Motivational Impairment is Accompanied by Corticoaccumbal Dysfunction in the BACHD-Tg5 Rat Model of Huntington's Disease

Neuropsychiatric symptoms, such as avolition, apathy, and anhedonia, precede the onset of debilitating motor symptoms in Huntington's disease (HD), and their development may give insight into early disease progression and treatment. However, the neuronal and circuit mechanisms of premanifest HD pathophysiology are not well-understood. Here, using a transgenic rat model expressing the full-length human mutant HD gene, we find early and profound deficits in reward motivation in the absence of gross motor abnormalities. These deficits are accompanied by significant and progressive dysfunction in corticostriatal processing and communication among brain areas critical for reward-driven behavior. Together, our results define early corticostriatal dysfunction as a possible pathogenic contributor to psychiatric disturbances and may help identify potential pharmacotherapeutic targets for the treatment of HD

Combined cocaine hydrolase gene transfer and anti-cocaine vaccine synergistically block cocaine-induced locomotion.

Mice and rats were tested for reduced sensitivity to cocaine-induced hyper-locomotion after pretreatment with anti-cocaine antibody or cocaine hydrolase (CocH) derived from human butyrylcholinesterase (BChE). In Balb/c mice, direct i.p. injection of CocH protein (1 mg/kg) had no effect on spontaneous locomotion, but it suppressed responses to i.p. cocaine up to 80 mg/kg. When CocH was injected i.p. along with a murine cocaine antiserum that also did not affect spontaneous locomotion, there was no response to any cocaine dose. This suppression of locomotor activity required active enzyme, as it was lost after pretreatment with iso-OMPA, a selective BChE inhibitor. Comparable results were obtained in rats that developed high levels of CocH by gene transfer with helper-dependent adenoviral vector, and/or high levels of anti-cocaine antibody by vaccination with norcocaine hapten conjugated to keyhole limpet hemocyanin (KLH). After these treatments, rats were subjected to a locomotor sensitization paradigm involving a "training phase" with an initial i.p. saline injection on day 1 followed by 8 days of repeated cocaine injections (10 mg/kg, i.p.). A 15-day rest period then ensued, followed by a final "challenge" cocaine injection. As in mice, the individual treatment interventions reduced cocaine-stimulated hyperactivity to a modest extent, while combined treatment produced a greater reduction during all phases of testing compared to control rats (with only saline pretreatment). Overall, the present results strongly support the view that anti-cocaine vaccine and cocaine hydrolase vector treatments together provide enhanced protection against the stimulatory actions of cocaine in rodents. A similar combination therapy in human cocaine users might provide a robust therapy to help maintain abstinence

A multivariate regressor of patterned dopamine release predicts relapse to cocaine

Summary: Understanding mesolimbic dopamine adaptations underlying vulnerability to drug relapse is essential to inform prognostic tools for effective treatment strategies. However, technical limitations have hindered the direct measurement of sub-second dopamine release in vivo for prolonged periods of time, making it difficult to gauge the weight that these dopamine abnormalities have in determining future relapse incidence. Here, we use the fluorescent sensor GrabDA to record, with millisecond resolution, every single cocaine-evoked dopamine transient in the nucleus accumbens (NAc) of freely moving mice during self-administration. We reveal low-dimensional features of patterned dopamine release that are strong predictors of cue-induced reinstatement of cocaine seeking. Additionally, we report sex-specific differences in cocaine-related dopamine responses related to a greater resistance to extinction in males compared with females. These findings provide important insights into the sufficiency of NAc dopamine signaling dynamics—in interaction with sex—for recapitulating persistent cocaine seeking and future relapse vulnerability

Scheme for testing locomotor responses to cocaine.

<p>Rat locomotor experiments were carried out in four distinct phases. Phase 1, “Acclimation", consisted of 3 consecutive days of 45-min in the test chamber with no interventions. Phase 2, “Training", involved 9 days of 90 min in the chamber with an i.p. injection of saline (S) or cocaine, 10 mg/kg C) at the 45-min time point. Phase 3, “No Drug", involved 15 “rest days" in the home cage with no interventions. Phase 4, “Challenge", was 2 days in the chamber with i.p. saline or cocaine at the respective 45-min time points.</p

Average antibody (µg/ml) and/or enzyme (mU/ml) levels for the VAC, VEC, VEC+VAC treated rats during the Training and Cocaine Challenge Phases.

<p>Cocaine hydrolase activity and anti-cocaine antibody levels were assessed midway through the training phase (day 8) and at the onset of the challenge phase (day 29). Means and standard errors are shown. Neither of the measured variables changed significantly across the course of the experiment, and there were no significant differences for either variable across treatment groups.</p

Selective enzyme inhibitor relieves CocH suppression of locomotor response.

<p>Mice (groups of 8) habituated to locomotor activity chambers were given enzyme (CocH, 1 mg/kg, i.p.) or inhibitor (iso-OMPA, 50 mg/kg, s.c.) or both, followed 3 hr later by cocaine (40 mg/kg, i.p.). Controls received either i.p. saline or iso-OMPA alone. ** p<0.01.</p

Mean daily beam breaks after cocaine during training phase.

<p>Data represent rat locomotor activity in 8 daily 45 min sessions immediately following cocaine injections. Statistical significance: * significantly <i>lower</i> locomotor activity in VEC+VAC group compared to all other groups (p<0.05); <b>†</b> significantly <i>greater</i> locomotor activity on the final training-phase day compared to the first day (p<0.05).</p