Contribution of cholinergic and gabaergic functions to memory processes in BALB/cANnCrlBR mice

Several lines of evidence indicate that glucose influences on memory depend on interactions between glucose, glucoregulation and hippocampal cholinergic function. We previously demonstrated that glucose and scopolamine differentially affected memory consolidation for an operant bar pressing task in two closely-related BALB/c mouse strains. Whereas glucose normally improves memory in several animal strains, memory consolidation was not effected by systemic glucose injections in BALB/cANnCrlBR mice. Moreover, these mice were relatively insensitive to the normally observed amnestic effects of scopolamine. We therefore sought to determine whether cholinergic mechanisms in the dorsal hippocampus were involved in such atypical drug effects on memory processing in that strain of mice. In Experiment 1, we examined whether post-training oxotremorine would also atypically influence memory consolidation for an appetitively reinforced operant bar pressing task following microinjection in the dorsal hippocampus. In Experiment 2, we examined the effects of intrahippocampal GABAA drugs on memory consolidation. The non-selective muscarinic agonist, oxotremorine, dose-dependently impaired memory and the GABAA antagonist, bicuculline, improved retention in BALB/cANnCrlBR mice. It was concluded that GABA-mediated influences on hippocampal pyramidal output in BALB/cANnCrlBR mice and other strains are similar; but the amnestic effects of oxotremorine from the dorsal hippocampus were opposite to facilitating effects normally observed in other animal strains. Results are discussed relative to possible altered septo-hippocampal cholinergic neurotransmission in BALB/cANnCrlBR mice.     

Effects of REM sleep deprivation on cholinergic receptor sensitivity and passive avoidance behavior in clomipramine model of depression

This study investigated the effects of REM (rapid eye movement) sleep deprivation (RSD) on the activity of central cholinergic receptors and passive avoidance retention in rats treated neonatally with clomipramine. Male rat pups treated with clomipramine (15 mg/kg, s.c.) twice daily from postnatal day 5 to 21 were subjected to RSD procedure at three months of age, for 4 days consecutively. In the post-RSD phase, RSD-control rats showed a significantly enhanced cholinomimetic-induced hypothermia and an improved retention in passive avoidance task. However, these measures were not significantly different in RSD-experimental group as compared to rats treated neonatally with saline. These results suggest that RSD reverses the sensitivity of central cholinergic receptors in rats given clomipramine neonatally, and this mechanism may be involved in mediating the antidepressant effects of RSD treatment in clomipramine model of depression.     

Drug induced hypothermia in adult and senescent rats

Temperature regulation was evaluated in senescent (34-40 month old) and adult (8-9 month old) female Iva:WIWU and Emd:Wi-AF/Han rats. Injection of 1.5 mg/kg BW apomorphine HCl or 1.0 mg/kg BW oxotremorine sesquifumarate produced comparable maximal hypothermic responses in adult and senescent rats. However, the latency to reach maximal hypothermia after oxotremorine (but not apomorphine) was longer in senescent than in adult rats of both strains.     

Correlation between brain dopamine levels and 1-dopa activity in anti-Parkinson tests

The activity of l-dopa and dopamine in anti-oxotremorine and reserpine reversal tests in mice was compared with l-Dopa-induced changes in brain dopamine levels. Oxotremorine-induced tremors and hypothermia were prevented by both l-Dopa and dopamine despite the fact that only l-Dopa increased brain dopamine levels. Furthermore, a peripheral decarboxylase inhibitor that increased brain dopamine levels completely abolished the activity of l-Dopa in the oxotremorine test. Reserpine-induced ptosis was also reversed by l-Dopa and dopamine. However, reserpine-induced catatonia was reversed only by l-Dopa and was directly correlated with brain dopamine levels. Pretreatment with a peripheral decarboxylase inhibitor increased l-Dopa reversal of reserpine catatonia correlating with increased brain dopamine levels. Since oxotremorine-induced tremors and hypothermia as well as reserpine-induced ptosis can be influenced by peripheral drug effects, the reversal of reserpine induced catatonia appears to be the better model to use in a search for anti-Parkinson drugs.     

Oxotremorine antagonism by prolyl-leucyl-glycine-amide administered by different routes and with several anticholinergics

Prolyl-leucyl-glycine amide (PLG) was given by oral, intravenous, or subcutaneous routes of administration and shown to antagonize the central and peripheral effects of oxotremorine. The previously demonstrated action of PLG in this system when injected intraperitoneally in a single dose was found to be unchanged when administered by the same route for five consecutive days. Although three anticholinergic compounds were also effective in reducing the effects of oxotremorine, no interactions between PLG and trihexyphenidyl hydrochloride, benzotropin mesylate, or scopolamine were observed. The results confirm and extend the demonstration of the extra-endocrine effects of PLG.     

Involvement of both cholinergic and catecholaminergic pathways in the central action of methylphenidate: A study utilizing lead-exposed rats

The effects of methylphenidate (MPH) and the cholinergic agonists nicotine and oxotremorine were tested on the spontaneous multiple unit activity in the mesencephalic reticular formation of two groups of rats. In control rats i.v. MPH (1 mg/kg), nicotine (0.125 mg/kg), and oxotremorine (0.5 mg/kg) all attenuated the unit activity with latencies of less than 10 min. In another group of rats, exposed to lead acetate since birth, the extent of attenuation of unit activity induced by MPH and nicotine was reduced and the latency of effect was delayed by 45–50 min. The latency of the oxotremorine effect was not changed but the attenuation of unit activity was more pronounced in the lead-treated group. Pretreatment with spiroperidol, to inhibit the aminergic receptors, diminished the inhibitory effect of MPH in the control group but not in the lead-treated group, whereas the attenuating effect of oxotremorine was not affected in either group. These data support our previous evidence that MPH exerts its action in the central nervous system by a cholinergic pathway in addition to published catecholaminergic pathways. Furthermore, the present findings indicate that chronic leadexposure in rats results in cholinergic hypofunction and supersensitivity at central cholinergic receptor sites. This alteration of central cholinergic function may be partially attributed to the malnutrition observed in the lead-exposed animals.Part of this work was presented in abstract form (Shih et al., 1976b)     

Cholinergic modulation of memory in rats

Central cholinergic systems have long been implicated in the modulation of learning and memory processes in animals and man. Drugs that affect the central cholinergic system have been found either to enhance or to hinder performance in tests of learning and memory. Few studies have evaluated the effects of different cholinergic drugs within a single experimental paradigm and with a relatively wide dose range. The studies reported here investigated the effects of cholinergic drugs with diverse modes of action on the retention of a passive avoidance response. Physostigmine, arecoline, oxotremorine, nicotine, and 4-aminopyridine were administered IP immediately following the acquisition of a one-trial passive avoidance task. All of the drugs were found to enhance 72-h retention of passive avoidance; however, the effective doses were different for each of the drugs studied.     

Effect of some cholinergic drugs on the conditioned pole jump response in rats

Rats were trained to pole jump to a buzzer as the conditioned response. Cholinergic agents, oxotremorine and physostigmine significantly depressed this response. The effect was blocked by atropine. Nicotine and carbachol failed to modify the conditioned pole jump response. It is suggested that the central muscarinic inhibitory receptors are involved in the action of these drugs.     

The role of nicotinic and muscarinic acetylcholine receptors in attention

Rationale: This study tried to determine the relative roles of muscarinic and nicotinic cholinergic receptors in attentional processing. Methods: The effects of cholinoceptor agonists and antagonists, and of an anticholinesterase, were studied on performance of rats in a five-choice serial reaction time task. Results: Scopolamine (0.1 mg/kg) and mecamylamine (5.0 mg/kg) produced deficits in accuracy and reaction time, respectively. This may suggest a differential role for the two types of cholinoceptors in information processing. Combinations of sub-threshold doses of scopolamine (0.01–0.03 mg/kg) and mecamylamine (0.5–1.6 mg/kg), which alone did not affect accuracy or reaction time, did not produce significant deficits in attention. However, the pattern of effects after combined treatment suggested that the differential deficits seen with these drugs alone remained. The anticholinesterase physostigmine (0.1 mg/kg) and the non- selective muscarinic agonist oxotremorine (0.03 mg/kg) induced severe behavioural disruption at doses that appeared to be relatively well tolerated in previous studies; this precluded the derivation of accuracy and response time data at these doses. At lower doses, neither physostigmine (0.05 mg/kg) nor oxotremorine (0.003 mg/kg) significantly affected any performance measure; this may reflect the ability of both drugs to indirectly or directly activate presynaptic muscarinic receptors that inhibit acetylcholine release, respectively. Conclusions: Both muscarinic and nicotinic cholinoceptors may be important in attention but they may serve different roles in information processing; this hypothesis could be tested using tasks that place different emphasis on different stages of information processing. Received: 21 March 1999 / Final version: 3 August 1999     

Cholinergic activity modulates the survival of retinal ganglion cells in culture: the role of M1 muscarinic receptors

The control of natural cell death is mediated by neurotrophins released by target, afferent and glial cells. In the present work we show that treatment of retinal cells ‘in vitro’ for 48 h with 25 μM carbamylcholine induced a two-fold increase in retinal ganglion cells survival. This effect was dose-dependent and mediated by M₁ receptors since it could be blocked by 1 μM telenzepine (a M₁ receptor antagonist) and mimicked by 200 μM oxotremorine (a M₁ receptor agonist). The effect of carbamylcholine was abolished by 10 μM BAPTA-AM (an intracellular Ca²⁺ chelator), 30 μM dantrolene (an inhibitor of ryanodinic receptors), 500 nM H-89 (an inhibitor of PKA), 1.25 μM chelerythrine chloride (an inhibitor of PKC) and 50 μM PD-98059 (a MEK inhibitor). Treatment with 10 μM genistein (an inhibitor of tyrosine kinase), 25 μM LY-294002 (a PI-3 kinase blocker), 30 nM brefeldin-A (a blocker of polypeptides release), 50 nM K-252a (a Trk receptor inhibitor) and 20 μM fluorodeoxyuridine (an inhibitor of cell proliferation) totally inhibited the effect of carbamylcholine. Taken together our results indicate that muscarinic activity controls the survival of retinal ganglion cells through a mechanism involving the release of polypeptides and activation of Irk receptors.