Broad-spectrum, non-opioid analgesic activity by selective modulation of neuronal nicotinic acetylcholine receptors.

Development of analgesic agents for the treatment of severe pain requires the identification of compounds that are devoid of opioid receptor liabilities. A potent (inhibition constant = 37 picomolar) neuronal nicotinic acetylcholine receptor (nAChR) ligand called ABT-594 was developed that has antinociceptive properties equal in efficacy to those of morphine across a series of diverse animal models of acute thermal, persistent chemical, and neuropathic pain states. These effects were blocked by the nAChR antagonist mecamylamine. In contrast to morphine, repeated treatment with ABT-594 did not appear to elicit opioid-like withdrawal or physical dependence. Thus, ABT-594 may be an analgesic that lacks the problems associated with opioid analgesia.

TRPV1 receptors in the CNS play a key role in broad-spectrum analgesia of TRPV1 antagonists.

Vanilloid receptor type 1 (TRPV1) is a ligand-gated nonselective cation channel that is considered to be an important integrator of various pain stimuli such as endogenous lipids, capsaicin, heat, and low pH. In addition to expression in primary afferents, TRPV1 is also expressed in the CNS. To test the hypothesis that the CNS plays a differential role in the effect of TRPV1 antagonists in various types of pain, the analgesic effects of two TRPV1 antagonists with similar in vitro potency but different CNS penetration were compared in vivo. Oral administration of either A-784168 (1-[3-(trifluoromethyl)pyridin-2-yl]-N-[4-(trifluoromethylsulfonyl)phenyl]-1,2,3,6-tetrahydropyridine-4-carboxamide) (good CNS penetration) or A-795614 (N-1H-indazol-4-yl-N'-[(1R)-5-piperidin-1-yl-2,3-dihydro-1H-inden-1-yl]urea) (poor CNS penetration) blocked capsaicin-induced acute pain with the same potency. In complete Freund's adjuvant (CFA)-induced chronic inflammatory pain, oral administration of either compound blocked thermal hyperalgesia with similar potency. Furthermore, intraplantar or intrathecal administration of A-784168 blocked CFA-induced thermal hyperalgesia, suggesting that both peripheral and CNS TRPV1 receptors may play a role in inflammatory thermal hyperalgesia. The effects of the two TRPV1 antagonists were further assessed in models presumably mediated by central sensitization, including CFA- and capsaicin-induced mechanical allodynia and osteoarthritic pain. In these models, the potency of the two compounds was similar after intrathecal administration. However, when administered orally, A-784168, with good CNS penetration, was much more potent than A-795614. Together, these results demonstrate that TRPV1 receptors in the CNS play an important role in pain mediated by central sensitization. In addition, these results demonstrate that significant CNS penetration is necessary for a TRPV1 antagonist to produce broad-spectrum analgesia.

Comparison of antinociceptive actions of standard analgesics in attenuating capsaicin and nerve-injury-induced mechanical hypersensitivity.

Intradermal capsaicin injection produces immediate spontaneous pain behaviors, and a secondary mechanical hypersensitivity (SMH) that is employed in the clinic as a model potentially predictive of human neuropathic pain. Presently, we have characterized capsaicin-induced SMH in rats, and compared pharmacological actions of standard analgesics in this and two nerve injury models, the L5/L6 spinal nerve ligation (SNL) and sciatic nerve chronic constriction injury (CCI) models. Intraplantar capsaicin produced dose-related SMH (enhanced paw withdrawal response to von Frey monofilament stimulation at an area away from injection site) that lasted for over 4 h. While pretreatment with a potent selective transient receptor potential vanilloid receptor-1 (TRPV1) antagonist A-425619 (1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea) prevented development of acute nocifensive (flinching) behavior immediately following capsaicin injection (ED(50)=4.9 mg/kg), the compound failed to attenuate the SMH when administered 2 h following capsaicin (10 microg/10 microl). Additional standard analgesics were also tested 3 h following intraplantar capsaicin in the SMH model. Comparison of their potencies in attenuating mechanical hypersensitivity in capsaicin, SNL and CCI models revealed similar ED(50)s for morphine (2.3 mg/kg, 1.6 mg/kg and 3.2 mg/kg, respectively), gabapentin (33.1 mg/kg, 33.9 mg/kg and 26.3 mg/kg, respectively) and lamotrigine (9.1 mg/kg, 8.9 mg/kg and 15.5 mg/kg, respectively). Duloxetine produced 50-65% effect at the highest tested dose (50 mg/kg), whereas the highest tested doses of morphine (10 mg/kg), gabapentin (85.5 mg/kg) and lamotrigine (30 mg/kg) all produced >70% efficacy in capsaicin SMH, SNL and CCI models. In contrast, celecoxib and ibuprofen showed weak effects in all three models. All standard analgesics generally had weak efficacy in attenuating capsaicin-induced immediate acute flinching behavior when administered before capsaicin. These results provide further support to the suggestions that distinct pharmacological mechanisms underlie capsaicin-induced acute nocifensive and SMH behaviors, and certain neuronal mechanisms underlying neuropathic pain states are also contributory to capsaicin-induced SMH.

Blockade of mGluR1 receptor results in analgesia and disruption of motor and cognitive performances: effects of A-841720, a novel non-competitive mGluR1 receptor antagonist.

BACKGROUND AND PURPOSE: To further assess the clinical potential of the blockade of metabotropic glutamate receptors (mGluR1) for the treatment of pain. EXPERIMENTAL APPROACH: We characterized the effects of A-841720, a novel, potent and non-competitive mGluR1 antagonist in models of pain and of motor and cognitive function. KEY RESULTS: At recombinant human and native rat mGluR1 receptors, A-841720 inhibited agonist-induced calcium mobilization, with IC50 values of 10.7+/-3.9 and 1.0 +/- 0.2 nM, respectively, while showing selectivity over other mGluR receptors, in addition to other neurotransmitter receptors, ion channels, and transporters. Intraperitoneal injection of A-841720 potently reduced complete Freund's adjuvant-induced inflammatory pain (ED50 = 23 micromol kg(-1)) and monoiodoacetate-induced joint pain (ED50 = 43 micromol kg(-1)). A-841720 also decreased mechanical allodynia observed in both the sciatic nerve chronic constriction injury and L5-L6 spinal nerve ligation (SNL) models of neuropathic pain (ED50 = 28 and 27 micromol kg(-1), respectively). Electrophysiological studies demonstrated that systemic administration of A-841720 in SNL animals significantly reduced evoked firing in spinal wide dynamic range neurons. Significant motor side effects were observed at analgesic doses and A-841720 also impaired cognitive function in the Y-maze and the Water Maze tests. CONCLUSIONS AND IMPLICATIONS: The analgesic effects of a selective mGluR1 receptor antagonist are associated with motor and cognitive side effects. The lack of separation between efficacy and side effects in pre-clinical models indicates that mGluR1 antagonism may not provide an adequate therapeutic window for the development of such antagonists as novel analgesic agents in humans.

Structure-activity studies on 2-methyl-3-(2(S)-pyrrolidinylmethoxy) pyridine (ABT-089): an orally bioavailable 3-pyridyl ether nicotinic acetylcholine receptor ligand with cognition-enhancing properties.

2-Methyl-3-(2(S)-pyrrolidinylmethoxy)pyridine, ABT-089 (S-4), a member of the 3-pyridyl ether class of nicotinic acetylcholine receptor (nAChR) ligands, shows positive effects in rodent and primate models of cognitive enhancement and a rodent model of anxiolytic activity and possesses a reduced propensity to activate peripheral ganglionic type receptors. The profiles of S-4, its N-methyl analogue, and the corresponding enantiomers across several measures of cholinergic channel function in vitro and in vivo are presented, together with in vitro metabolism and in vivo bioavailability data. On the basis of its biological activities and favorable oral bioavailability, S-4 is an attractive candidate for further evaluation as a treatment for cognitive disorders.

Identification and initial structure-activity relationships of (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594), a potent, orally active, non-opiate analgesic agent acting via neuronal nicotinic acetylcholine receptors.

New members of a previously reported series of 3-pyridyl ether compounds are disclosed as novel, potent analgesic agents acting through neuronal nicotinic acetylcholine receptors. Both (R)-2-chloro-5-(2-azetidinylmethoxy)pyridine (ABT-594, 5) and its S-enantiomer (4) show potent analgesic activity in the mouse hot-plate assay following either intraperitoneal (i.p.) or oral (p.o.) administration, as well as activity in the mouse abdominal constriction (writhing) assay, a model of persistent pain. Compared to the S-enantiomer and to the prototypical potent nicotinic analgesic agent (+/-)-epibatidine, 5 shows diminished activity in models of peripheral side effects. Structure-activity studies of analogues related to 4 and 5 suggest that the N-unsubstituted azetidine moiety and the 2-chloro substituent on the pyridine ring are important contributors to potent analgesic activity.

Animal models of cognitive function.

Various of animal models of cognitive function have been developed both to discover neural processes underlying cognition and to develop and test novel therapeutic interventions. Lesion models used in basic research have specified brain circuits involved in discrete cognitive behaviors, and simple system models have identified electrophysiological and biochemical events that might mediate processes such as learning and memory. Models used for drug screening for potential cognition enhancers have been less successful. Drug-screening models have identified several compounds as being of potential use as treatments for cognitive dysfunction prominent in conditions such as Alzheimer's disease. Unfortunately, most of these compounds have not been successful in clinical studies. This paper reviews representative model systems used for basic research and provides a more extensive treatment of models used to screen drugs, with an emphasis on models that attempt to mimic the cholinergic hypofunction characteristic of Alzheimer's disease. Included also are evaluations of the utility of models for drug screening and a discussion of possible reasons for discrepancies between preclinical and clinical evaluations of potential cognition enhancers.

Therapeutic potential of neuronal nicotinic acetylcholine receptor agonists as novel analgesics.

Pharmacological treatments for pain have come largely from two classes of compounds--the opioids and the nonsteroidal anti-inflammatory drugs (NSAIDs). Because of deficiencies associated with these two classes of compounds, exploration of novel approaches to pain relief has intensified of late. Nicotine, a neuronal nicotinic acetylcholine receptor (nAChR) agonist, has long been known to have antinociceptive effects in both experimental animals and humans. The relatively modest antinociceptive effects and the toxicities associated with nicotine preclude its development as an analgesic agent. However, recent discoveries in the nAChR field have stimulated interest in nAChR-targeted compounds as potential analgesic agents. Epibatidine, a potent nAChR agonist, was found to have full efficacy relative to opioids in preclinical pain models. Although epibatidine is toxic, these observations demonstrated that modest efficacy is not a general limitation of nAChR agonists. Moreover, exploration of the molecular biology of nAChRs revealed evidence of receptor diversity, suggesting that nAChR subtype-selective agents less toxic than nicotine might be discovered; and early medicinal chemistry efforts already have resulted in compounds with improved safety profiles. For example, ABT-594 is a nAChR agonist with the antinociceptive efficacy of epibatidine, but with an improved safety profile. This commentary reviews recent findings with nAChR-targeted compounds, explores potential mechanisms responsible for nAChR-mediated antinociception, and raises issues that must be addressed in developing compounds of this class as analgesics.

The therapeutic potential of nicotinic acetylcholine receptor agonists for pain control.

Due to the limitations of currently available analgesics, a number of novel alternatives are currently under investigation, including neuronal nicotinic acetylcholine receptor (nAChR) agonists. During the 1990s, the discovery of the antinociceptive properties of the potent nAChR agonist epibatidine in rodents sparked interest in the analgesic potential of this class of compounds. Although epibatidine also has several mechanism-related toxicities, the identification of considerable nAChR diversity suggested that the toxicities and therapeutic actions of the compound might be mediated by distinct receptor subtypes. Consistent with this view, a number of novel nAChR agonists with antinociceptive activity and improved safety profiles in preclinical models have now been identified, including A-85380, ABT-594, DBO-83, SIB-1663 and RJR-2403. Of these, ABT-594 is the most advanced and is currently in Phase II clinical evaluation. Nicotinically-mediated antinociception has been demonstrated in a variety of rodent pain models and is likely mediated by the activation of descending inhibitory pathways originating in the brainstem with the predominant high-affinity nicotine site in brain, the alpha4beta2 subtype, playing a critical role. Thus, preclinical findings suggest that nAChR agonists have the potential to be highly efficacious treatments in a variety of pain states. However, clinical proof-of-principle studies will be required to determine if nAChR agonists are active in pathological pain.

Effects of systemic and intracerebroventricular administration of mecamylamine, a nicotinic cholinergic antagonist, on spatial memory in rats.

The effects of both systemic and intracerebroventricular administration of mecamylamine, a nicotinic antagonist, were tested on the Morris water maze performance of rats. In experiment 1, mecamylamine (0, 3, and 10 mg/kg, IP) was administered before daily training sessions on the Morris water maze, a task in which rats use environmental cues to learn the location of an invisible escape platform in a large pool of water. The escape latencies of rats given the higher dose of mecamylamine were significantly longer than the latencies of rats given either saline or the peripherally-acting nicotinic antagonist hexamethonium (10 mg/kg). Analysis of search patterns during a free swim trial conducted in the absence of an escape platform confirmed the disruptive effects of the higher dose of mecamylamine. Similar drug effects were not observed when these rats were trained to a visible platform, and mecamylamine did not affect the retrieval of spatial information in well-trained rats. In experiment 2, similar effects were observed with ICV administration of mecamylamine (0, 10, 30, and 100 micrograms). The two higher doses increased escape latencies during the last day of place training and all three doses significantly impaired performance on a free swim. No significant effects were noted on subsequent training to a visible platform, and only the highest dose marginally impaired the retrieval of spatial information in well-trained animals. Thus, mecamylamine appears to impair the acquisition of spatial information in the Morris water maze but does not affect retrieval of previously acquired spatial information at comparable doses.

Enhancement of sustained attention performance by the nicotinic acetylcholine receptor agonist ABT-418 in intact but not basal forebrain-lesioned rats.

RATIONALE: Loss of telencephalic cholinergic projections has been postulated to contribute significantly to the cognitive decline associated with aging and dementia. OBJECTIVE: The effects of the nicotinic acetylcholine receptor agonist ABT-418, a potential therapeutic drug for the treatment of the age- and dementia-associated cognitive disorders, were tested in an animal model of the cortical cholinergic deafferentation-induced impairments in sustained attention. METHODS: Animals were trained in an operant task designed to test sustained attention performance. A partial loss of cortical cholinergic inputs was produced by infusions of 192 IgG-saporin into the basal forebrain. The effects of the systemic administration of ABT-418 (0.04, 0.13, 0.39 mg/kg) and the psychostimulant methylphenidate (0.2, 0.4, 0.8 mg/kg) were assessed. RESULTS: Compared with sham-lesioned animals, this lesion resulted in a decrease in the relative number of hits while the relative number of correct rejections remained unaffected. Administration of ABT-418 significantly improved the relative number of hits. Furthermore, this effect of ABT-418 interacted with the effects of the lesion. Unexpectedly, this interaction was based on a significant enhancement of the performance of sham-lesioned animals while no effects were found in 192 IgG-saporin-lesioned animals. Administration of methylphenidate did not affect performance. CONCLUSIONS: While these data do not support the hypothesis that administration of ABT-418 attenuates the impairments in attentional performance that result from loss of cortical cholinergic inputs, they support previous notions about this drug's ability to enhance cognitive processes in intact subjects.

A comparison of the effects of scopolamine and diazepam on acquisition and retention of inhibitory avoidance in mice.

Administration of either the muscarinic antagonist scopolamine or the benzodiazepine diazepam prior to training produced a dose-dependent impairment in the retention of one-trial inhibitory avoidance training in mice. To investigate the nature of this drug effect, the effects of scopolamine and diazepam were subsequently assessed on both acquisition and retention of inhibitory avoidance using a multiple-trial, training-to-criterion procedure. The training was conducted using either continuous trials in which the mouse was free to shuttle back and forth between shock and safe compartments or discrete trials in which the mouse was moved from the shock compartment of the safe compartment at the start of each trial. In either case, training continued until the mouse refrained from crossing into the shock compartment for a specified length of time on a single trial. Scopolamine (1.0 mg/kg) administered before training significantly increased the number of trials required to attain criterion, but did not affect retention when these mice were tested 2, 16, or 28 days later. In contrast, diazepam (1.0 mg/kg) did not significantly alter the number of trials necessary to reach criterion, but impaired retention of the inhibitory response in mice trained using discrete trials. The differences in the amnestic effects of scopolamine and diazepam revealed by this detailed analysis suggest that diazepam does not impair inhibitory avoidance performance through an effect on cholinergic function.

ABT-418: discriminative stimulus properties and effect on ventral tegmental cell activity.

Previous studies have established that ABT-418 [(S)-3-methyl-5-(1 methyl-2-pyrrolidinyl)isoxazole hydrochloride] is a novel neuronal nicotinic acetylcholine receptor (nAChR) ligand with cognitive enhancing and anxiolytic-like activity 3- to 10-fold more potent than (-)-nicotine in rodents. A series of experiments was conducted to determine the discriminative stimulus properties of ABT-418 in comparison with (-)-nicotine, and to determine the relative potencies of these compounds on ventral tegmental area (VTA) neurons. While rats were able to discriminate (-)-nicotine 1.9 mumol/kg in 39 days, they were not able to discriminate 1.9 or 6.2 mumol/kg ABT-418 from a saline solution during 50 days of training. In rats trained to discriminate 1.9 mumol/kg (-)-nicotine, a reduced generalization was induced by ABT-418 at 1.9 and 6.2 mumol/kg, an effect completely blocked by the cholinergic channel blocker mecamylamine (15 mumol/kg, IP). However, in extensively trained rats, intraperitoneal or subcutaneous injections of ABT-418 induced 78-82% generalization at the 6.2 mumol/kg dose. The predominant metabolites of (-)-nicotine and ABT-418 (continine and A-87770, respectively) were devoid of any effect in nicotine-trained rats. The reduced potency of ABT-418 in nicotine-trained rats is consistent with the electrophysiological findings showing that ABT-418 is 3-fold less potent than (-)-nicotine in activating dopamine-containing neurons in the VTA area.

Improvement in performance of a delayed matching-to-sample task by monkeys following ABT-418: a novel cholinergic channel activator for memory enhancement.

ABT-418, a newly characterized centrally acting cholinergic channel activator (ChCA), was evaluated for its ability to improve performance in a delayed matching-to-sample (DMTS) task by mature macaques well trained in the task. Previous studies in rodents have indicated that ABT-418 shares the memory/cognitive enhancing actions of nicotine, but without many of nicotine's dose-limiting side effects. As DMTS provides a measure both of general cognitive function (the matching concept) and of recent memory, it was hypothesized that some doses of ABT-418 would enhance the monkeys' ability to correctly perform the DMTS task. Intramuscular administration of ABT-418 significantly enhanced DMTS performance at low (2-32.4 nmol/kg) doses. In fact, the drug was slightly more potent that nicotine in this regard, and all eight animals tested in this study exhibited enhanced performance at one or more doses. ABT-418 produced the greatest improvement in DMTS performance at the longest delay interval. In animals repeatedly tested with their individualized "Best Dose", DMTS performance increased on average by 10.1 +/- 3.5 percentage points correct, which was equivalent to an increase of 16.2% over baseline performance. ABT-418 did not significantly affect response times, i.e., latencies to make a choice between stimuli, or latencies to initiate new trials. Whereas nicotine enhanced DMTS performance both on the day of administration and on the following day (in the absence of drug), ABT-418-induced enhanced performance was detected only on the day of administration. Finally, single daily administration of the individualized best dose in three monkeys over a period of 8 days generally maintained enhancement of DMTS performance. Thus, the data were not consistent with the development of significant tolerance to the drug's mnemonic actions. In contrast to nicotine, no overt toxicity or side effects to acute or repeated administration of the drug were noted. Thus, ABT-418 represents a prototype of a new class of nicotinic agonists designed for the potential treatment of human dementias having a low profile of toxicity.

Central nicotinic receptor agonists ABT-418, ABT-089, and (-)-nicotine reduce distractibility in adult monkeys.

Increased distractibility is associated with both Alzheimer's disease and attention deficit disorder. The present study examined the effects of (-)-nicotine and the novel central nicotinic receptor (nAChR) agonists ABT-418 [(S)-3-methyl-2-pyrrolidinyl)isoxazole] and ABT-089 [2-methyl-3-(2-(S)-pyrrolindinylmethoxy)pyridine dihydrochloride] on the delayed recall accuracy of adult monkeys exposed to distracting stimuli. Unpredictable exposure to a random visual array produced marked decrements in recall accuracy on trials with the shortest delay intervals, reducing the accuracy on these trials by 23.4%. Intramuscular (i.m.) administration of (-)-nicotine, in doses of 5.4-43.3 nmol/kg, attenuated the effect of the distractor, but did not completely prevent it. Both ABT-418 (2.0-16.2 nmol/kg, i.m.) and ABT-089 (16.4-32.8 nmol/kg, i.m.) prevented distractibility, producing increases of 7.5-25.0% in accuracy on trials disrupted by distractor exposure. Further, both compounds also improved accuracy on trials during which distractors were not presented, an effect which was not observed after (-)-nicotine administration. Nicotinic-mediated side effects were not observed following administration of any compound. Thus, nAChR stimulation reduces distractibility in adult monkeys and may, therefore, represent a target for the pharmacologic treatment of disorders associated with susceptibility to distraction. ABT-418 and ABT-089 appear to be particularly useful in this regard, a likely result of their selective agonist activity at nAChRs expressed in the brain.

Effects of stimulation or blockade of central nicotinic-cholinergic receptors on performance of a novel version of the rat stimulus discrimination task.

This study evaluated the effects of two central nicotinic-cholinergic receptor agonists and an antagonist on performance accuracy of a rat, delayed stimulus discrimination task (DSDT). Rats were trained to discriminate between an auditory and visual stimulus by pressing a right or left lever. To diminish the rat's ability to use mediating spatial strategies to solve the task, computer automated, retractable doors separated the animal from the levers during delay intervals, thus reducing positioning at the lever. After stable baselines were achieved, rats were grouped and administered placebo (saline) and nicotine, lobeline or mecamylamine in a randomized dose series. Each group received two complete series of the selected compound on different occasions. Mecamylamine impaired DSDT accuracy in a dose-dependent manner while optimal doses of nicotine and lobeline significantly improved accuracy. Nicotine differed from lobeline in regard to its interaction with a dose of mecamylamine (1.0 mg/kg) that had not impaired DSDT accuracy. Combined administration of lobeline and mecamylamine was followed by a significantly increased level of DSDT accuracy that was similar to the improvement following administration of lobeline alone. In contrast, combined administration of nicotine and mecamylamine did not result in increased DSDT accuracy. Furthermore, lobeline administration similarly improved accuracy of trials associated with both the light and the tone, while nicotine improved accuracy of trials associated with the light to a much greater degree. These data suggest that the increases in DSDT accuracy associated with lobeline may be expressed through non-nicotinic mechanisms or a nicotinic receptor which is not blocked by mecamylamine.

Improvement in accuracy of delayed recall in aged and non-aged, mature monkeys after intramuscular or transdermal administration of the CNS nicotinic receptor agonist ABT-418.

ABT-418 was evaluated for its ability to enhance accuracy on a delayed matching-to-sample (DMTS) task by aged monkeys following intramuscular administration, and in non-aged mature monkeys following transdermal application. Aged monkeys were impaired in their performance of the DMTS task such that the longest delay intervals performed at above-chance levels extended only to 20 s. In contrast, for non-aged, mature animals, delay intervals extended to 140 s. In aged monkeys, the response to ABT-418 was highly individualized with animals responding to one or more doses in the range of 2-259 nmol/kg. A systematic dose-dependent enhancement of DMTS accuracy was not observed. When the individualized "best dose" was administered on a separate occasion, overall DMTS accuracy was increased by 12.6%. By 24 h after administration, accuracy was at control levels. In young monkeys, a significant dose-dependent enhancement of DMTS performance (an overall increase of 11.25% above baseline accuracy) was observed 5 h after application of a transdermal patch designed to maintain steady-state plasma levels of ABT-418 of 40-60 ng/ml over a 24-h period. Again there was some individual responsiveness to one of the three doses. When data included only the individualized best doses of ABT-418 for each animal, a similar enhancement of accuracy was observed for both the 5-h and 24-h test intervals. In neither the aged nor the young cohorts was enhancement of performance associated with altered response latencies or with any overt side effects of ABT-418. Thus, these data are consistent with the ability of ABT-418 to improve DMTS performance in both young and aged monkeys. In aged monkeys, this response was observed only after administration of individualized optimal doses for different monkeys. In young monkeys, a more systematic enhancement of DMTS accuracy was observed. Further, transdermal delivery of ABT-418 in non-aged monkeys demonstrated prolonged performance enhancement compared with IM injection to at least 24 h after patch administration.

The role of neuronal nicotinic acetylcholine receptors in antinociception: effects of ABT-594.

ABT-594, a nicotinic acetylcholine receptor agonist, has antinociceptive effects in rat models of acute thermal, persistent chemical, and neuropathic pain. Direct injection of ABT-594 into the nucleus raphe magnus (NRM) is antinociceptive in a thermal threshold test and destruction of serotonergic neurons in the NRM attenuates the effect of systemic ABT-594. However, lidocaine-inactivation of the NRM prevents the antinociceptive effect of systemic (-)-nicotine but not that of systemic ABT-594.

Comparison of site specific injections into the basal forebrain on water maze and radial arm maze performance in the male rat after immunolesioning with 192 IgG saporin.

In this study we investigated the effects of 192 IgG saporin injections into the medial septal area (MSA), or nucleus basalis magnocellularis (NBM), and combined injections into the MSA and NBM, on the water maze and radial arm maze performance in the male rat. The results of the present study reveal a dissociation between the effects of 192 IgG saporin injections into the basal forebrain on the performance of two tasks of spatial learning in the rat. Bilateral injections of 192 IgG saporin into the NBM, MSA or combined MSA/NBM failed to disrupt water maze performance when compared to controls. In contrast, injections of 192 IgG saporin into the MSA, NBM or MSA/NBM induced mild impairments on a radial arm maze task. Overall, the disruption of spatial learning observed in this study however was relatively mild compared to deficits in spatial learning reported using less selective lesions of the cholinergic basal forebrain. Consequently, the results of this study suggest that a selective reduction in cholinergic transmission in the basal forebrain is by itself, insufficient to account for the functional impairments observed in spatial learning in the rat. Although our data does support the use of 192 IgG saporin as a selective cholinergic toxin in the basal forebrain, it further suggests that assessment of spatial learning in the rat following 192 IgG saporin lesions of the basal forebrain in combination with lesions to other neurotransmitter systems, may be a more viable approach to the elucidation of the neuropathological mechanisms that are associated with the cognitive deficits seen in Alzheimer's Disease.

Comparison of site-specific injections into the basal forebrain on water maze and radial arm maze performance in the male rat after immunolesioning with 192 IgG saporin.

In this study, we investigated the effects of 192 IgG saporin injections into the medial septal area (MSA), or nucleus basalis magnocellularis (NBM), and combined injections into the MSA and NBM, on water maze and radial arm maze performance in the male rat. The results of the present study reveal a dissociation between the effects of 192 IgG saporin injections into the basal forebrain on the performance of two tasks of spatial learning in the rat. Bilateral injections of 192 IgG saporin into the NBM, MSA or combined MSA/NBM failed to disrupt water maze performance when compared to controls. In contrast, injections of 192 IgG saporin into the MSA, NBM or MSA/NBM induced mild impairments on a radial arm maze task. Overall, the disruption of spatial learning observed in this study was, however, relatively mild compared to deficits in spatial learning reported using less selective lesions of the cholinergic basal forebrain. Consequently, the results of this study suggest that a selective reduction in cholinergic transmission in the basal forebrain is, by itself, insufficient to account for the functional impairments observed in spatial learning in the rat. Although our data do support the use of 192 IgG saporin as a selective cholinergic toxin in the basal forebrain, they further suggests that assessment of spatial learning in the rat following 192 IgG saporin lesions of the basal forebrain in combination with lesions to other neurotransmitter systems, may be a more viable approach to the elucidation of the neuropathological mechanisms that are associated with the cognitive deficits seen in Alzheimer's disease.