Biomedical subjects

Diana S Woodruff-Pak

Publications and source records attributed to Diana S Woodruff-Pak.

10 recordsLinked to original sources

PubMed2006

Preclinical investigation of the functional effects of memantine and memantine combined with galantamine or donepezil.

Combinations of drugs approved to treat Alzheimer's disease (AD) were tested in older rabbits with delay eyeblink classical conditioning, a form of associative learning severely impaired in AD. In Experiment 1 (n=49 rabbits), low doses (0.1, 0.5, 1.0, and 0.0 (vehicle) mg/kg) of memantine (Namenda) were tested. These three doses neither improved nor impaired acquisition at a statistically significant level. The 0.5 mg/kg dose had the greatest effect numerically and did not cause sensitization or habituation in explicitly unpaired controls. In Experiment 2 (n=56), doses of galantamine (Razadyne; 3.0 mg/kg) and donepezil (Aricept; 0.75 mg/kg) that had comparable magnitudes of cholinesterase inhibition were tested alone and in combination with 0.5 mg/kg memantine. Older rabbits treated with galantamine and with galantamine+memantine learned significantly better than vehicle-treated rabbits, but adding memantine did not improve learning over galantamine alone. Older rabbits treated with donepezil or a combination of memantine and donepezil did not learn significantly better than rabbits treated with vehicle. Galantamine has two mechanisms of action: mild cholinesterase inhibition and allosteric modulation of nicotinic acetylcholine receptors (nAChRs). When equated for cholinesterase inhibition, galantamine had significant efficacy in the eyeblink conditioning model system, but donepezil did not, indicating that modulation of nAChRs may be the mechanism that significantly ameliorates learning deficits in this model. In the absence of AD neuropathology in older rabbits, memantine had no efficacy alone or in combination with the other drugs.

Acetylcholinesterase↗

PubMed2006

Efficacy of MEM 1003, a novel calcium channel blocker, in delay and trace eyeblink conditioning in older rabbits.

Eyeblink conditioning is a relatively simple form of associative learning that shows neurobiological and behavioral parallels across several species, including humans. Aged subjects acquire eyeblink conditioning more slowly than young ones. In addition, eyeblink conditioning effectively discriminates patients with Alzheimer's disease from healthy older adults. The present study evaluated the effect of a novel L-type Ca2+ channel antagonist, MEM 1003, on delay and trace eyeblink conditioning in older (mean 33.4 months old) female New Zealand white rabbits. In the delay conditioning paradigm, an 850 ms tone conditioning stimulus (CS) was followed 750 ms after its onset by a 100 ms corneal air puff. Several trace conditioning paradigms were evaluated, with a silent period of 300, 400 or 500 ms between the end of the tone CS and the delivery of the air puff. Learning was more difficult in the longer trace paradigms than in the delay paradigm. MEM 1003, at a dose of 2.0 mg/kg, s.c., given daily 30 min prior to training on each of the 15 training days, enhanced learning compared to vehicle injections in both delay and trace paradigms. However, higher or lower doses were ineffective. These results support previous work demonstrating that modulation of Ca2+ channel activity can reduce age-related cognitive impairments.

Age Factors↗

PubMed2006

Inactivation of sodium channel Scn8A (Na-sub(v)1.6) in Purkinje neurons impairs learning in Morris water maze and delay but not trace eyeblink classical conditioning.

To examine the isolated effects of altered currents in cerebellar Purkinje neurons, the authors used Scn8a-super(flox/flox), Purkinje cell protein-CRE (Pcp-CRE) mice in which Exon 1 of Scn8a is deleted only in Purkinje neurons. Twenty male Purkinje Scn8a knockout (PKJ Scn8a KO) mice and 20 male littermates were tested on the Morris water maze (MWM). Subsequently, half were tested in 500-ms delay and half were tested in 500-ms trace eyeblink conditioning. PKJ Scn8a KO mice were impaired in delay conditioning and MWM but not in trace conditioning. These results provide additional support for the necessary participation of cerebellar cortex in normal acquisition of delay eyeblink conditioning and MWM and raise questions about the role, if any, of cerebellar cortex in trace eyeblink conditioning.

Analysis of Variance↗

PubMed2005

Associative and motor learning in 12-month-old transgenic APP+PS1 mice.

Doubly transgenic 12-month-old amyloid precursor protein and presenilins 1 (APP+PS1) mice (n=14) and littermate control mice (n=17) were tested on eyeblink classical conditioning-a task impaired in humans with Alzheimer's disease (AD). Mice were also tested on a motor learning task (rotorod) and on sensory tasks (prepulse inhibition [PPI] and acoustic startle). Transgenic mice had impaired motor performance on rotorod. Overall, APP+PS1 mice performed similarly to controls on both 500ms delay and 500ms trace eyeblink conditioning as well as on prepulse inhibition (PPI) and acoustic startle. However, within the transgenic group, cortical amyloid burden correlated significantly with decreased trace eyeblink conditioning. Moreover, cortical amyloid burden and hippocampal microglia activation correlated significantly with decreased PPI. These data suggest that only those transgenic mice with the most severe amyloid pathology exhibited deficits in hippocampus-dependent tasks. Transgenic mouse models of amyloid deposition differ from Alzheimer patients not only by the absence of major neuronal loss, but also by the general absence of severe impairments in eyeblink conditioning, except for mice with the greatest amyloid pathology.

Alzheimer Disease↗

PubMed2004

Nefiracetam and physostigmine: separate and combined effects on learning in older rabbits.

Physostigmine and nefiracetam were tested alone and in combination in 104 rabbits with a mean age of 28 months conditioned in the 750 ms delay eyeblink classical conditioning procedure. In Experiment 1, five doses of physostigmine (0.0005-0.2 mg/kg) enhanced conditioning. In Experiment 2, combinations of 10 mg/kg nefiracetam and 0.01, 0.1 and 0.2 mg/kg physostigmine improved the rate and magnitude of learning over rabbits treated with vehicle or 10 mg/kg nefiracetam alone. Brain AChE levels were significantly lower than vehicle for all doses of physostigmine and physostigmine plus nefiracetam. Control rabbits tested in the explicitly unpaired condition demonstrated that physostigmine alone and nefiracetam plus physostigmine had no non-associative effects. Physostigmine had a dramatic cognition-enhancing effect in older rabbits, and when nefiracetam was combined with physostigmine at a low dose, the ameliorating effect of physostigmine on learning was improved indicating that drug combinations for cognition enhancement may have therapeutic efficacy.

Acetylcholinesterase↗

PubMed2003

Mecamylamine reversal by nicotine and by a partial alpha7 nicotinic acetylcholine receptor agonist (GTS-21) in rabbits tested with delay eyeblink classical conditioning.

The aim of this experiment was to investigate the effects of nicotinic acetylcholine receptor (nAChR) agonism and antagonism on learning. Eyeblink classical conditioning (750ms delay procedure) was tested for 15 daily sessions in a total of 82 young rabbits: 58 rabbits were tested in the paired procedure when the conditioned stimulus (CS) was always followed by the unconditioned stimulus (US), and 24 rabbits were tested in the explicitly unpaired procedure in which CS and US presentations were independent. We used the nAChR agonists nicotine and GTS-21 (a selective alpha7 nAChR partial agonist that antagonizes alpha4beta2 nAChRs) and the relatively nonselective nAChR antagonist, mecamylamine. Groups of young rabbits were injected with 0.5mg/kg mecamylamine alone and in combination with two doses of nicotine or GTS-21 and compared to vehicle-treated rabbits. Explicitly unpaired control groups received vehicle, mecamylamine plus the highest nicotine dose, or mecamylamine plus the highest GTS-21 dose. Both GTS-21 and nicotine reversed the deleterious effect of mecamylamine on the acquisition of conditioned responses. Combinations of GTS-21 or nicotine and mecamylamine did not cause sensitization or habituation in the unpaired condition. Reversal of mecamylamine-induced learning deficits by nicotine and GTS-21 suggests that nAChR agonists may have efficacy in ameliorating deficits caused by the loss of some types of nAChRs in diseases such as AD.

Animals↗

PubMed2002

The long-term effects of nefiracetam on learning in older rabbits.

Classical conditioning of the nictitating membrane (NM)/eyeblink response has proven utility in the study of age-related memory disorders. The 750 ms delay eyeblink conditioning procedure was used to investigate the magnitude and duration of the nootropic drug nefiracetam's effect on retention and relearning. After administering daily injections of 0 (vehicle), 5, 10, or 15 mg/kg nefiracetam to 34 retired breeder rabbits during 15 days of acquisition, we tested retention and relearning 1, 5, and 12 weeks post-training. Rabbits received no drug after the initial 15 daily injections. Significant relearning was observed in the 10 mg/kg nefiracetam group 1 and 5 weeks after initial acquisition. Differences in tone-alone retention did not achieve statistical significance, although responses were numerically greater in the 10 mg/kg nefiracetam group. The effect of nefiracetam upon the ability of older rabbits to relearn a previously learned task is apparent up to 5 weeks after drug administration. Under normal conditions, a drug is administered continuously. In this experiment, nefiracetam had a significant effect long after drug administration had ceased. Prolonged administration of nefiracetam may have ameliorating effects greater than those observed in only 15 days of drug administration.

Aging↗

PubMed2002

Nicotinic cholinergic modulation: galantamine as a prototype.

Nicotinic acetylcholine receptor pharmacology is becoming increasingly important in the clinical symptomatology of neurodegenerative diseases in general and of cognitive and behavioral aspects in particular. In addition, the concept of allosteric modulation of nicotinic acetylcholine receptors has become a research focus for the development of therapeutic agents. In this review the scientific evidence for changes in nicotinic acetylcholine receptors in Alzheimer's disease is described. Within this context, the pharmacology of galantamine, a recently approved drug for cognition enhancement in Alzheimer's disease, is reviewed along with preclinical studies of its efficacy on learning and memory. Galantamine modestly inhibits acetylcholinesterase and has an allosteric potentiating ligand effect at nicotinic receptors. The data collected in this review suggest that the unique combination of acetylcholinesterase inhibition and nicotinic acetylcholine receptor modulation offers potentially significant benefits over acetylcholinesterase inhibition alone in facilitating acetylcholine neurotransmission.

Acetylcholine↗

PubMedDate not supplied

The effect of scopolamine in older rabbits tested in the 750 ms delay eyeblink classical conditioning procedure.

We investigated the effect of several doses of scopolamine in older rabbits that were trained for 20 days in the 750 ms delay eyeblink classical conditioning procedure. Our aim was to determine if the scopolamine-injected older rabbit would be a useful model for testing drugs for cognition enhancement in Alzheimer's disease (AD). A total of 39 rabbits with a mean age of 31 months received classical eyeblink conditioning with daily injections of 0.25, 0.75, or 1.5 mg/kg scopolamine hydrobromide or sterile saline vehicle. Doses of 0.75 and 1.5 mg/kg scopolamine significantly impaired acquisition, whereas acquisition was not significantly impaired with 0.25 mg/kg scopolamine. Results exhibit parallels in performance on delay eyeblink classical conditioning between scopolamine-treated older rabbits and human patients diagnosed with AD.

Aging↗

PubMedDate not supplied

Age-related impairment in the 250-millisecond delay eyeblink classical conditioning procedure in C57BL/6 mice.

In this study we tested 4-, 9-, 12-, and 18-month-old C57BL/6 mice in the 250-msec delay eyeblink classical conditioning procedure to study age-related changes in a form of associative learning. The short life expectancy of mice, complete knowledge about the mouse genome, and the availability of transgenic and knock-out mouse models of age-related impairments make the mouse an excellent species for expanding knowledge on the neurobiologically and behaviorally well-characterized eyeblink classical conditioning paradigm. Based on previous research with delay eyeblink conditioning in rabbits and humans, we predicted that mice would be impaired on this cerebellar-dependent associative learning task in middle-age, at ~9 months. To fully examine age differences in behavior in mice, we used a battery of additional behavioral measures with which to compare young and older mice. These behaviors included the acoustic startle response, prepulse inhibition, rotorod, and the Morris water maze. Mice began to show impairment in cerebellar-dependent tasks such as rotorod and eyeblink conditioning at 9 to 12 months of age. Performance in hippocampally dependent tasks was not impaired in any group, including 18-month-old mice. These results in mice support results in other species, indicating that cerebellar-dependent tasks show age-related deficits earlier in adulthood than do hippocampally dependent tasks.

Acoustic Stimulation↗