Novel anticonvulsants for reducing alcohol consumption: A review of evidence from preclinical rodent drinking models.

Alcohol use disorders (AUDs) are a major public health issue and have an enormous social and economic burden in developed, developing, and third-world countries. Current pharmacotherapies for treating AUDs suffer from deleterious side effects and are only effective in preventing relapse in a subset of individuals. This signifies an essential need for improved medications to reduce heavy episodic drinking and alcohol-related problems. Growing literature has provided support for the use of anticonvulsants in suppressing symptoms induced by alcohol withdrawal. Emerging clinical and preclinical evidence suggests that a number of well-tolerated anticonvulsants may also decrease alcohol drinking. This review will focus on recent evidence supporting the efficacy of novel anticonvulsants in reducing voluntary alcohol consumption in rodent models. The data demonstrate that anticonvulsants reduce drinking in standard home cage two-bottle choice paradigms, self-administration of alcohol in operant chambers, and cue- and stress-induced reinstatement of alcohol seeking behaviors in rats and mice. This review also highlights evidence that some anticonvulsants were only moderately effective in reducing drinking in select strains of rodents or models. This suggests that genetics, possible neuroadaptations, or the pharmacological target affect the ability of anticonvulsants to attenuate alcohol consumption. Nonetheless, anticonvulsants are relatively safe, have little abuse potential, and can work in combination with other drugs. The results from these preclinical and clinical studies provide compelling evidence that anticonvulsants are a promising class of medication for the treatment of AUDs.

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.

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.

Prenatal stress influences 8-OH-DPAT modulated startle responding and [3H]-8-OH-DPAT binding in rats.

The present study was to investigate some aspects of the 5-HT1A receptor system in adult-aged rats (50-60 days) that were either exposed to prenatal stress (PS) or not exposed to prenatal stress (CON). In the first series of experiments, rats were pretreated with vehicle, the 5-HT1A agonist 8-OH-DPAT or the 5-HT1A antagonist, WAY-100635 and exposed to 120 acoustic startle stimuli (95 dB) using a 30 s inter-trial interval. 8-OH-DPAT produced a dose-dependent increase in acoustic startle responding in CON and PS rats, with the PS rats exhibiting greater responding than CON rats. WAY-100635 depressed startle amplitudes only in the CON group. Finally, radioligand binding studies using [3H]-8-OH-DPAT indicated a significant decrease in receptor density in hippocampal homogenates from PS rats but no difference in [3H]-8-OH-DPAT binding from homogenates of the amygdala. Our results are consistent with earlier reports indicating that prenatal stress alters the serotonergic system. Specifically, our results indicate that gestational exposure to chronic mild stress enhances startle amplitudes following 8-OH-DPAT administration, prevents the depression in startle amplitudes following WAY-100635 administration and reduces [3H]-8-OH-DPAT binding in hippocampal preparations.

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.

Mild prenatal stress in rats is associated with enhanced conditioned fear.

We tested the hypothesis that prenatal stress would enhance conditioned fear in adult rats. Pregnant Sprague-Dawley rats were stressed by exposure to a novel environment and subcutaneous injection of saline (0.1 ml 0.9% NaCl) at random times daily from Days 14 to 21 of pregnancy. When compared to adult control (CON) male rats from unmanipulated pregnancies, adult prenatally stressed (PS) male rats showed increased freezing behavior in response to acute footshock as well as increased freezing behavior the next day in the same context, without shock delivery. In another experiment, the gestational stressor was examined for elevations in corticosterone and ACTH. At gestational days (G)15, G17, G19 and G21, maternal and fetal plasma was collected. Analysis showed elevations in corticosterone and ACTH in the PS dams when compared to the CON dams. Additionally, increased corticosterone was found in the PS fetuses when compared to the CON fetuses. Finally, some CON and PS litters were examined for alterations in length of gestation, number of pups born, bodyweight on postnatal day (P)1 and anogenital distance on P1 and differences were not found. In conclusion, our data demonstrate that a mild stressor during gestation, sufficient to raise plasma corticosterone and ACTH, is associated with enhanced conditioned fear during adulthood.

Intravenous glomus tumor of the forearm.

An intravenous glomus tumor occurring in a forearm vein is reported. The patient had a painful subcutaneous mass which was completely excised. This mass was a neoplasm which expanded the lumen of a vein and extended throughout its wall into the surrounding subcutaneous fat. The neoplasm consisted of sheets of rounded cells with a capillary stroma. The neoplastic cells were closely apposed to the capillary vessels and were positive for vimentin, smooth muscle actin and muscle specific actin. The cells were negative for desmin, factor VIII-related antigen, epithelial membrane antigen, cytokeratins, S-100 protein and chromogranin. This is the 2nd reported case of intravenous glomus tumor of the forearm. This unusual presentation may be due to intravascular extension by a cutaneous glomus tumor. The potential for intravascular growth by glomus tumor should be recognized by surgeons, dermatologists and pathologists.