and consummatory responses while sucrose was faded from the ethanol solutions. Experiment 2 examined lever responding and ethanol intake (1) during saccharin fading; (2) when reinforcement schedules, reward availability, and primary conditioned reinforcers were manipulated; and (3) when mice were allowed chronic ethanol consumption followed by forced abstinence. Experiment 3 examined the effects of low doses of naltrexone on ethanol reward. RESULTS: Lever responding for ethanol can be established in non-food-deprived mice with the sucrose and saccharin fading procedures commonly used for rats. Lever responses increased with decreases in the reinforcer and increases in schedule demand, which indicated the reward value of the ethanol solution. Removal of ethanol from the solution reduced consumption with no change in the appetitive, instrumental response, which indicated that the two responses were under control of different stimuli, perhaps mediated by different neural mechanisms. Forced abstinence after chronic ethanol exposure increased responding for the drug, which suggested increased reward value. Naltrexone reduced responding as previously reported for food-deprived B6 mice. CONCLUSIONS: Ethanol appears to serve as a reinforcer for non-food-deprived or non-water-deprived B6 mice. Its reinforcing effects are increased by forced abstinence after chronic exposure and are decreased by naltrexone.

Delta-opioid and 5-HT3 receptor antagonist effects on ethanol reward and discrimination in C57BL/6 mice.

The effects of the receptor antagonists MDL 72222 (MDL, 5-HT3) and naltrindole (delta-opioid) on ethanol reward and its discrimination were examined in ethanol-preferring C57BL/6 (C57) mice. MDL attenuated lever responding for 12% ethanol delivered on a fixed-ratio 8 reinforcement schedule at a dose that did not influence responding for water reward, thus confirming a previous report that ICS 205-930 reduced ethanol reward for Long-Evans rats. Our study in combination with the reduced ethanol consumption reported for C57 mice injected with odansetron indicates that 5-HT3 receptor systems are involved in mediating behavior directed toward obtaining ethanol as well as its consumption. By attenuating the rewarding effects of ethanol or of ethanol conditioned cues (e.g., the operant environment), 5-HT3 antagonists may be useful in the treatment of alcohol abuse. The 5-HT3 antagonist effects in this study are comparable with the effects of naltrexone on ethanol reward in C57 mice, although higher doses were required to reduce operant responding for ethanol reward. In contrast to the 5-HT3 antagonist and naltrexone effects, naltrindole, an antagonist with greater specificity for the delta-opioid receptor, was without effect on ethanol reward. This result and recent reports for rats and monkeys suggests that the general antagonists might be more efficacious in attenuating ethanol reward. Both MDL and naltrindole produced only slight reductions in the ethanol discriminative cue, suggesting that the rewarding and discriminative effects of ethanol are not likely mediated by identical neural mechanisms as previously suggested.

Periadolescent nicotine exposure reduces cocaine reward in adult mice.

Fully mature mice exposed to low levels of nicotine during periadolescence exhibited reductions in the rewarding and subjective effects of cocaine. These results provide converging validity that periadolescent nicotine exposure can permanently decrease a subject's sensitivity to the reinforcing effects of cocaine. These changes were noted long after exposure, suggesting that nicotine may have altered neural systems mediating drug reward. Since reductions in the rewarding value of abused drugs are associated with increased self-administration, periadolescent nicotine exposure might increase the risk for substance abuse problems. The study thus provides biological support that nicotine might serve a "gateway" function for substance abuse.

Ethanol consumption and place-preference conditioning in the alcohol-preferring C57BL/6 mouse: relationship with motor activity patterns.

Ethanol place-preference conditioning (PC) was conducted in drug-naive and ethanol pre-exposed female and male C57BL/6J (C57) mice to assess whether environmental cues can develop positive incentive value for ethanol-preferring animals when associated with administration of ethanol. After 12 days episodic access to free-choice ethanol and/or water self-administration, mice received eight ethanol injections (1.75 g/kg/i.p.) 5 min before placement in their nonpreferred PC chamber and eight saline injections paired with their preferred chamber. Control mice received eight saline injections (20 ml/kg) in both their preferred and nonpreferred chambers. Mice of both sexes developed strong ethanol PC. Correlational analysis indicated that the strength of ethanol PC for mice with a prior ethanol drinking experience was inversely related to the amount of ethanol consumed regardless of gender. Furthermore, depending on gender and previous ethanol drinking experience, ethanol PC was differentially related to initial baseline motor activity, the initial motor response to ethanol, or rapid change in the motor response to ethanol. Thus, a complicated relationship between neural systems that mediate ethanol reward and motor activity may exist as suggested by current addiction theory.

Ethanol consumption by C57BL/6 mice: influence of gender and procedural variables.

Both sexes of C57BL/6 (C57) mice consumed substantial quantities of ethanol without food or water deprivation whether access was continuous or limited. Food deprivation increased the amount of ethanol consumed, and the amount consumed depended upon when the animals were tested with reference to their daily food allotment. Ethanol consumption was greater if the mice were tested postprandially, high thirst motivation, rather than preprandially (approximately 10 vs. approximately 4.5 g/kg/30 min). Preference for ethanol over water, however, was greater when mice were under low thirst motivation (i.e., tested preprandially or with water available during the test). Compared to males, female mice consumed more of a high-ethanol concentration solution (10%) when access was continuous or limited to the first hour of the dark (active) phase of the circadian cycle. Also, in contrast to males, female mice exhibited increased ethanol consumption across days of drinking experience. Finally, although ethanol consumption under the food deprivation conditions of this experiment did not differ according to sex, females had higher blood ethanol concentrations than male C57 mice, a finding not previously reported for rodents but common to humans.

Operant ethanol reward in C57BL/6 mice: influence of gender and procedural variables.

Food-deprived C57BL/6 (C57) mice of either sex responded for oral ethanol rewards delivered on ratio schedules of reinforcement, thus extending to female C57 mice effects previously reported only for male members of the strain. Lever responding for ethanol reward was influenced by thirst motivation (post- vs. preprandial tests), time of access to ethanol reward, ethanol concentration, and reinforcement schedule. A particularly high response output for 12% ethanol delivered on a PR2 schedule (e.g., approximately 1400/15 min test session) indicates its efficacy as a reinforcer for C57 mice. Estimated consumption of ethanol differed from lever responding when reward access time was relatively long (10 s) and response demand of the reinforcement schedule was low, but paralleled lever responding when reward access time was restricted (3 s) and response demands were greater. Gender influenced lever responding for ethanol reward and its consumption, the difference depending upon reward access time and reinforcement schedule. When the response demands were low and the reward access time long, females tended to respond more than males for ethanol reward; with greater response demands and shorter reward access time, males tended to respond more. In conjunction with our companion report, the present study helps define the behavioral conditions under which ethanol is rewarding for C57 mice and establish the conditions under which ethanol reward differs for male and female mice.

Do alcohol and cocaine abuse alter the course of HIV-associated dementia complex?

Although psychoactive drugs are commonly used by AIDS patients, it is unclear whether commonly abused drugs, such as cocaine and ethanol, affect the course of HIV-associated dementia (HADC). Epidemiological studies have resulted in conflicting conclusions as to what role, if any, abused drugs play in HADC. In this review we discuss the clinical and pathological evidence that cocaine and ethanol might exacerbate the detrimental effects of HIV infection on the brain. We also review studies of cocaine and ethanol effects on various components of the immune system both in the presence and absence of retroviral infection. Data from these studies indicate that cocaine and ethanol have profound effects on the immune system that, in many respects, are enhanced by retroviral infection. We conclude that abused drugs likely affect the course of HADC but that proof awaits an examination of their interactive effects in an appropriate in vivo system of retroviral encephalitis.

Naltrexone effects on ethanol reward and discrimination in C57BL/6 mice.

The effects of the opioid antagonist, naltrexone, on operant responding for oral ethanol reward delivered on a fixed-ratio schedule, and on the discriminative stimulus properties of intraperitoneally injected ethanol, was examined in two separate experiments. The ages, food/water motivational conditions, and naltrexone doses for the two experiments were similar to allow a direct comparison of naltrexone effects on the two measures. Male food-deprived C57BL/6 mice responded for ethanol during either preprandial (low thirst, high hunger motivation) or postprandial (high thirst, low hunger motivation tests). The reinforcing value of ethanol relative to water was greater during the preprandial tests; however, the amounts of ethanol consumed was greater during the postprandial tests, with some mice becoming unconscious during the 15-min test session. Naltrexone produced dose-responsive reductions in responding for ethanol under either testing condition. During postprandial tests, naltrexone reduced responding for ethanol reward at a dose (1.25 mg/kg) that had little effect on responding for water reward, suggesting some selectivity for ethanol reward. In addition, doses of naltrexone that reduced responding for ethanol rewards did not alter the discrimination of ethanol (g/kg) in an operant discrimination task, but did reduce the total number of responses made during these tests. Thus, under similar motivational and dosing conditions, the opiate antagonist attenuated the reinforcing, but not the discriminative properties of ethanol, suggesting that the latter is mediated by either different or additional neural mechanisms in C57BL/6 mice.

SCID mice with HIV encephalitis develop behavioral abnormalities.

Severe combined immunodeficient (SCID) mice inoculated intracerebrally (i.c.) with HIV-infected human monocytes develop brain pathology similar to that in humans with HIV encephalitis. This includes HIV-positive macrophages and multinucleated giant cells, astrogliosis, microglial nodules, and neuronal dropout. These xenografts survive about 1 month. To develop a model of chronic HIV encephalitis and to assay the resulting behavioral abnormalities, we reinoculated SCID mice i.c. every 4 weeks for 3 months with either HIV-infected human monocytes (n = 5) or uninfected human macrophages (n = 4) or administered no inoculation (n = 6); these three groups were monitored for behavioral abnormalities. Tests of cognitive function in a Morris water maze 3.5 months after the first inoculation suggested that HIV-infected mice performed poorly compared with controls. Following testing in the water maze on days 4 and 5 of acquisition, motor activity of infected mice was reduced in comparison with that of controls. Retention of goal location when tested 1 week later was impaired in HIV-infected mice compared with controls. Histopathologic analysis of brains revealed significant astrogliosis and strongly suggested higher numbers of major histocompatibility complex (MHC) class II-positive multinucleated macrophages in HIV-infected compared with control mice. Thus, our preliminary studies indicate that SCID mice with HIV encephalitis develop behavioral abnormalities reminiscent of human disease. These behavioral abnormalities are associated with significantly increased astrogliosis, the presence of HIV, and probably multinucleated giant cells. These studies further support the use of this SCID animal model system for studies of the pathogenesis of HIV encephalitis and for drug interventions.