Incomplete nigrostriatal dopaminergic cell loss and partial reductions in striatal dopamine produce akinesia, rigidity, tremor and cognitive deficits in middle-aged rats.

The present study was conducted to determine if the full array of parkinsonian symptoms could be detected in rats with nigrostriatal cell loss and striatal dopamine depletions similar to levels reported in the clinical setting, and to determine if older rats exhibit more robust parkinsonian deficits than younger rats. Young (2 months old) and middle-aged (12 months old) rats received bilateral striatal infusions of 6-OHDA, over the next 3 months they were assessed with a battery of behavioral tests, and then dopaminergic nigrostriatal cells and striatal dopamine and DOPAC levels were quantified. The results of the present study suggest that: (1) the full array of parkinsonian symptoms (i.e. akinesia, rigidity, tremor and visuospatial cognitive deficits) can be quantified in rats with incomplete nigrostriatal dopaminergic cell loss and partial reductions in striatal dopamine levels (2) parkinsonian symptoms were more evident in middle-aged rats with 6-OHDA infusions, and (3) there was evidence of substantial neuroplasticity in the older rats, but regardless of the age of the animal, endogenous compensatory mechanisms were unable to maintain striatal dopamine levels after rapid, lesion-induced nigrostriatal cell loss. These results suggest that using older rats with nigrostriatal dopaminergic cell loss and reductions in striatal dopamine levels similar to those in the clinical condition, and measuring behavioral deficits analogous to parkinsonian symptoms, might increase the predictive validity of pre-clinical rodent models.

Methadone maintenance. Does dose determine differences in outcome?

We conducted a naturalistic study to determine if higher methadone doses were more effective than lower doses in the outcome variables of illicit drug use, treatment retention, missed medication days, and ratings of patient progress by assigned counselor among 265 patients in a Department of Veterans Affairs Methadone Maintenance Treatment Program. Results indicated no significant differences on any outcome variable by methadone dose. However, we found a significant effect by assigned therapist. Some therapists achieved better outcome results on these same variables compared to other assigned therapists independent of dose level. We conclude that, while methadone maintenance dose is an important variable, researchers need to pay more attention to the interpersonal aspects of methadone maintenance treatment.

Rats with partial striatal dopamine depletions exhibit robust and long-lasting behavioral deficits in a simple fixed-ratio bar-pressing task.

It is widely accepted that enduring parkinsonian symptoms are only evident if there are few remaining dopaminergic neurons in the substantia nigra and dopamine levels in the basal ganglia are very low [26,41]. In the present study, partial dopamine depletions were produced by infusing 6-OHDA bilaterally into the ventrolateral striatum as previously described [11,12,44]. Consistent with previous studies, behavioral deficits were detectable in rats with partial lesions with a simple fixed-ratio bar-pressing task. The present study demonstrated that these behavioral deficits were long-lasting, and that the sensitivity of this bar-pressing task could be increased by manipulating the level of difficulty of the task-higher fixed ratios were more sensitive to partial dopamine depletions. Deficits in rats with partial dopamine depletions could also be detected using non-automated neurological tests of parkinsonian symptoms developed for rats with severe unilateral dopamine depletions, but these deficits were transient and not as robust as those detected with the bar-pressing task. Oral Sinemet (L-DOPA:carbidopa) did not attenuate behavioral deficits related to partial dopamine depletions in this simple fixed-ratio bar-pressing task, but the present results suggest that Parkinson's patients might be identifiable earlier in the disease process, at a time when they could benefit from treatment with neuroprotective/neurotrophic agents. In addition, the results of the present study demonstrate that robust behavioral deficits may emerge with age. Mild dopamine depletions that were not detectable behaviorally at the time of the insult became clearly evident 10 months after the lesion with this bar-pressing task, and this may represent a more clinically relevant rodent model of Parkinson's disease.

Somatic delivery of catecholamines in the striatum attenuate parkinsonian symptoms and widen the therapeutic window of oral sinemet in rats.

Guidelines for clinical transplantation studies for Parkinson's disease emphasize that transplants should be considered as an adjunct to systemic L-DOPA, yet few preclinical studies have specifically assessed the potential of transplants as an adjunct to the clinical gold standard treatment. The objectives of the present study were to determine if encapsulated PC12 cells implanted in rats with severe unilateral dopamine depletions: (i) have a direct therapeutic effect on measures of parkinsonian symptoms; and/or (ii) increase the therapeutic window of oral sinemet in this model. Rats with severe unilateral dopamine depletions received striatal implants of encapsulated PC12 cells producing dopamine and L-DOPA. These rats were tested on a battery of behavioral measures of parkinsonian symptoms, at a range of doses of oral sinemet (0, 12, 24, and 36 mg/kg). Stereotypies/dyskinesias were also quantified after high doses of oral sinemet (36 and 50 mg/kg). The results confirm that parkinsonian symptoms can be quantified in rats with severe dopamine depletions, and the validity and clinical relevance of these measures are supported by the fact that the clinical gold standard treatment, oral sinemet, attenuates these parkinsonian symptoms. Somatic delivery of dopamine and L-DOPA, directly to the dopamine-depleted striatum, also attenuates parkinsonian symptoms. In fact, the magnitude of the therapeutic effect produced by continuous, site-specific, somatic delivery of dopamine and L-DOPA was larger than the effect produced by acute, systemic, oral sinemet. The beneficial effects of oral sinemet and striatal implants of catecholamine-producing devices were additive, but there were no adverse effects related to striatal catecholamine-producing devices, and these devices did not increase the adverse effects related to oral sinemet. Therefore, striatal implants of catecholamine-producing devices have direct therapeutic effects which are fairly robust, and they widen the therapeutic window of oral sinemet.

Intraventricular encapsulated calf adrenal chromaffin cells: viable for at least 500 days in vivo without detectable adverse effects on behavioral/cognitive function or host immune sensitization in rats.

Numerous studies have reported that adrenal chromaffin cell transplants, including encapsulated xenogeneic adrenal chromaffin cells, have analgesic effects. However, in addition to efficacy, the clinical utility of encapsulated xenogeneic adrenal chromaffin cells for treatment of chronic pain is dependent on the duration of cell viability in vivo, and their relative safety. The objectives of the present study in rats were to: (1) examine encapsulated calf adrenal chromaffin (CAC) cells for evidence of viable cells and continued release of analgesic agents after an extended period in vivo; (2) determine if intraventricular encapsulated CAC cells produce detectable adverse effects on behavioral/cognitive function; and (3) test for evidence of host immune sensitization after an extended period of exposure to encapsulated xenogeneic adrenal chromaffin cells. Results of the present study suggest that some encapsulated CAC cells remain viable for nearly 1.5 years in vivo and continue to produce catecholamines and met-enkephalin. Post-explant device norepinephrine output was equivalent to amounts previously shown to produce analgesic effects with intrathecal implants. Encapsulated adrenal chromaffin cells also appeared relatively safe, even when implanted in the cerebral ventricals, with a lower side-effect profile than systemic morphine (4 mg/kg). There was no evidence that encapsulated CAC-cells implanted in the ventricles affected body weight, spontaneous activity levels, or performance in the delayed matching to position operant task which is sensitive to deficits in learning, memory, attention, motivation, and motor function. Finally, encapsulated CAC cells produced no detectable evidence of host immune sensitization after 16.7 months in vivo, although unencapsulated CAC cells produced a robust immune response even in aged rats. The results of the present study suggest that adrenal chromaffin cells remain viable in vivo for long periods of time, and that long-term exposure to encapsulated xenogeneic adrenal chromaffin cell implants appears relatively safe.