Effects of local and repeated systemic administration of (−)nicotine on extracellular levels of acetylcholine,norepinephrine, dopamine,and serotonin in rat cortex

Systemically administered (–)nicotine (0.2–1.2 mg/kg, s.c.) significantly increased the release of acetylcholine (ACh), norepinephrine (NE) and dopamine (DA) in rat cortex. The lowest dose of (–)nicotine examined (0.2 mg/kg, s.c) also significantly elevated extracellular serotonin (5-HT) levels, and the maximal increases of extracellular ACh (122% at 90 min post injection) and DA levels (249% at 120 min post-injection) were observed following this dose. In contrast, the maximal increase of NE release (157% at 30 min post-injection) was observed following the highest dose of (–)nicotine injected (1.2 mg/kg, s.c.). This higher dose consistently produced generalized seizures. Repeating the (–)nicotine (0.58 mg/kg, s.c.) injection four hours after the first administration significantly elevated extracellular NE levels and also appeared to increase DA and CCh release. In addition, extracellular ACh and DA levels increased significantly in the dialysate after (–)nicotine was administered directly to the neocortex through the microdialysis probe membrane. Norepinephrine levels appeared to be elevated in the cortex following local administration as well.     

Exogenous Choline Enhances the Synthesis of Acetylcholine Only Under Conditions of Increased Cholinergic Neuronal Activity

Abstract: The effect of choline (60 mg/kg, i.p.) on fluphenazine- and pentylenetetrazol-induced alterations in the concentration of acetylcholine (ACh) and/or the rate of sodium-dependent high-affinity choline uptake (HACU) in rat striatum and hippocampus was studied. Systemic administration of the dopamine receptor blocking agent fluphenazine hydrochloride (0.5 mg/kg, i.p.) decreased the concentration of ACh in the striatum; this effect was prevented by the prior administration of choline. The central nervous system stimulant pentylenetetrazol (30 mg/kg, i.p.) reduced the concentration of ACh in both striatum and hippocampus and increased the velocity of HACU in the hippocampus. Pretreatment with choline totally prevented the depletion of ACh induced by pentylenetetrazol in the striatum. In the hippocampus, prior administration of choline prevented the pentylenetetrazol-induced increase in the rate of HACU and attenuated the effect of pentylenetetrazol on the levels of ACh. Results indicate that the acute administration of choline antagonizes pharmacologically induced alterations in cholinergic activity as assessed by the rate of HACU and the steady-state concentration of ACh. Furthermore, data support the hypothesis that the administration of choline increases the ability of central cholinergic neurons to synthesize ACh under conditions of increased neuronal activity.     

Effects of Choline Administration on In Vivo Release and Biosynthesis of Acetylcholine in the Rat Striatum as Studied by In Vivo Brain Microdialysis

The purpose of the present study is to clarify the effects of the administration of choline on the in vivo release and biosynthesis of acetylcholine (ACh) in the brain. For this purpose, the changes in the extracellular concentration of choline and ACh in the rat striatum following intracerebroventricular administration of choline were determined using brain microdialysis. We also determined changes in the tissue content of choline and ACh. When the striatum was dialyzed with Ringer solution containing 10 microM physostigmine, ACh levels in dialysates rapidly and dose dependently increased following administration of various doses of choline and reached a maximum within 20 min. In contrast, choline levels in dialysates increased after a lag period of 20 min following the administration. When the striatum was dialyzed with physostigmine-free Ringer solution, ACh could not be detected in dialysates both before and even after choline administration. After addition of hemicholinium-3 to the perfusion fluid, the choline-induced increase in ACh levels in dialysates was abolished. Following administration of choline, the tissue content of choline and ACh increased within 20 min. These results suggest that administered choline is rapidly taken up into the intracellular compartment of the cholinergic neurons, where it enhances both the release and the biosynthesis of ACh.     

The effect of prolyl oligopeptidase inhibition on extracellular acetylcholine and dopamine levels in the rat striatum

Prolyl oligopeptidase (PREP, EC 3.4.21.26) inhibitors have potential as cognition enhancers, but the mechanism of action behind the cognitive effects remains unclear. Since acetylcholine (ACh) and dopamine (DA) are known to be associated with the regulation of cognitive processes, we investigated the effects of two PREP inhibitors on the extracellular levels of ACh and DA in the rat striatum using in vivo microdialysis. KYP-2047 and JTP-4819 were administered either as a single systemic dose (50 μmol/kg～17 mg/kg i.p.) or directly into the striatum by retrodialysis via the microdialysis probe (12.5, 37.5 or 125 μM at 1.5 μl/min for 60 min). PREP inhibitors had no significant effect on striatal DA levels after systemic administration. JTP-4819 significantly decreased ACh levels both after systemic (by ～25%) and intrastriatal (by ～30-50%) administration. KYP-2047 decreased ACh levels only after intrastriatal administration by retrodialysis (by ～40-50%) when higher drug levels were reached, indicating that higher brain drug levels are needed to modulate ACh levels than to inhibit PREP. This result does not support the earlier hypothesis that the positive cognitive effects of PREP inhibitors in rodents would be mediated through the cholinergic system. In vitro specificity studies did not reveal any obvious off-targets that could explain the observed effect of KYP-2047 and JTP-4819 on ACh levels, instead confirming the concept that these compounds have a high selectivity towards PREP.     

Neuromechanical effects of pyrethroids, allethrin, cyhalothrin and deltamethrin on the cholinergic processes in rat brain

Our previous microdialysis study of freely moving rats demonstrated that 3 pyrethroids, allethrin (type I), cyhalothrin (type II) and deltamethrin (type II) differentially modulate acetylcholine (ACh) release in the hippocampus. To better understand the mechanisms of their modulatory effects and also other effects on the cholinergic system in the brain, the activities of ACh hydrolyzing enzyme acetylcholinesterase (AChE), ACh synthesizing enzyme choline acetyltransferase (ChAT) and ACh synthesizing rate-limiting step, high-affinity choline uptake (HACU) were examined in the present study. The pyrethroids studied had no effect on AChE activity in the cortex, hippocampus and striatum. These pyrethroids had no significant effect on ChAT in the cortex and hippocampus, but striatal ChAT was increased at higher dosage (60 mg/kg) by all three compounds. Lineweaver-Burk analysis of hippocampal HACU revealed that the pyrethroids did not alter the Michaelis-Menten constant (Km) value but caused alteration of maximal velocity (Vmax). Allethrin (60 mg/kg) and cyhalothrin (20 and 60 mg/kg) decreased while deltamethrin (60 mg/kg) increased the Vmax for HACU. In vitro study showed that at higher concentrations (> or = 10(-) (6) M) allethrin and cyhalothrin reduced the hippocampal HACU but deltamethrin increased it. These results suggest that mechanisms of ACh synthesis are involved in the modulatory effects of the pyrethroids on ACh release and other cholinergic activities.     

Dopaminergic Regulation of Septohippocampal Cholinergic Neurons

Abstract: The extent to which acetylcholine (ACh) release in the hippocampus is regulated by dopaminergic mechanisms was assessed using in vivo microdialysis in freely moving rats. Systemic administration of the dopamine (DA) receptor agonist apomorphine (1.0 mg/kg) or the specific D₁ agonist CY 208–243 (1.0 mg/kg) increased microdialysate concentrations of ACh in the hippocampus. The D₂ receptor agonist quinpirole (0.5 mg/kg) produced a small but statistically significant decrease in hippocampal ACh release. d -Amphetamine (2.0 mg/kg) increased ACh release, an effect that was blocked by the D₁ receptor antagonist SCH 23390 (0.3 mg/kg) but not by the D₂ antagonist raclopride (1.0 mg/kg). These findings suggest that endogenous DA stimulates septo-hippocampal cholinergic neurons primarily via actions at D₁ receptors. In addition, these results are similar to previous findings regarding the dopaminergic regulation of cortical ACh release, and suggest that the anatomical continuum formed by basal forebrain cholinergic neurons that project to the cortex and hippocampus acts as a functional unit, at least with respect to its regulation by DA.     

Treatment with Oxiracetam or Choline Restores Cholinergic Biochemical and Pharmacological Activities in Striata of Decorticated Rats

Interruption of the corticostriatal pathway by undercutting the frontal cortex resulted after 2 weeks in a 40% reduction of basal acetylcholine (ACh) release in vivo, and in inhibition of the striatal sodium-dependent high-affinity uptake of choline (SDHACU) to the same extent. The lesion, too, completely prevented the rise (about 35%) in striatal ACh content induced by oxotremorine and apomorphine acting at muscarine and dopamine receptors, respectively. Acute intraperitoneal injections of 100 mg/kg of either oxiracetam or choline chloride resulted in time-dependent recovery of ACh output from the striata of decorticated rats to control levels. Oxiracetam also normalized the ex vivo striatal SDHACU activity of decorticated rats 2 h after administration without any effect in sham-operated rats. Oxiracetam or choline chloride administered before oxotremorine (0.8 mg/kg, i.p.) or apomorphine (1 mg/kg, i.p.) reinstated the ACh-increasing effect of these agonists. It is suggested that choline chloride acts directly simply by being the precursor for ACh, whereas oxiracetam may act indirectly, possibly by increasing the availability of choline chloride for ACh synthesis. Furthermore, the frontally decorticated rat could constitute a useful model for studying means to restore the deficit in striatal cholinergic neurotransmission.     

Antifertility mechanisms of gossypol acetic acid in female rats

Gossypol acetic acid was administered orally (30, 60, 90 and 120 mg/kg/day) on Days 1-5 post coitum to mature female rats. At autopsy on Day 10, pregnancy in most treated animals (6/7 and 6/8) was blocked at high doses (90 and 120 mg/kg/day respectively). As the daily dose decreased to 60 mg/kg/day half (4/8) were not pregnant. However, at a lower dose (30 mg/kg/day), or at a single dose of 200 mg/kg at Day 1 p.c., pregnancy was not blocked. The concentrations of progesterone in the serum of these females were significantly decreased except at the low dose. The numbers of implantation sites in the treated females that did remain pregnant were similar to those in control females except at the dose of 120 mg/kg/day. Gossypol did not retard the development of the preimplantation embryo or cavitation. The Pontamine Blue test revealed that the drug did not interfere with the initiation of implantation. We suggest that gossypol has an antifertility effect in the female rat because it is luteolytic and disrupts post-implantation development.     

Effect of fluoxetine and metergoline on amphetamine-induced rise in plasma corticosterone

The effect of the serotonin reuptake inhibitor, fluoxetine, and the serotonin antagonist, metergoline, on the rise in plasma corticosterone induced by amphetamine was studied in the conscious, unrestrained rat. Fluoxetine (2.5 mg/kg) did not affect plasma corticosterone. However, this dose of fluoxetine when administered two hours prior to amphetamine (0.1 or 0.5 mg/kg) significantly potentiated the amphetamine-induced rise in plasma corticosterone. Fluoxetine had no effect on the response induced by the highest dose of amphetamine (1.0 mg/kg) utilized in the study. In contrast, metergoline produced a dose-dependent increase in plasma corticosterone over the range 0.1 – 5.0 mg/kg. This response reached maximum 30 minutes after drug administration and had a duration of approximately 120 minutes. Pretreatment of animals with metergoline (5.0 mg/kg) three hours before the administration of amphetamine (1.0 mg/kg) resulted in a significant decrease in the corticosterone rise induced by amphetamine. Lower doses of metergoline were ineffective in reducing the amphetamine-induced response. These observations support the hypothesis that the amphetamine-induced rise in plasma corticosterone is due, in part, to stimulation of serotonergic neurons.     

The effect of hemicholinium-3 on choline and acetylcholine levels in a sympathetic ganglion.

Pregangliaaonic stimulation of the cat's superior cervical ganglion in the presence of hemicholinium-3 (HC-3) produced the expected depletion of acetylcholine (ACh) stores, but failed to cause a corresponding reduction in the choline content. These results suggest that either HC-3 possesses an intracellular site of action or that in lower doses it selectively inhibits a specialized choline transport system in cholinergic nerves. At a dose of 2 mg/kg, HC-3 probably blocked ACh synthesis completely in ganglia stimulated at 20 Hz. Under these conditions, there was a rapid depletion of ACh to about 50% of control levels during the first 5 min of stimulation and thereafter the rate of decline in ACh levels proceeded at a much slower pace. Since the 2 mg/kg dose of HC-3 did not raise plasma choline concentrations, it may be assumed that non-specialized choline transport systems in other tissues were not significantly inhibited by this dose of HC-3. However, when the dose of HC-3 was increased to 4 mg/kg, plasma choline levels increased by 58%.     

4-(1-Naphthylvinyl)pyridine Decreases Brain Acetylcholine In Vivo, but Does Not Alter the Level of Acetyl-CoA

The effects of intraperitoneally administered 4-(1-naphthylvinyl)pyridine (NVP; 200 mg/kg) on the concentrations of acetylcholine (ACh), choline (Ch), and acetyl-CoA (AcCoA) in rat striatum, cortex, hippocampus, and cerebellum were investigated. Twenty minutes after treatment, the content of ACh was significantly diminished, whereas that of Ch was increased. In response to stress (swimming for 20 min), these changes were enhanced. However, the AcCoA content did not change in any of the brain regions. It is thus very likely that the decrease of brain ACh concentration induced by NVP is due to the drug's effect on choline acetyltransferase (ChAT) and/or the reduction of the high-affinity Ch uptake, and not on the availability of AcCoA. Presumably, the pharmacologically diminished activity of ChAT may become the rate-limiting factor in the maintenance of ACh levels in cholinergic neurons.     

Prostacyclin (PGI2) effects on anterior pituitary hormones in the rat in vivo.

Intravenous injection of 600 microgram PGE2 or PGI2 significantly increased serum LH and prolactin levels in estradiol treated ovariectomized rats. There was no effect on serum FSH concentration. PGE2 and PGI2 stimulated LH release in a non-dose dependent manner, while prolactin levels were positively correlated with the dose administered following PGI2 treatment. 6-keto-PGF1 alpha at a comparable dose had no effect on pituitary hormone levels. Subcutaneous administration of 1 mg/kg or 60 mg/kg PGI2 for seven days significantly depressed serum LH level both in male and female rats. These doses had no effect on serum FSH or prolactin levels.     

D1 and D2 Dopaminergic Regulation of Acetylcholine Release from Striata of Freely Moving Rats

The effects of selective D1 and D2 dopaminergic agents on the extracellular acetylcholine (ACh) content in striata of freely moving rats were determined by the microdialysis technique. LY 171555, a selective D2 agonist, reduced ACh output by approximately 30% within 20 min at the dose of 0.2 mg/kg, i.p., whereas the D2 antagonists (-)-remoxipride (10 mg/kg, s.c.) and L-sulpiride (50 mg/kg, i.p.) induced maximal increases of approximately 50% within 10 and 20 min, respectively. In contrast, the D1 antagonist SCH 23390 (0.25 mg/kg, s.c.) decreased the extracellular ACh content by approximately 30% in 20 min, but lower doses--0.025 and 0.05 mg/kg--had no such effect. The stimulation of ACh release by LY 171555 was prevented by (-)-remoxipride but not by SCH 23390 (0.25 mg/kg, s.c.). In addition, the D1 agonist SKF 38393 failed to modify the ACh increasing effect of (-)-remoxipride. Thus, the D1 and D2 receptors subserve opposing functions on ACh release. The D1/D2 dopaminergic agonist R-apomorphine, at the does of 1 mg/kg, i.p., reduced ACh output by approximately 35% only when D1 receptors were blocked by SCH 23390 (0.025 mg/kg, s.c.). The results provide clear in vivo evidence of the tonic inhibition exerted by dopaminergic nigrostriatal input on the cholinergic system of the basal ganglia through D1 and D2 receptors.     

Dopaminergic Regulation of Striatal Acetylcholine Release: The Critical Role of Acetylcholinesterase Inhibition

Abstract: This study examined the effects of different levels of acetylcholinesterase (AChE) inhibition on dopaminergic regulation of striatal acetylcholine (ACh) release as estimated by in vivo brain microdialysis. Systemic administration of d-amphetamine (2 or 10 mg/kg) increased the striatal output of ACh when the AChE inhibitor neostigmine (0.1 µM) was present in the perfusion fluid. In contrast, when the same experiments were conducted at 0.01 µM neostigmine, d-amphetamine failed to affect (2 mg/kg) or significantly decreased (10 mg/kg) striatal ACh output. The inhibitory action of the D₂ receptor agonist quinpirole (0.2 mg/kg) was significantly greater at 0.01 µM than at 0.1 µM neostigmine. Similarly, there was a nonsignificant trend for the D₂ antagonist raclopride (1 mg/kg) to stimulate ACh release to a greater extent at the low neostigmine concentration. In contrast, the stimulant effects of systemic administration of the D₁ agonist A-77636 (1.46 mg/kg) on striatal ACh release were the same at the two neostigmine concentrations. These results demonstrate that the concentration of an AChE inhibitor in the perfusion solution can quantitatively and even qualitatively influence the manner in which dopaminergic agents regulate ACh overflow in the striatum. On comparing the present results with earlier reports concerning the effects of d-amphetamine on tissue concentrations of ACh, it is tentatively concluded that a low neostigmine concentration is the more physiologically relevant condition. Under such conditions, at moderate doses d-amphetamine does not appear to alter striatal ACh release, with this likely being due to the opposing actions of D₁ and D₂ receptors. Nevertheless, until the endogenous interstitial concentrations of striatal ACh can be measured by other methods, the physiological relevance of ACh microdialysis studies in the striatum will remain uncertain.     

Effect of Pentylenetetrazole-Induced Kindling on Acetylcholine Release in the Hippocampus of Freely Moving Rats

Abstract: The role of γ-aminobutyric acid (GABA) modulation of septohippocampal cholinergic neurons in kindling was investigated. Hippocampal acetylcholine release was evaluated with the microdialysis technique in freely moving rats either after acute administration of isoniazid (an inhibitor of GABA synthesis) or pentylenetetrazole (PTZ)(a blocker of the GABA_A receptor-associated Cl⁻ channel) or after chronic administration of PTZ. Short-term treatment with PTZ (5–50 mg/kg, i.p.) or isoniazid (150–250 mg/kg, s.c.) increased hippocampal acetylcholine release in a dose-dependent manner. In contrast, the basal concentration of acetylcholine in the dialysate from the hippocampus of rats chronically treated with PTZ (kindled animals) was significantly reduced relative to that of vehicle-treated rats (2.39 ± 0.21 vs. 4.2 ± 0.31 pmol per 20-min sample; p < 0.01). Moreover, the release of acetylcholine was markedly more sensitive to the effect of a challenge injection of PTZ (10 or 20 mg/kg, i.p.) in kindled rats than in naive rats or rats chronically treated with vehicle. Abecarnil, a selective benzodiazepine receptor agonist with marked anticonvulsant activity, was administered together with chronic PTZ to evaluate whether persistent activation of GABA_A receptors and suppression of seizures during kindling might affect the sensitivity of septohippocampal cholinergic neurons to a challenge dose of PTZ. Abecarnil (1 mg/kg, i.p.) administered 40 min before each PTZ injection neither antagonized the decrease in basal acetylcholine release (2.26 ± 0.19 pmol per 20-min sample) nor prevented the development of kindling. In contrast, abecarnil prevented the chronic PTZ-induced increase in the sensitivity of acetylcholine release to a challenge dose of PTZ. These results provide novel in vivo data concerning the role of hippocampal acetylcholine function in the development of kindling and potentially in the learning and memory deficits associated with this phenomenon.     

SODIUM-DEPENDENT HIGH AFFINITY CHOLINE UPTAKE: A REGULATORY STEP IN THE SYNTHESIS OF ACETYLCHOLINE

The sodium-dependent high affinity choline uptake into synaptosomes from rat brain has been studied after in vivo treatments which would alter the activity of cholinergic neurons. We utilized a number of treatments to reduce the activity of cholinergc neurons in the brain. Administration of pentobarbital (65 mg/kg), chloral hydrate (40 mg/kg) and γbutyrelactone (750 mg/kg) caused a 50-80% reduction in sodium-dependent high affinity choline uptake in several brain regions (30 min). This depression was not found 24 h after injection. Interruption of the cholinergic septal-hippocampal or habenuleinterpeduncular tracts by lesions (10 min-1 h) also caused a similar, large reduction in sodium-dependent high affinity choline uptake in the hippocampus and the interpeduncular nucleus respectively. We reversed the inactivity after pentobarbital administration by direct electrical stimulation of the cholinergic septal-hippocampal tract. Stimulation (40 Hz) for 10-15 min completely reversed the depression in sodium-dependent high affinity choline uptake. Stimulation at lower frequencies or for shorter times caused a partial reversal. Administration of pentylenetetrazol (75 mg/kg), a convulsant, was utilized to increase the activity of central cholinergic neurons. After drug administration, we found a large (60%) increase in sodium-de-pendent high affinity choline uptake. This increase was not found in the hippocampus when cholinergic afferents were interrupted by septal lesion prior to drug administration. We also examined the uptake after administration of cholinergic drugs. Oxotremorine (0.75 mg/kg), a muscarinic agonist which reduces acetylcholine release and turnover, caused a reduction in uptake. On the other hand, administration of scopolamine (5 mg/kg), a cholinergic antagonist which increases acetylcholine turnover, caused an increase in sodium-dependent high affinity choline uptake. Addition of any drug utilized, drectly to uptake samples, did not alter uptake. We examined the conversion of [³H]choline to [³H]acetylcholine in hippocampal synaptosomes after septal lesion, pentylenetetrazol administration and in untreated controls. In all cases, 60-70% of the total sodium-dependent tritium content was present as [³H]acetylcholine. Evidence was presented that homoexchange is not or is less involved in choline uptake than in GABA uptake. A kinetic analysis of sodium-dependent high affinity choline uptake was performed after all treatments. We found changes in V_max, after all treatments, which were consistently in the same direction as the alterations in activity. The proposal is made that the sodium-dependent high affinity choline uptake is coupled to cholinergic activity in such a way as to regulate the entry of choline for the maintenance of acetylcholine synthesis. The findings also lead us to propose that sodium-dependent high affinity choline uptake in vitro be utilized as a rapid, relative measure of the activity of cholinergic nerve terminals in vivo.     

Stress- and Yohimbine-Induced Release of Cholecystokinin in the Frontal Cortex of the Freely Moving Rat: Prevention by Diazepam but Not Ondansetron

Abstract: The in vivo release of cholecystokinin (CCK)-like material (CCKLM) was measured in the frontal cortex of freely moving rats using the microdialysis technique combined with a sensitive radioimmunoassay. Local perfusion of K⁺ (100 m M )-enriched artificial CSF resulted in a 10-fold increase in CCKLM outflow, as compared with that occurring under basal resting (K⁺ = 3.0 m M ) conditions, and this effect could be completely prevented by removal of Ca²⁺ in the perfusing fluid. Chromatographic analyses demonstrated that CCK-8S contributed to 70% of CCKLM. Stressful stimuli such as a 2-min exposure to diethyl ether and a 30-min restraint produced a marked but transient increase in cortical CCKLM release. In addition, anxiety-like behavior induced by the systemic administration of yohimbine (5 mg/kg i.p.) was associated with a long-lasting enhancement in the peptide outflow. Pretreatment with the potent anxiolytic drug diazepam (5 mg/kg i.p., 5 min before each condition), which exerted no effect on its own, completely prevented CCKLM overflow due to diethyl ether, restraint, or yohimbine administration. In contrast, neither the systemic injection (0.1 mg/kg i.p.) nor the local application (100 µ M through the microdialysis probe) of the serotonin 5-HT₃ antagonist ondansetron affected the increased release of CCKLM in rats restrained for 30 min or treated with yohimbine. These results indicate that cortical CCKergic neurotransmission is increased during stress or anxiety-like behavior in rats. Prevention of this effect by diazepam suggests that an inhibitory influence of benzodiazepines on cortical CCKergic neurons might participate in the anxiolytic action of these drugs.     

Evidence that 5'-Cytidinediphosphocholine Can Affect Brain Phospholipid Composition by Increasing Choline and Cytidine Plasma Levels

Abstract: We examined the effects of orally administered 5'-cytidinediphosphocholine (CDP-choline) on arterial plasma choline and cytidine levels and on brain phospholipid composition in rats. Animals receiving a single oral dose of 100, 250, or 500 mg/kg showed peak plasma choline levels 6–8 h after drug administration (from 12 ± 1 to 17 ± 2, 19 ± 2, and 24 ± 2 µ M , respectively). The area under the plasma choline curve at >14 µ M , i.e., at a concentration that induces a net influx of choline into the brain, was significantly correlated with CDP-choline dose. In rats receiving 500 mg/kg this area was 2.3 times that of animals consuming 250 mg/kg, which in turn was 1.8 times that of rats receiving 100 mg/kg. Plasma cytidine concentrations increased 5.4, 6.5, and 15.1 times baseline levels, respectively, 8 h after each of the three doses. When the oral CDP-choline treatment was prolonged for 42 and 90 days, brain phosphatidylcholine concentrations increased significantly (by 22–25%; p < 0.05) in rats consuming 500 mg/kg/day. Brain phosphatidylethanolamine and phosphatidylserine concentrations also increased significantly under some experimental conditions; levels of other phospholipids were unchanged.     

Acetylcholine Release in the Rat Prefrontal Cortex In Vivo: Modulation by α2-Adrenoceptor Agonists and Antagonists

Abstract: We have previously shown that the release of acetylcholine (ACh) in the medial prefrontal cortex of the conscious rat, as measured by microdialysis, is increased following intraperitoneal injection of the selective α₂-adrenoceptor antagonist (+)-efaroxan. To characterize further the receptor pharmacology of this response, the effects of other selective α₂-adrenoceptor ligands were examined. The α₂-adrenoceptor antagonists idazoxan (2.5 and 20 mg/kg), atipamezole (2.5 mg/kg), and fluparoxan (10 mg/kg) increased ACh outflow by up to 250–325% of basal levels over a 3-h period following intraperitoneal injection. The α₂-adrenoceptor agonists UK-14304 (2.5 mg/kg) and guanabenz (2.5 mg/kg) reduced ACh outflow by 80 and 60%, respectively. Clonidine (0.00063–0.16 mg/kg) had no significant depressant effect and at 2.5 mg/kg increased ACh outflow to 233% of basal levels. These results indicate a modulatory role for α₂-adrenoceptors on the release of ACh in the rat prefrontal cortex in vivo. Based on the facilitatory effects produced by the antagonists alone, this α₂-adrenoceptor modulation appears to be tonic and inhibitory. The ability of α₂-adrenoceptor antagonists to enhance ACh outflow suggests a therapeutic usefulness in disorders where cortical ACh release deficits have been implicated.     

The effect of the antipsychotic drug mosapramine on the expression of Fos protein in the rat brain: comparison with haloperidol, clozapine and risperidone

In this study, we examined the effect of the acute p.o. administration of the antipsychotic drug mosapramine, as well as the antipsychotic drugs clozapine, haloperidol and risperidone, on the expression of Fos protein in the medial prefrontal cortex, nucleus accumbens and dorsolateral striatum of rat brain. The administration of mosapramine (1 or 3 mg/kg) significantly increased the number of Fos protein positive neurons in the medial prefrontal cortex, but not in the dorsolateral striatum. In addition, mosapramine (1, 3 or 10 mg/kg) produced a dose-dependent increase in the number of Fos protein positive neurons in the nucleus accumbens. The acute administration of 10 mg/kg of mosapramine significantly increased the number of Fos protein positive neurons in all brain regions. The acute administration of clozapine (30 mg/kg), similarly to mosapramine at lower doses (1 or 3 mg/kg), significantly increased the number of Fos protein positive neurons in the medial prefrontal cortex and nucleus accumbens, but not dorsolateral striatum. In contrast, haloperidol (0.3 mg/kg) significantly increased the number of Fos protein positive neurons in the nucleus accumbens and dorsolateral striatum, but not medial prefrontal cortex. The acute administration of risperidone (0.3 or 1 mg/kg) did not affect the number of Fos protein positive neurons in the medial prefrontal cortex, nucleus accumbens or dorsolateral striatum of rat brain, whereas a 3 mg/kg dose of risperidone significantly increased the number of Fos protein positive neurons in all brain regions. These results suggest that the ability of mosapramine to enhance expression of Fos protein in the medial prefrontal cortex may contribute to a clozapine-like profile with respect to actions on negative symptoms in schizophrenia. Furthermore, the lack of effect of low doses of mosapramine on Fos protein expression in the dorsolateral striatum, an area believed to play a role in movement, suggests that it may have a lower tendency to induce neurological side effects.