Biomedical subjects

R K McNamara

Publications and source records attributed to R K McNamara.

35 records · Page 2Linked to original sources

PubMed1996

Kindling of hippocampal field CA1 impairs spatial learning and retention in the Morris water maze.

We used two procedures to assess the spatial learning and memory of rats in the Morris water maze task subsequent to kindling of hippocampal field CA1: (1) seizures were kindled with stimulation of CA1 prior to training in the water maze (acquisition); and (2) maze training was imposed until performance stabilized, seizures were kindled with stimulation of CA1, and then performance in the maze was reassessed (retention). In both conditions, behavioral testing occurred 24 h after the last kindled seizure. When the effects of CA1 kindling on acquisition were tested, we found that kindling of generalized seizures with stimulation of field CA1 (kindling), but not kindling of non-convulsive or partial seizures (partial kindling), produced deficits in the water maze. When the effects of CA1 kindling on retention were tested, however, we found that kindling of either partial or generalized seizures produced deficits in the water maze. The results suggest that the processing of spatial information is vulnerable to the long-lasting changes in neural excitability associated with kindling.

Animals↗

PubMed1996

Myristoylated alanine-rich C kinase substrate (MARCKS): a molecular target for the therapeutic action of mood stabilizers in the brain?

BACKGROUND: Lithium remains a first-line treatment for the acute and prophylactic management of bipolar illness. Previous studies in our laboratory have demonstrated that chronic, but not acute, exposure to therapeutic concentrations of lithium significantly reduces the expression of the protein kinase C (PKC) substrate MARCKS (myristoylated alanine-rich C kinase substrate) in the rat hippocampus and an immortalized hippocampal cell line (HN33). The anticonvulsant drugs valproate and carbamazepine are emerging as efficacious alternative and adjunctive treatments for bipolar disorder. In the present study, we sought to determine the effects of valproate and carbamazepine on MARCKS protein levels by using our hippocampal cell model. METHOD: HN33 immortalized hippocampal cells were exposed acutely or chronically to sodium valproate 1 mM, carbamazepine 100 microM, lithium chloride 5 mM, or lithium chloride 5 mM + sodium valproate 1 mM. Additionally, cells were exposed to lithium chloride 5 mM in the absence or presence of inositol 5 microM, or sodium valproate 1 mM in the absence or presence of inositol 40 microM. After drug exposure, cells were collected, separated into soluble and membrane fractions, and MARCKS protein assayed by Western blot analysis using polyclonal rabbit antibody. Immunoreactive bands were quantitated by densitometric analysis. RESULTS: We report that chronic exposure of HN33 cells to either lithium or valproate produced a time-dependent down-regulation of MARCKS protein. Maximal reduction in MARCKS levels were observed after 3 days of exposure to valproate and after 7 days of exposure to lithium. The reduction of MARCKS produced by lithium and valproate alone were additive when the two drugs were combined. The reduction in MARCKS produced by lithium was reversed by the addition of inositol to the media, whereas the reduction produced by valproate was unaffected by the addition of inositol. Carbamazepine failed to affect MARCKS protein levels at each dose and time tested. CONCLUSION: These data provide evidence that, like lithium, chronic exposure to valproate produces a significant time-dependent down-regulation of the PKC substrate MARCKS, whereas carbamazepine is without effect. The MARCKS reduction produced by valproate appears to occur independently of inositol concentrations yet is additive with the reduction produced by lithium, which is inositol-reversible. Valproate- and lithium-induced regulation of MARCKS expression appears to be mediated by different mechanisms that may utilize PKC, and may be associated with the clinical profile of these mood stabilizers. Regulation of MARCKS expression may be associated with the prophylactic efficacy of lithium in the long-term stabilization of the recurrent affective episodes in bipolar disorder, and valproate may share this property.

Animals↗

PubMed1995

NMDA receptor blockade prevents kainate induction of protein F1/GAP-43 mRNA in hippocampal granule cells and subsequent mossy fiber sprouting in the rat.

Granule cells in the adult rat hippocampus do not constitutively express the growth-related axonal protein F1 (a.k.a. B-50, GAP-43, neuromodulin, pp46), yet kainic acid (KA) can induce extensive growth of granule cell axons, the mossy fibers, into the supragranular layer. Does this KA-induced growth occur in the absence of protein F1/GAP-43? Using quantitative in situ hybridization, we found that 16-24 h after KA (10 mg/kg, s.c.) F1/GAP-43 mRNA was in fact induced in granule cells and remained elevated above control levels for at least 20 days. The induction of F1/GAP-43 mRNA in granule cells was blocked either by MK-801 or pentobarbital pretreatment. If pentobarbitol was given 55 min, but not 90 min, after KA, F1/GAP-43 mRNA was also blocked. Since induction of F1/GAP-43 occurred when pentobarbitol was given 90 min after KA, a 35 min window of activation is required, beyond the initial 55 min, for F1/GAP-43 mRNA induction. As both MK-801 and pentobarbital blocked behavioral seizures their anti-convulsant action may be important for blocking F1/GAP-43 mRNA induction. Mossy fiber sprouting observed 30 days after KA was also blocked when either MK-801 or pentobarbital was given prior to KA. These results are consistent with the proposal that protein F1/GAP-43 promotes axonal growth in the adult brain in an input-dependent manner, and may also be of clinical relevance to the molecular mechanisms underlying structural remodeling in epilepsy.

Animals↗

PubMed1993

Effects of intracranial infusions of chlordiazepoxide on spatial learning in the Morris water maze. I. Neuroanatomical specificity.

The present investigation sought to determine the neuroanatomical locus through which the amnesic and anxiolytic effects of the benzodiazepine agonist chlordiazepoxide are mediated. Rats were infused with either chlordiazepoxide (60 nmol/microliters) or artificial CSF (1 microliter) into either the frontal cortex, nucleus basalis magnocellularis/substantia innominata, amygdala, medial septum, hippocampus, or cerebellum and run in the open field to assess anxiety as thigmotaxia and in the Morris water maze to assess spatial learning. Other rats were given chlordiazepoxide (5 mg/kg) or saline (1 ml/kg) systemically and run in the open field and water maze. When chlordiazepoxide was administered systemically, rats showed significantly less thigmotaxia, but not overall activity, than controls in the open field, and were deficit in spatial learning, but not cue learning or swim speed, in the water maze. Intracranial infusions revealed a neuroanatomical specificity for the amnesic and anxiolytic actions of chlordiazepoxide. Infusions of chlordiazepoxide into the amygdala, but none of the other structures, reduced thigmotaxia without affecting overall activity levels whereas infusions into the medial septum, but none of the other structures, prevented spatial learning, but not cue learning, and reduced swim speed in the water maze. Together, these finding suggest that the medial septum and the amygdala mediate the amnesic and anxiolytic actions of chlordiazepoxide, respectively. Moreover, these results provide direct evidence that the amnesic and anxiolytic actions of chlordiazepoxide are independent.

Amnesia↗

PubMed1993

Effects of intracranial infusions of chlordiazepoxide on spatial learning in the Morris water maze. II. Neuropharmacological specificity.

In the preceding paper it was found that infusions of chlordiazepoxide (CDP) into the medial septal region, but not several other regions possessing a high density of benzodiazepine receptors, impaired spatial learning, but not cue learning or swim speed, in the Morris water maze. The present investigation sought to further characterize the neuropharmacological profile of this effect. Initially, it was reconfirmed that systemically administered CDP impaired spatial learning, but not cue learning or swim speed, in the water maze. Additionally, it was found that systemically administered scopolamine, a muscarinic antagonist, impaired both spatial and cue learning, but not swim speed, confirming the detrimental effects of cholinergic hypofunction on maze learning. In new rats, a dose-response assessment revealed that 60 and 30 nmol, but not 10 nmol, CDP infused into the medial septum impaired spatial learning, but not cue learning or swim speed. On the following day, rats from each dose group, now undrugged, acquired a reversed platform location at control levels, suggesting that the previously observed impairment was not due to a neurotoxic effect. Additionally, it was found that systemically administered flumazenil (10 mg/kg) blocked the spatial learning deficit produced by the 60 nmol dose of CDP infused into the medial septum. However, intraseptal infusions of flumazenil (10, 20, or 30 nmol) failed to attenuate the spatial learning deficit produced by systemically administered CDP. Finally, systemically administered tetrahydroaminoacridine (1 or 3 mg/kg), an acetylcholinesterase inhibitor, failed to attenuate the spatial learning deficit produced by intraseptal CDP (60 nmol). Together these results implicate benzodiazepine receptors in the medial septum in the amnesic actions of CDP but suggest that additional sites also mediate this action. The present results fail to support the idea that the spatial learning deficit produced by intraseptal infusions of CDP is due to a suppression of septo-hippocampal cholinergic activity and it is proposed that CDP impairs spatial learning by exacerbating hippocampal inhibition by inhibiting septo-hippocampal GABAergic projection neurons.

Animals↗

PubMed1993

Differential effects of benzodiazepine receptor agonists on hippocampal long-term potentiation and spatial learning in the Morris water maze.

The amnesic effect of benzodiazepine drugs has been well documented, though the mechanisms mediating this effect are unknown. Long-term potentiation (LTP) has been proposed as a mechanism by which information is stored in the mammalian central nervous system. This experiment sought to determine if benzodiazepines impair mnemonic processes by blocking LTP. Rats implanted with a stimulating electrode in the perforant path and a recording electrode in the dentate gyrus were given high-frequency stimulation after the administration of either chlordiazepoxide (5 mg/kg), diazepam (5 mg/kg) or CL 218,872 (10 mg/kg). None of these drugs completely blocked the induction of LTP as measured by changes in the magnitude of the population spike amplitude, though CL 218,872 significantly suppressed potentiation over the duration of recording (24 h). Moreover, the potentiation observed in diazepam-treated rats returned to baseline after 24 h. Two weeks after the last recording, the same implanted rats were given their previous drug and dose and then tested for spatial learning ability in the Morris water maze. Each drug resulted in a severe impairment of spatial learning, but had no effect on cue learning. Two days later, in the absence of drugs, the same rats readily acquired a reversed platform location. Together these results suggest that CL 218,872 may impair spatial learning by suppressing LTP in the perforant path but that chlordiazepoxide and diazepam can impair spatial learning in the absence of LTP suppression in this pathway.

Animals↗

PubMed1993

Differential effects of kindling and kindled seizures on place learning in the Morris water maze.

There is some controversy about the role of long-term potentiation (LTP) in spatial learning. The authors have found that triggering generalized kindled seizures with stimulation of the perforant path disrupts spatial learning in the Morris water maze but that kindling per se does not affect spatial learning. It is suggested that abnormal electrical activity induced by high-frequency stimulation of the perforant path may have been responsible for the disruption of spatial learning previously attributed to LTP saturation.

Animals↗

PubMed1993

CL 218,872 a triazolopyridazine with a selective affinity for the benzodiazepine BZ1 receptor subtype, retards the development and expression of amygdaloid-kindled seizures: effects of flumazenil.

To clarify the role of benzodiazepine receptors in kindling, the present experiment assessed the effects of CL 218,872 (1, 5, 10, and 20 mg/kg), a triazolopyridazine with a selective affinity for the putative benzodiazepine BZ1 receptor subtype, on the development and expression of amygdaloid-kindled seizures. Additionally, we assessed the effects of flumazenil (10 mg/kg), a non-specific benzodiazepine receptor antagonist, on kindling and the expression of kindled seizures alone or concomitantly with CL 218,872 (20 mg/kg). CL 218,872 retarded the development of kindled seizures in a linear dose-dependent manner; rats treated with 5, 10, and 20 mg/kg, but not 1 mg/kg, of CL 218,872 required a greater number of afterdischarges (ADs) to develop generalized seizures than controls. Flumazenil also retarded kindling and failed to attenuate the prophylactic effect of CL 218,872. In a cross-over procedure rats that did not develop generalized seizures after 30 ADs while under drug were rekindled under vehicle and rats kindled under vehicle were subsequently tested under drug. Rats crossed over to vehicle rekindled at a faster rate than did controls during initial kindling, suggesting that some kindling had occurred under the drug. CL 218,872 also dose-dependently depressed kindled seizures and this was attenuated by flumazenil, which had little effect on kindled seizures by itself. Together, these data suggest that CL 218,872 is a potent anticonvulsant, implicating the BZ1 receptor subtype in seizure development and in the expression of kindled seizures.

Amygdala↗

PubMed1992

Limbic seizures, but not kindling, reversibly impair place learning in the Morris water maze.

We investigated the effects of kindling and kindled seizures in different limbic structures on place and cue learning in the Morris water maze. The triggering of seizures by stimulation of the perforant path, septum, or amygdala prior to daily training impaired place learning, but had little effect on visible platform training or swim speed. Seizures triggered by stimulation of the medial perforant path after daily training also impaired place learning. Conversely, place learning proceeded normally in rats tested 24 h after kindling triggered by stimulation of the perforant path, septum, or amygdala, indicating that kindling per se does not affect place learning. Each group was able to learn the location of a reversed platform when pretraining seizures were discontinued; and perforant path and septal kindled rats, but not amygdaloid kindled rats, were impaired at learning the location of a reversed platform when seizures were triggered before training. The results confirm previous reports that limbic seizures produce amnesia, but they contradict the finding that hippocampal kindling impairs learning on tasks sensitive to hippocampal lesions.

Amygdala↗

PubMed1992

Bilateral knife cuts to the perforant path disrupt spatial learning in the Morris water maze.

Both the hippocampus and the entorhinal cortex are known to be crucial for spatial learning, but the contribution of the pathway linking the two structures, the perforant path (PP), has never been tested in a spatial learning paradigm. The present study examined the role of the PP in spatial learning using the Morris water maze. Seven days after bilateral transection of the PP with a fine-bladed knife, rats were habituated to the pool, then trained to swim from varying start locations to a platform submerged in a fixed location. After 28 training trials over 5 days, probe trials (without any platform present) were given to assess spatial memory for the location. Compared to sham-operated controls, lesioned rats showed slower learning and poorer asymptotic performance in terms of both swim path distance and escape latency, and less preference for the correct quadrant during probe trials. When the platform location was "reversed" to the opposite quadrant, the lesioned rats again showed poorer learning, poorer asymptotic performance, and reduced preference for the correct quadrant on the probe trial. When tested with a visible platform whose position varied from trial to trial, lesioned rats performed as well as controls. These results are congruent with previous analyses of the contributions of the entorhinal cortex and hippocampus to spatial learning and suggest that for spatial learning, the PP is a critical functional link between these two structures.

Animals↗

PubMed1992

Like diazepam, CL 218,872, a selective ligand for the benzodiazepine omega 1 receptor subtype, impairs place learning in the Morris water maze.

The sedative, anxiolytic, and amnesic effects of diazepam were compared to those of CL 218,872, a triazolopyridazine that has a preferential affinity for the benzodiazepine omega 1 receptor subtype. Spontaneous locomotion was assessed using a running wheel, anxiety was assessed using an open-field divided into central and peripheral areas (thigmotaxis), and amnesia was assessed using the Morris water maze. It was found that CL 218,872, like diazepam, depressed spontaneous locomotion, reduced anxiety, and impaired place learning in a dose-dependent manner. Flumazenil, a benzodiazepine receptor antagonist with a similar affinity for both omega 1 and omega 2 subtypes, reversed all of the effects of diazepam and antagonized the anxiolytic and amnesic effects, and some but not all of the sedative effects of CL 218,872. These results suggest that the selective activation of the omega 1 receptor subtype by CL 218,872 is sufficient to produce sedation, anxiolysis, and amnesia in a manner similar to that produced by the coactivation of both the omega 1 and omega 2 receptor subtypes with diazepam.

Animals↗

PubMed1992

Pharmacological dissociation between the spatial learning deficits produced by morphine and diazepam.

This study sought to determine whether the place learning deficits produced by diazepam are a secondary result of opioid release. Rats pretreated with diazepam (3 mg/kg) or morphine (15 mg/kg) were trained in the Morris water maze. Diazepam impaired place learning-slowing acquisition and preventing the formation of a quadrant preference. Morphine also slowed acquisition, but did not prevent place learning, and impaired escape to a visible platform. Flumazenil blocked the deficits produced by diazepam, but not morphine. Naloxone (2 mg/kg) blocked the deficits produced by morphine, but not diazepam. A high dose of naloxone (10 mg/kg) slowed acquisition, and exacerbated the deficit produced by diazepam. These results demonstrate that diazepam interferes with mnemonic processes through endogenous benzodiazepine receptors, independently of opioidergic systems. Further, they suggest that morphine interferes with motivational processes through opioidergic systems, independently of endogenous benzodiazepine systems.

Animals↗

PubMed1992

Assessment of a cholinergic contribution to chlordiazepoxide-induced deficits of place learning in the Morris water maze.

This investigation sought to characterize the interaction between benzodiazepine and cholinergic systems in place learning in the Morris water maze. In the first experiment, rats were treated with scopolamine (1 mg/kg) alone or concomitantly with one of two doses of flumazenil (15 and 30 mg/kg) or with chlordiazepoxide (5 mg/kg) alone or concomitantly with flumazenil (15 mg/kg). Chlordiazepoxide and scopolamine severely impaired place learning but not cue learning. The low dose of flumazenil completely reversed the impairment produced by chlordiazepoxide and both high and low doses of flumazenil attenuated the place learning deficit produced by scopolamine. Neither dose of flumazenil affected place learning when administered alone. In the second experiment, rats were administered chlordiazepoxide (5 mg/kg) or scopolamine (1 mg/kg) alone or concomitantly with one of four doses of physostigmine (0.05, 0.10, 0.25, and 0.5 mg/kg). Once again, both chlordiazepoxide and scopolamine impaired place but not cue learning. Physostigmine reversed the impairment produced by scopolamine in a dose-dependent manner but failed at every dose to attenuate the impairment produced by chlordiazepoxide. The higher doses of physostigmine impaired place learning when administered alone. None of the drug treatments impaired cue learning. Together, these results suggest that the scopolamine-induced impairment of place learning is due to an increase in benzodiazepine/GABA activity, and contradict the notion that benzodiazepines impair memory by cholinergic mechanisms.

Acetylcholine↗

PubMed1991

Diazepam impairs acquisition but not performance in the Morris water maze.

Diazepam is known to produce anterograde amnesia in both humans and animals. The present investigation sought to determine if this impairment is a direct result of diazepam's interference with mnemonic processes or a result of deficits in performance or retrieval. Diazepam (3 mg/kg) was administered prior to training in the Morris water maze either before or after the rats had acquired the location of a submerged escape platform. Diazepam was found to impair acquisition but not retrieval of spatial information and this impairment was not due to the sedative, hypothermic or state-dependent learning effects of diazepam. These results replicate previous findings in the Morris water maze and provide new evidence that this deficit is primarily mnemonic in nature.

Animals↗

PubMed1990

Blockade of hoarding in rats by diazepam: an analysis of the anxiety and object value hypotheses of hoarding.

The "security hypothesis" suggests food hoarding by rats serves to preempt attack and therefore might be motivated by "anxiety". The "object value" hypothesis suggests rats hoard objects that they perceive as valuable as related to some state or need. These hypotheses were evaluated with the anxiolytic drug diazepam, which is purported to both decrease anxiety and increase motivation to eat, and which accordingly either may decrease or increase hoarding. Using a new hoarding paradigm, diazepam (Valium: 0.25-5 mg/kg), was found to produce a dose-related reduction in hoarding that was dependent upon food pellet size and that was reversed by flumazenil (Ro 15-1788), a benzodiazepine receptor antagonist. Diazepam also slowed eating speed, blocked "dodging", a movement used to initiate hoarding, and impaired spatial navigation in a learning-set swimming pool task. The results fail to support the object value hypothesis of hoarding. Since perception of food size, motivation, motor ability and spatial abilities all probably contribute to successful food hoarding, the results provide several explanations other than, or in addition to, anxiety reduction for the drug's effects on hoarding. Nevertheless, the study provides a number of new sensitive measures of the effects of anxiolytic drugs and new insights into their behavioral effects.

Animals↗

PubMed1990

Psychophysical methods for study of sensory-motor behavior using a food-carrying (hoarding) task in rodents.

Rodents (rat, mouse, gerbil) display species-typical food-handling movements that are dependent upon features of the food they are given. They swallow small pieces of food directly, eat medium-sized pieces from their forepaws, and carry (hoard) large pieces of food to refugees for consumption or storage. Both food size and anticipated eating time influence the occurrence of a given movement. Response speeds are also influenced by food size. The latency to initiate food-carrying and travel-speed during food-carrying are inversely related to the size of food, while the latency to return to the food source for more food is directly related to the amount of food just eaten. Using menu-driven computer programs, event relays and photocells, and videorecording methods, the food handling movements can be both monitored and quantified. Use of the method is illustrated by showing how manipulations such as familiarity with the environment, environmental lighting, food pellet size and peripheral and central processes influence movements and response speeds. The procedure provides a useful way to study sensorimotor processes, motivation and reinforcement processes, and memory and cognitive processes used in foraging.

Animals↗

PubMedDate not supplied

The neuropharmacological and neurochemical basis of place learning in the Morris water maze.

The Morris water maze (MWM) offers several advantages over other methods of studying the neurochemical basis of learning and memory, particularly with respect to its ability to dissociate deficits in memory formation from deficits in sensory, motor, motivational and retrieval processes. The contributions of nearly all of the major neurotransmitter systems have been investigated and consistent patterns have emerged. Normal function in glutamatergic and cholinergic systems is necessary for spatial learning, as blockade of NMDA receptors and cholinergic hypofunction prevents spatial learning but does not impair recall. Peptides such as adrenal and sex hormones and somatostatin may also be necessary for spatial learning. In contrast, activity in either GABAergic or opioidergic systems impairs spatial learning, though by quite different means. GABAergic activity prevents memory function, whereas opioidergic activity reduces motivation. Normal monoaminergic activity is necessary for normal performance in the MWM, but not for spatial learning per se. However, noradrenergic and serotonergic systems may enhance cholinergic-mediated mnemonic processes. Further research into the relative contributions of different receptor subtypes as well as interactions between neurochemical systems should provide significant advances in our understanding of the neural basis of learning and memory in mammals.

Animals↗