Chronic lithium attenuates dopamine D1-receptor mediated increases in acetylcholine release in rat frontal cortex

The effects of chronic lithium treatment on methylphenidate-, D₁ dopamine receptor agonist (A-77636)-, and tactile stimulation-induced increases in frontal cortical acetylcholine release were studied in the rat using in vivo brain microdialysis. Cortical acetylcholine release in control rats was maximally stimulated by methylphenidate (1.25 and 2.5 mg/kg) to 173% and 212% above baseline, respectively. The effect of methylphenidate (2.5 mg/kg) was blocked by pretreatment with the dopamine D₁ receptor antagonist SCH 23390 (0.3 mg/kg). Chronic treatment with lithium chloride (3–4 weeks) produced plasma lithium concentrations of 0.45±0.02 meq/l. Chronic lithium significantly reduced increases in cortical acetylcholine release produced by methylphenidate. Stimulation of dopamine D₁ receptors with the full D₁ receptor agonist A-77636 (0.73 mg/kg) increased cortical acetylcholine release. Chronic lithium significantly reduced this effect of A-77636. In contrast, lithium failed to influence the increases of cortical acetylcholine release produced by tactile stimulation. These results suggest that while lithium does not influence normal, arousal-related increases in cortical acetylcholine release, this ion selectively attenuates dopamine mediated increases and/or abnormally large increase, which in the present circumstances were pharmacologically induced. The relevance of these findings to the antimanic actions of lithium is discussed.     

Depolarisation-evoked release of acetylcholine can mediate phosphoinositide hydrolysis in slices of rat cerebral cortex

Depolarisation of [3H]inositol prelabelled slices of cerebral cortex of the rat, with elevated extracellular K+ or the alkaloid veratrine, induced a marked accumulation of [3H]inositol monophosphate in the presence of 5 mM Li+. The effects of these stimuli were concentration-related with maximal responses obtained at 30 mM K+ and 30 microM veratrine. Larger concentrations produced submaximal responses but also markedly suppressed the incorporation of [3H]inositol into phospholipid. The responses to K+ or veratrine were not sensitive to atropine, prazosin, mepyramine, ketanserin or the peptidase inhibitor bacitracin. However, in the presence of the cholinesterase inhibitor physostigmine, the responses to these stimuli were greatly enhanced and this could be blocked by atropine. Both veratrine and K+ markedly stimulate release of endogenous acetylcholine from the slices. Release appears to be linear with time over the 45 min period of continuous stimulation. Reduction of extracellular calcium severely suppressed both the release of acetylcholine and the atropine-sensitive component of the phosphoinositide response to K+. The results suggest that endogenous acetylcholine can stimulate phosphoinositide metabolism by interacting with muscarinic receptors. The atropine-insensitive component, at least in part, represents entry of Ca2+ through voltage-sensitive channels and perhaps a direct effect on phosphoinositide metabolism.     

Effects of huperzine A on acetylcholinesterase isoforms in vitro: comparison with tacrine,donepezil, rivastigmine and physostigmine

Five inhibitors of acetylcholinesterase, huperzine A, donepezil, tacrine, rivastigmine and physostigmine, were compared with regard to their effects on different molecular forms of acetylcholinesterase in cerebral cortex, hippocampus, and striatum from the rat brain. In general, huperzine A preferentially inhibited tetrameric acetylcholinesterase (G4 form), while tacrine and rivastigmine preferentially inhibited monomeric acetylcholinesterase (G1 form). Donepezil showed pronounced selectivity for G1 acetylcholinesterase in striatum and hippocampus, but not in cortex. Physostigmine showed no form-selectivity in any brain region. In cortex, the most potent inhibitors of G4 acetylcholinesterase were huperzine A (K(i) 7 x 10(-9) M) and donepezil (K(i) 4 x 10(-9) M). The potent inhibitors of cortical G1 acetylcholinesterase were donepezil (K(i) 3.5 x 10(-9) M) and tacrine (K(i) 2.3 x 10(-8) M). In hippocampus, huperzine A and physostigmine were the most potent inhibitors of G4 acetylcholinesterase, while donepezil and tacrine were most potent against G1 acetylcholinesterase. In striatum, huperzine A and donepezil were the most potent against G4 acetylcholinesterase, while again donepezil was the most potent against G1. Although the inhibition constants (K(i)) of these acetylcholinesterase inhibitors differed significantly from region to region, the nature of the inhibition did not vary. These results suggest that the use of acetylcholinesterase inhibitors in treatment of Alzheimer's disease must consider both form-specific and region-specific characteristics of acetylcholinesterase inhibition.     

Dopamine D1 receptor stimulation increases striatal acetylcholine release in the rat

The effect of selective D1 receptor agonists on acetylcholine (ACh) release in the striatum was investigated using in vivo microdialysis. Administration of the reactive enantiomer, (+)-SKF 38393 (2, 10 mg/kg s.c.), doses which elevate grooming and sniffing behaviour, increased ACh release by 40 and 75%, respectively. Another D1 receptor agonist CY 204-283 (1 mg/kg s.c.) also produced a 75% increase in ACh output. The racemate (+/-)-SFK 38393 (20 mg/kg s.c.) increased ACh output by 60% and this was completely blocked by the D1 receptor antagonist SCH 23390 (0.3 mg/kg s.c.). In contrast, administration of the D2 receptor antagonist raclopride (1 mg/kg s.c.), 60 min after (+/-)-SKF 38393 (20 mg/kg s.c.), further increased ACh release. These results suggest that activation of D1 receptors increases ACh release in vivo and that D1 and D2 receptors have opposing roles in the regulation of striatal ACh release.     

The selective 5-HT1A receptor antagonist NAD-299 increases acetylcholine release but not extracellular glutamate levels in the frontal cortex and hippocampus of awake rat

The effects of the HT_1A receptor antagonist NAD-299 on extracellular acetylcholine (ACh) and glutamate (Glu) levels in the frontal cortex (FC) and ventral hippocampus (HPC) of the awake rats were investigated by the use of in vivo microdialysis. Systemic administration of NAD-299 (0.3; 1 and 3 µmol/kg s.c.) caused a dose-dependent increase in ACh levels in FC and HPC (peak value of 209% and 221%, respectively) and this effect was comparable to that induced by donepezil (2.63 µmol/kg s.c.). Moreover, the ACh levels in the FC increased even after repeated (14 days) treatment with NAD-299 and when NAD-299 was injected locally into the nucleus basalis magnocellularis or perfused through the microdialysis probe implanted in the cortex. In contrast, NAD-299 failed to alter the extracellular levels of glutamate after systemic (3 µmol/kg s.c.) or local (100 µM) administration. The present data support the hypothesis that cholinergic transmission in cortico-limbic regions can be enhanced via blockade of postsynaptic 5-HT_1A receptors, which may underlie the proposed cognitive enhancing properties of NAD-299 in models characterized by cholinergic deficit.     

Stimulating action of atropine on the release of acetylcholine by rat cerebral cortex in vitro

1. In cortical slices from rat brain incubated in a medium containing the irreversible cholinesterase inhibitor, soman (0.005 mM) and a high concentration of KCl (25 mM), atropine exerts a stimulating action on the release of acetylcholine (ACh).2. Two possible explanations for this action were examined. Atropine might expel ACh from the nerve endings by occupying its storage sites or it might prevent an inhibitory action of the released ACh on its further release by occupying muscarinic receptors at the presynaptic endings; its action would then be a kind of ;disinhibition.'3. The stimulating action of atropine on ACh release persisted during prolonged incubation (up to 3.5 h) provided choline was added to the medium. This finding would be difficult to explain if atropine acted by expelling ACh from its storage sites.4. The stimulating action of atropine on ACh release was inhibited by oxotremorine and by methacholine, added to the medium in high concentrations. This finding is readily explained if atropine acts by ;disinhibition.'     

Pyroglutamic acid administration modifies the electrocorticogram and increases the release of acetylcholine and GABA from the guinea-pig cerebral cortex

Pyroglutamic acid (1-PCA), a cyclic derivative of glutamic acid, was administered i.p. (7.7 mmol/kg) or intracerebroventricularly (25 - 50 mumol) to freely moving guinea-pigs, provided with semi-permanently implanted epidural cups. The effect of this compound on cortical Acetylcholine (ACh) and GABA outflow, as well as on gross behaviour and electrocorticogram (E.Co.G.) was investigated. 1-PCA increased the release of ACh and GABA from the cortical surface, did not change their cortical content, decreased the spontaneous motor activity and synchronized the E.Co.G.. These results suggest that 1-PCA increases GABA release, possibly by changing amino acid transport through the biological barrier or by acting as antagonist on the receptors for glutamic acid. In turn, the activation of the GABA system increases, as previously demonstrated, the cortical ACh release and causes mild sedation and E.Co.G. synchronization.     

Relationship between acetylcholine synthesis and its concentration in rat cerebral cortex

1. The synthesis of carbon-14 labelled acetylcholine ((14)C-ACh) from carbon-14 uniformly labelled glucose (U.L. (14)C-glucose) under different conditions has been studied.2. Increasing KCl concentration from 4 mM to 31 mM was associated with a large increase in the amount of (14)C-ACh in the medium and a significant decrease in the amount of (14)C-ACh in the tissue. This effect was observed in slices and minces but not in homogenate.3. Increasing KCl concentration from 4 mM to 31 mM resulted in the release of pre-formed (14)C-ACh.4. Elevated pre-incubation levels of ACh in slices incubated in 4 mM KCl medium was associated with a decrease in the formation of (14)C-ACh.5. These findings are consistent with the hypothesis that the concentration of ACh in the vicinity of the site of synthesis regulates the rate of ACh formation.     

Effect of cholecystokinin octapeptide and ceruletide on release of acetylcholine from cerebral cortex of the rat in vivo

The effect of cholecystokinin octapeptide (CCK-8) and its analogue, ceruletide on release of acetylcholine (ACh) from the cerebral cortex was investigated in urethane-anaesthetized and in unanaesthetized rats. Cholecystokinin octapeptide and ceruletide markedly stimulated output of ACh at doses of 1.5 and 5.0 micrograms/kg (i.p.), respectively. This effect was prevented by proglumide (160 mg/kg i.p.), a specific cholecystokinin receptor antagonist. At doses of 10 micrograms/kg (i.p.) and more, both CCK-8 and ceruletide decreased output of ACh from the cerebral cortex. The decrease was prevented by naloxone (1 mg/kg, s.c.), and replaced by a short-lasting increase. Cholecystokinin octapeptide and ceruletide appear therefore to affect the activity of cortical cholinergic fibres by acting upon both specific and opiate receptors. The interaction between CCK-8 and ceruletide, and opiate receptors either direct or through the release of endogenous opiates, was also demonstrated by the antagonism between ceruletide (1, 5 and 10 micrograms/kg, i.p.) and analgesia induced by morphine (5 mg/kg, s.c.), evaluated by the tail-flick test in the rat.     

Sertraline, a selective serotonin reuptake inhibitor modulates extracellular noradrenaline in the rat frontal cortex

The selective action of selective serotonergic reuptake inhibitors (SSRIs) on 5-hydroxytryptamine (5-HT) neurotransmission underlies the therapeutic effectiveness of this class of drugs. Yet there is increasing evidence that changes in extracellular 5-HT content may result in changes in the regulation of other neurotransmitter systems. The present study examines the effects of acute and chronic administration of the SSRI sertraline on release of endogenous noradrenaline (NA) in the frontal cortex and hippocampus of the rat using in vivo microdialysis. Acute administration of sertraline did not significantly alter NA release in either the cortex or the hippocampus. However, 24 h after chronic (14 days) administration of the drug (10 mg/kg i.p. once daily), NA release in the cortex but not hippocampus was significantly enhanced. The lack of an effect on NA release following a challenge with the alpha2-antagonist idazoxan suggests that chronic drug treatment has reduced the sensitivity of cortical pre-synaptic alpha2-adrenoceptors, activation of which would normally inhibit further NA release. The possible mechanisms underlying the regional specificity of the effect of chronic and not acute sertraline administration and the implications of these results for our understanding of depression are discussed.     

An open-label,comparative study of rivastigmine,donepezil and galantamine in a real-world setting

SUMMARY

Objective:We analysed the effects of donepezil, rivastigmine and galantamine, prescribed for the treatment of Alzheimer disease in a real-world setting in Italy.

Methods: Outcome measures included the Mini-Mental State Examination (MMSE), the Alzheimer Disease Assessment Scale cognitive subscale (ADAS-cog), Instrumental Activity of Daily Living (IADL) and ADL scales.

Results: Seventy patients were treated with donepezil, 121 with rivastigmine and 51 with galantamine. At 6 months, rivastigmine-treated patients improved by 1.29 points from baseline on the ADAS-cog, while donepezil- and galantamine-treated patients showed 'no change' (changes of < 0.2 points). On the IADL, patients treated with rivastigmine, donepezil and galantamine showed decreases of 0.42,0.58 and 0.75 points, respectively. On the ADL, donepezil- and galantamine-treated patients showed decreases of 0.44 and 0.86 points, respectively, while there was 'no change' with rivastigmine. On the MMSE,

donepezil- and rivastigmine-treated patients showed 'no change' and galantamine-treated patients showed a mean decrease of 1.19 points. A subgroup analysis of 'pseudo-randomised' patients (rivastigmine, n?=?63; donepezil, n?=?55; galantamine, n?=?51) supported the main findings. Side effects were similar (in type and frequency) in the three treatment groups.

Conclusions: This is the first study to compare the effects of the three most commonly-used cholinesterase inhibitors on the MMSE, ADAS-cog, IADL and ADL. Limitations included its small population size, its open-label design, and the fact that patients were randomised only after the introduction of galantamine. There were no statistically significant differences between the three drugs at 3 months. While numerical trends were observed suggesting the effect of rivastigmine > donepezil > galantamine, larger, longer-term prospective studies are needed to confirm whether there are important differences in the long-term efficacy of the three drugs.     

An open-label, comparative study of rivastigmine, donepezil and galantamine in a real-world setting

OBJECTIVE: We analysed the effects of donepezil, rivastigmine and galantamine, prescribed for the treatment of Alzheimer disease in a real-world setting in Italy. METHODS: Outcome measures included the MiniMental State Examination (MMSE), the Alzheimer Disease Assessment Scale cognitive subscale (ADAS-cog), Instrumental Activity of Daily Living (IADL) and ADL scales. RESULTS: Seventy patients were treated with donepezil, 121 with rivastigmine and 51 with galantamine. At 6 months, rivastigmine-treated patients improved by 1.29 points from baseline on the ADAS-cog, while donepezil- and galantamine-treated patients showed 'no change' (changes of < 0.2 points). On the IADL, patients treated with rivastigmine, donepezil and galantamine showed decreases of 0.42, 0.58 and 0.75 points, respectively. On the ADL, donepezil- and galantamine-treated patients showed decreases of 0.44 and 0.86 points, respectively, while there was 'no change' with rivastigmine. On the MMSE, donepezil- and rivastigmine-treated patients showed 'no change' and galantamine-treated patients showed a mean decrease of 1.19 points. A subgroup analysis of 'pseudo-randomised' patients (rivastigmine, n = 63; donepezil, n = 55; galantamine, n = 51) supported the main findings. Side effects were similar (in type and frequency) in the three treatment groups. CONCLUSIONS: This is the first study to compare the effects of the three most commonly-used cholinesterase inhibitors on the MMSE, ADAS-cog, IADL and ADL. Limitations included its small population size, its open-label design, and the fact that patients were randomised only after the introduction of galantamine. There were no statistically significant differences between the three drugs at 3 months. While numerical trends were observed suggesting the effect of rivastigmine > donepezil > galantamine, larger, longer-term prospective studies are needed to confirm whether there are important differences in the long-term efficacy of the three drugs.     

Effects of diazepam on adenosine and acetylcholine release from rat cerebral cortex: further evidence for a purinergic mechanism in action of diazepam.

1 Diazepam administered intraperitoneally (0.25 mg/kg) enhanced the rate of efflux of [3H]-adenosine and its metabolites from rat cerebral cortex. At a lower dose (0.05 mg/kg), this effect could be detected in only one of four rats. 2 Diazepam (0.05 and 0.25 mg/kg i.p.) depressed acetylcholine release from the rat cerebral cortex. Its effect was reversed by theophylline. 3 Theophylline (15 and 30 mg/kg) enhanced acetylcholine release from the rat cerebral cortex. Diazepam (0.25 mg/kg) administered after theophylline failed to cause a reduction in the rate of release, rather there appeared to be a further enhancement of release. 4 Pentobarbitone sodium (5, 10 and 15 mg/kg i.p.) did not elicit any increase in adenosine release. 5 These results support the proposal that benzodiazepines may exert their pharmacological actions by preventing adenosine uptake, thus enhancing the levels of extracellular adenosine.     

Stress increases noradrenaline release in the rat frontal cortex: prevention by diazepam

Foot-shock produced a more than 2-fold increase in noradrenaline (NA) release from the frontal cortex of freely moving rats. The effect of acute stress was almost completely prevented by the administration of diazepam (5 mg/kg i.p.). Diazepam alone inhibited cortical NA release, the maximal inhibition (-57%) being observed 90 min after the injection. Cortical NA release therefore appears to be a reliable index of central noradrenergic activity in response to stressful conditions.     

The effect of morphine on purine and acetylcholine release from rat cerebral cortex: Evidence for a purinergic component in morphine's action

Morphine enhances the release of adenosine and its metabolites from the rat cerebral cortex and inhibits the release of acetylcholine. Naloxone antagonizes the effects of morphine on both purine and acetylcholine release. The adenosine antagonists, caffeine and theophylline, reduce morphine's effects on acetylcholine release, and at the same time increase the spontaneous release of acetylcholine. It is suggested that morphine, acting at a naloxone-sensitive site, enhances the level of extracellular adenosine, which in turn inhibits the release of acetylcholine, and that some of morphine's actions are mediated by a purinergic step.     

Role of postsynaptic serotonin1A receptors in risperidone-induced increase in acetylcholine release in rat prefrontal cortex

Most atypical antipsychotic drugs increase acetylcholine release in the prefrontal cortex, but the detailed mechanism is still unknown. The present study examined the role of serotonin (5-HT)1A receptors in risperidone-induced increases in acetylcholine release in rat prefrontal cortex. Systemic administration of risperidone at doses of 1 and 2 mg/kg increased acetylcholine release in the prefrontal cortex in a dose-dependent manner. This increase was antagonized by systemic administration of high doses (1 and 3 mg/kg) of N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)cyclohexanecarboxamide (WAY100635), a 5-HT1A receptor antagonist/dopamine D4 receptor agonist, but not by a low dose (0.1 mg/kg) of the antagonist which antagonizes preferentially presynaptic 5-HT1A autoreceptors. Furthermore, local application of WAY100635 into the prefrontal cortex also attenuated risperidone-induced increases in acetylcholine release. WAY100635 alone did not affect acetylcholine release in the prefrontal cortex. On the other hand, local application of risperidone (3 and 10 microM), the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (1 and 10 microM), and the dopamine D4 receptor antagonist 3-(4-(4-iodophenyl)piperazine-1-yl)methyl-1H-pyrrolo[2,3-b]pyridine (1 and 10 microM) into the cortex did not affect acetylcholine release in the prefrontal cortex. These results suggest that risperidone increases acetylcholine release in the prefrontal cortex through a complex mechanism which is enhanced by prefrontal 5-HT1A receptor activation.     

Comparative studies of huperzine A, donepezil, and rivastigmine on brain acetylcholine, dopamine, norepinephrine, and 5-hydroxytryptamine levels in freely-moving rats

AIM: To assess the effects of cholinesterase inhibitors huperzine A, donepezil and rivastigmine on cerebral neurotransmitters in the cortex and hippocampus in freely-moving rats. METHODS: Double-probe cerebral microdialysis and HPLC with electrochemical detection were used to detect neurotransmitters. RESULTS: Our results showed that huperzine A (0.25, 0.5, and 0.75 micromol/kg, po) dose-dependently elevated extracellular acetylcholine (ACh) levels in the medial prefrontal cortex (mPFC) and hippocampus. Oral administration of donepezil (5.4 micromol/kg) or rivastigmine (1 micromol/kg) also elicited significant increases in ACh in the mPFC and hippocampus. The time course of cortical acetylcholinesterase (AChE) inhibition with the 3 inhibitors mirrored the increases of ACh at the same dose. The marked elevation of ACh after oral administration of huperzine A (0.5 micromol/kg) and donepezil (5.4 micromol/kg) was associated with a significantly increased release of dopamine (DA) in the mPFC or hippocampus. None of the 3 inhibitors affected norepinephrine (NE) and 5-hydroxytryptamine (5-HT) levels in the mPFC and hippocampus. The effects of huperzine A and rivastigmine did not depend on the route of administration, but donepezil was less efficacious by the oral route than by ip injection. The ability of huperzine A to increase ACh levels was unchanged when tests were performed after multiple oral administration of the drug at 0.5 micromol/kg, once per day for 30 d. CONCLUSION: The present findings showed that, in molar terms, huperzine A had similar potency on increasing mPFC ACh and DA levels as compared to the 11- and 2-fold dosages of donepezil and rivastigmine, respectively, and had longer lasting effects after oral dosing.