Clonidine improves attentional and memory components of delayed response performance in a model of early Parkinsonism.

Cognitive deficits, including attention and working memory deficits, are often described in Parkinson's disease (PD) patients even during the early stages of the disease. However, cognitive deficits associated with PD have proven difficult to treat and often do not respond well to the dopaminergic therapies used to treat the motor symptoms of the disease. Chronic administration of low doses of the neurotoxin 1-methy,4-phenyl,1,2,3,6-tetrahydropyridine (MPTP) can induce cognitive dysfunction in non-human primates, including impaired performance on a variable delayed response (VDR) task with attentional and memory components. Since alpha-2 adrenergic receptor agonists have been suggested to improve attention and working memory in a variety of conditions, the present study assessed the extent to which the alpha-2 noradrenergic agonist clonidine might influence VDR performance in early Parkinsonian non-human primates. Clonidine (0.02-0.10 mg/kg) improved performance on both attentional and memory components of the task, performed in a modified Wisconsin General Test Apparatus, in a dose-dependent manner and the cognition enhancing effects of clonidine were blocked by co-administration of the alpha-2 noradrenergic antagonist idazoxan (0.10 mg/kg). These data suggest that clonidine or drugs of this class, perhaps with greater receptor subtype selectivity and low sedation liability, might be effective therapeutics for cognitive dysfunction associated with PD.

Interaction between nicotinic and dopaminergic therapies on cognition in a chronic Parkinson model.

While levodopa therapy for Parkinson's disease (PD) may effectively relieve motor symptoms, many of the cognitive deficits experienced by PD patients (and in animal models of PD) are not effectively managed by this treatment. In contrast, previous work has shown positive effects of nicotinic therapies on cognition in PD models. The present study evaluated the effects of levodopa, nicotine and the nicotinic acetylcholine receptor agonist SIB-1553A alone and in combination on cognition in a non-human primate model of early PD. Three adult male Rhesus monkeys, previously administered low doses of the neurotoxin MPTP over several months to produce cognitive deficits, were trained to perform a modified spatial delayed response task in which the attentional demands of the task were manipulated by varying the duration of the cue presentation while keeping the memory demands of the task low and constant. Task performance was assessed after administration of levodopa, nicotine ditartrate, or SIB-1553A and after administration of drug combinations. Animals performed normally when task attentional load was low (i.e., with long cue durations) but performance was significantly impaired on short cue duration trials. Levodopa further impaired performance on short cue duration trials and induced a deficit on long cue duration trials. Nicotine and SIB-1553A improved performance on short cue trials and when co-administered with levodopa, counteracted levodopa-induced deficits. These results confirm that nicotinic therapies may be useful for treating cognitive deficits associated with PD and suggest that negative effects of levodopa on cognition may be amenable to correction with adjunctive nicotinic therapies.

Effects of chronic manganese exposure on working memory in non-human primates.

Human exposure to manganese (Mn) has been associated with a variety of cognitive deficits including learning and memory deficits. However, results from epidemiological studies have been inconsistent in describing the nature of such cognitive deficits. The present study was conducted to evaluate the effects of chronic Mn exposure on memory functioning in non-human primates and to correlate behavioral outcome with brain Mn levels in an attempt to explain outcome variability seen in prior studies. Cynomolgus macaque monkeys were trained to perform memory-related tasks (spatial working memory, non-spatial working memory, reference memory) and exposed to manganese sulfate (15-20 mg/kg/week) over an exposure period lasting 227.5+/-17.3 days. Blood manganese levels were in the upper range of levels reported for human environmental, medical or occupational exposures. By the end of the manganese exposure period, animals developed mild deficits in spatial working memory, more significant deficits in non-spatial working memory and no deficits in reference memory. Linear regression analyses showed that for most brain regions sampled, there was a significant inverse relationship between working memory task performance and brain Mn concentration. These results suggest that chronic exposure to levels of manganese achieved in this study may have detrimental effects on working memory and that Mn levels achieved in several brain regions are inversely related to working memory performance.

Postnatal lead poisoning impairs behavioral recovery following brain damage.

Lead is a potent environmental toxicant with well-known effects on intelligence, school achievement and behavior. Lead exposure is also associated with an increased risk of a variety of health problems including cancer, hypertension, cardiovascular disease, and renal disease. Considering the risk of hypertension, cardiovascular problems, and stroke following lead exposure, the current research assessed the extent to which postnatal exposure to environmentally relevant levels of lead could impair the recovery from a later occurring brain injury. Using a photochemical thrombotic stroke model we found that postnatal lead exposure significantly impaired post-stroke recovery of beam walking ability and proprioceptive limb placing. Considering the increased risk for hypertension and cardiovascular disease in lead-exposed humans, diminished capacity for repair or adaptation following lead exposure needs to now be examined in greater detail.

Effects of nicotinic therapies on attention and executive functions in chronic low-dose MPTP-treated monkeys.

Chronic administration of low doses of the neurotoxin MPTP to nonhuman primates induces cognitive deficits similar to those seen in early Parkinson's disease (PD) patients, without the confounding effect of significant motor impairment. The present study assessed the extent to which specific attentional and central executive deficits in chronic low dose (CLD) MPTP-treated monkeys could be modified by nicotinic therapies. Four adult male rhesus monkeys were trained to perform attention and executive function tasks and were then administered low doses of MPTP (dose range: 0.025-0.1 mg/kg, i.v.) over 98-158 days until stable cognitive deficits appeared. Results showed that both nicotine and the alpha4beta4 subtype-selective nAChR agonist SIB-1553A could improve certain aspects of attentional and central executive functioning in this model of early Parkinsonism. Nicotine failed to improve performance of CLD-MPTP-treated animals on an attention set-shifting task while SIB-1553A significantly improved at least some aspects of performance, suggesting that the compound increased the animals' ability to maintain a previously formed response set and restored cognitive flexibility. Both nicotine and SIB-1553A caused a dose-dependent enhancement of performance on the focused attention (cued reaction time) task, decreasing reaction times on both cued and noncued trials. Nicotine caused a significant reduction in reaction times but did not alter the error profile on an impulse (motor readiness) task. SIB-1553A reduced reaction times but caused an increase in bar release (i.e. impulsivity) errors. These data suggest that nicotinic drugs may have therapeutic potential for treating cognitive dysfunction in PD.

Attention and executive function deficits in chronic low-dose MPTP-treated non-human primates.

Parkinson's disease (PD) is a complex disorder consisting of motor deficits coupled with dysfunction in cognitive domains that are dependent upon the integrity of the frontal lobes and/or the fronto-striatal axis. Although it is increasingly acknowledged that PD patients have attentional and executive function deficits, it has been difficult to model these in nonhuman primates because of the nature of the cognitive tasks that have been used previously. The present studies were conducted to further define the nature of the cognitive impairment in a nonhuman primate model of early parkinsonism consequent to chronic low dose MPTP exposure and to further validate this model in monkeys trained to perform a battery of attentional and executive function tasks. Following chronic low dose MPTP exposure, monkeys developed deficits in maintenance of a response set as well problems in shifting attentional sets, suggesting decreased mental flexibility. On other tasks inattentiveness, an impaired ability to sustain spatial attention or to focus attention, a deficit in motor readiness and planning, and impaired time estimation were also observed. These results provide direct evidence of attention and executive function deficits in a nonhuman primate model of early parkinsonism. Based on these findings, we suggest that in addition to being useful for studying the cognitive deficits related to early PD and for developing new therapeutics for these problems, this model and these testing procedures may also provide a useful large animal model for studying attention deficit disorder and for developing new therapeutics for that condition as well.

Attentional cueing reverses deficits in spatial working memory task performance in chronic low dose MPTP-treated monkeys.

Chronic low dose MPTP-treated monkeys develop difficulty in performing spatial working memory tasks. Since these tasks have both attentional and memory components, the extent to which task performance deficits are attentional or memory in nature was examined. Using a modified variable delayed response (VDR) task, employment of an attentional cue prior to stimulus presentation significantly improved task performance, suggesting a strong attentional component to the deficit in spatial working memory task performance. These findings suggest that procedures to enhance attention may be useful in ameliorating some of the "memory" deficits associated with early Parkinson's disease.

The inclusion of fluoxetine into gamma-cyclodextrin increases its bioavailability: behavioral, electrophysiological and pharmacokinetic studies.

The inclusion of a drug into cyclodextrin generally results in the modification of its physical and chemical properties and sometimes can increase its oral bioavailability. The aim of this study was to compare the effects of the fluoxetine HCl/gamma-cyclodextrin complex to that of traditional fluoxetine HCl. In the forced swimming test in mice, fluoxetine HCl/gamma-cyclodextrin was more effective than fluoxetine HCl, the ED30s being, respectively, 9.5 and 16.9 mg/kg PO. Both compounds (10 mg/kg PO) were able to reduce the firing rate of dorsal raphe neurons in the rat. However, between-groups comparisons showed no significant differences between fluoxetine HCl treated animals and the vehicle group, while fluoxetine HCl/gamma-cyclodextrin appeared significantly more effective than vehicle from minute 25 of the measurement period. In healthy volunteers, the relative oral bioavailability, calculated as the ratio AUC 0-infinity fluoxetine HCl/gamma-cyclodextrin on AUC 0-infinity fluoxetine HCl (20 mg PO), was equal to 249.9%. The three experiments taken together suggest that the complexation of fluoxetine HCl into gamma-cyclodextrin increases its pharmacological efficacy in animals, this effect being related to an enhancement of its oral bioavailability as demonstrated in human healthy subjects.

Differential regulation of striatal dopamine D(1) and D(2) receptors in acute and chronic parkinsonian monkeys.

The contribution of the duration of the striatal dopamine (DA) depletion and the expression of parkinsonian signs to changes in D(1) and D(2) receptor number was investigated in the present study. Some animals (N=4) received large doses of 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP) over short periods of time and were symptomatic for a short period of time (1-3 months; acute parkinsonian group). Other animals (N8 months; chronic parkinsonian group). Despite similar symptomatology and similar degrees of striatal DA denervation, only acute parkinsonian animals had significantly increased numbers of D(1) receptors in most striatal regions. Striatal D(2) receptor binding was elevated in acute parkinsonian monkeys but only in some lateral striatal subregions at mid and caudal levels. These findings further suggest that the duration of parkinsonism is a critical factor in modulating changes in striatal neurochemistry.

Striatal preproenkephalin gene expression is upregulated in acute but not chronic parkinsonian monkeys: implications for the contribution of the indirect striatopallidal circuit to parkinsonian symptomatology.

This study examined the extent of striatal dopamine (DA) denervation and coincident expression of preproenkephalin (PPE) mRNA in monkeys made parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration. Some animals (n = 4) became moderately parkinsonian after receiving large doses of MPTP over short periods of time and were symptomatic for only a short period of time (1-3 months; acute parkinsonian group). Other animals became moderately parkinsonian after receiving either escalating doses of MPTP over long periods (4-6 months; n = 5) or a high dose of MPTP over a short period (<1 month; n = 1) and remained symptomatic for an extended period (>8 months; chronic parkinsonian group). Despite similar symptomatology and similar degrees of striatal DA denervation at the time of their deaths, only acute parkinsonian animals had significantly increased PPE expression in sensorimotor striatal regions. PPE expression in chronic parkinsonian animals was either not changed or significantly decreased in most striatal regions. These findings suggest that the duration and not the extent of striatal DA denervation is a critical factor in modulating changes in striatal PPE expression. Furthermore, these results question the role of increased activity in the enkephalin-containing indirect striatopallidal pathway in the expression of parkinsonian symptoms.

Comparative study of pirlindole, a selective RIMA, and its two enantiomers using biochemical and behavioural techniques.

The interaction with monoamine oxidase A (MAO-A) and B has been shown to be sensitive to the absolute configuration of molecules. Therefore, the aim of this study was to compare the effects of the racemic pirlindole (a selective and reversible MAO-A inhibitor) and its two enantiomers using biochemical techniques (in vitro and ex vivo determination of rat brain MAO-A and MAO-B activity) and behavioural models (forced swimming test and reserpine-induced hypothermia and palpebral ptosis test). In vitro, the MAO-A IC50 of (+/-)-pirlindole, R-(-)-pirlindole and S-(+)-pirlindole were 0.24, 0.43 and 0.18 microM, respectively. Ex vivo, their ID50 were 24.4, 37.8 and 18.7 mg/kg i.p. The differences between the three compounds were not significant, with a ratio between the two enantiomers [R-(-)/S-(+)] of 2.2 in vitro and 2.0 ex vivo. MAO-B was only slightly inhibited. In the forced swimming test and the reserpine-induced hypothermia and ptosis model, the three compounds had an antidepressant profile. In the forced swimming test, the minimal effective dose ratio between the R-(-) and the S-(+) was again around 2.0. The behavioural observations were thus clearly in accordance with the biochemical data.