Increase In Striatal Acetylcholine Research Articles

Effects of perinatal buprenorphine and methadone exposures on striatal cholinergic ontogeny

The effects of exposure to various doses of buprenorphine, methadone or water during the perinatal period were studied on striatal cholinergic development in the rat. Rats were exposed to buprenorphine (0.3 or 3.0 mg/kg/day), methadone (9 mg/kg/day) and/or water prenatally, postnatally or both pre- and postnatally via maternally implanted osmotic minipumps. The effects of buprenorphine varied with the dose used. There were some similarities between the effects of perinatal buprenorphine and perinatal methadone, such as a reduction in striatal acetylcholine (ACh) content in 4-day-old pups exposed prenatally to methadone or buprenorphine (0.3 mg/kg/day). However, differences were also observed between the effects of the two drugs. Unlike methadone, the 0.3-mg/kg/day dose of buprenorphine produced a sex-related increase in striatal ACh in male postnatal day (PND) 21 pups. The 3-mg/kg/day dose of buprenorphine produced a completely different range of results, such as decreased striatal ACh content in 4-day-old pups exposed to the drug postnatally and in 21-day-old pups exposed both pre- and postnatally. Differences in the effects of the two drugs may be related to the different affinities and efficacies of the drugs at different opioid receptor subtypes.

Effect of intrastriatal injection of soman on acetylcholine, dopamine and serotonin metabolism

Intrastriatal injection of soman (14.85 nmol) inhibits cholinesterase (ChE) activity in the striatum with much smaller decreases in ChE activity in other brain areas of the rat. As would be expected, there is a substantial increase in striatal acetylcholine (ACh) content shortly after soman injection. However, this increase is no longer significant 1 h following intrastriatal injection. There is no change in striatal K ACh 20 min, 1 h or 24 h following soman injection. ACh content is not affected in the parietal cortex, hippocampus, or medulla/pons following intrastriatal soman injection. However, K ACh and/or ACh turnover are reduced in these brain areas following soman injection. There is no consistent effect on dopamine (DA) metabolism in any of the brain areas studied. However, serotonin (5-HT) metabolism appears to be affected in the cortex, hippocampus and medulla/pons following intrastriatal injection of soman. Possible mechanisms of the actions of local injection of soman on brain ACh and 5-HT metabolism are discussed, as well as the differences observed between the effects of local and peripheral administration of soman on DA metabolism in the striatum.

BM-5, a centrally active partial muscarinic agonist with low tremorogenic activity. In vivo and in vitro studies.

The acute and chronic effects of the centrally active oxotremorine analog, BM-5, [N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)-acetamide] were examined in rats and mice. In vivo studies in mice and rats indicated that this compound is a partial muscarinic agonist with large regional differences in its efficacy: BM-5 produced low tremor in doses which evoke full salivary response. The maximal tremor response to BM-5 was much smaller than that produced by oxotremorine, while the maximal salivary response to BM-5 was greater than that evoked by oxotremorine. The tremor response to BM-5 was bell-shaped, the peak dose being around 2 mg/kg. In contrast, the salivary response increased with increasing doses of BM-5. The apparent muscarinic antagonist properties of higher doses of BM-5 were specific to the striatum in which BM-5 (0.05-10 mg/kg) caused significant decreases in the level of acetylcholine while these levels were unaltered in the cerebral cortex, hippocampus, and brainstem. Pretreatment of rats with BM-5 (5 mg/kg) also prevented the increase in striatal acetylcholine induced by oxotremorine (0.75 mg/kg). Chronic treatment of mice with BM-5 (0.2-2 mg/kg) for 14 days also showed that BM-5 at higher doses, behaved as an antagonist, since it caused supersensitivity to oxotremorine on the tremor response. In addition, the number of receptor sites, as measured by binding of 3H-3-quinuclidinyl benzilate (3H-3-QNB), was increased in the striatum while no similar increase was observed in other brain areas.(ABSTRACT TRUNCATED AT 250 WORDS)

Frontal decortication and adaptive changes in striatal cholinergic neurons in the rat

Interruption of the corticostriatal pathway by undercutting the cortex resulted in a reduction of glutamate uptake by 55% and in a depression of acetylcholine (ACh) synthesis by 30% in striatum after two postlesion weeks without affecting the content of ACh and choline, the specific binding of [ 3H]dexetimide to muscarinic receptors, the activity of choline acetyltransferase and the levels of noradrenaline, serotonin, dopamine and 3,4-dihydroxyphenylacetic acid. The influence of this excitatory pathway on striatal cholinergic neuropharmacology was investigated. It was found that the effect of a number of agonists (R-apomorphine, bromocriptine, lisuride, quinpirole, JL-14389, 2-chloroadenosine, oxotremorine and methadone), capable of depressing cholinergic activity in the striatum through receptor-mediated responses — reflected as an increase in ACh content — is operative only when the corticostriatal pathway is intact. By contrast, antagonists capable of decreasing ACh content, i.e. the typical neuroleptics pimozide, haloperidol and the atypical ones clozapine, l-sulpiride, as well as the anti-muscarinic agent scopolamine, were not influenced by the lesion. The possibility that the lesion non-specifically damaged striatal cells on which the agonists, but not the antagonists acted was excluded by results showing, firstly, that the increase in striatal ACh elicited by the ACh precursor, choline, was not blocked by decortication, and secondly, that the degeneration of the corticostriatal neurons did not prevent the ACh-increasing effect of bromocriptine, a long-acting ergot alkaloid, when sufficient time was allowed for the drug to act. It was furthermore possible to restore the inhibitory action of apomorphine of cholinergic neurons either by short-term chemical lesion of the nigrostriatal dopaminergic input or by the administration of choline. The results suggest that the deafferentiated cholinergic neurons, being already inhibited by the loss of the excitatory input, cannot further be depressed by drugs that slow down their activity and their ACh turnover rate. Finally, some comments on the relationship between the dopaminergic, cholinergic and excitatory inputs in the striatum will be given.

Neurochemical effects of minaprine, a novel psychotropic drug, on the central cholinergic system of the rat.

Minaprine, a novel psychotropic drug with antidepressant, anticataleptic and antiaggressive properties, produced an increase in rat brain regional acetylcholine content at a subconvulsant dose of 30 mg/kg IP. The greatest increase (60%) was produced in the striatum, whereas an increase of about 35% was obtained in the hippocampus and the rest of the cortex. A small but significant increase of 14% was also found in the midbrain-hindbrain region. Minaprine decreased choline content only in the striatum. No tolerance to acute challenge was observed after 10-day chronic treatment. In vitro, the drug had no effect on striatal choline acetyltransferase activity up to a concentration of 160 microM and only weakly displaced (3H) dexetimide from its specific muscarinic receptor binding sites in striatum (IC50, 2 X 10(-4) M). After in vivo administration the drug did not affect sodium-dependent high affinity choline uptake by a hippocampal homogenate. On the other hand, the drug inhibited both striatal and hippocampal acetylcholinesterase activity at high (40-160 microM) concentrations in vitro. In vivo the drug produced a brief (5 min), small (18%) decrease in the enzymic activity which corresponded in time to the peak drug level attained in the brain, but was not concomitant with a change in striatal acetylcholine content. By contrast, the increase in striatal acetylcholine appeared after 30 min when there was no longer inhibition of acetylcholinesterase activity and when the level of minaprine in brain was reduced by 78%. Blockade of dopamine receptors by pimozide pretreatment partially prevented the increase in striatal acetylcholine produced by minaprine, whereas interference with cholinergic or serontonergic neurotransmission was without effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Increase in rat striatal acetylcholine content by bromocriptine: Evidence for an indirect dopaminergic action

Bromocriptine, at the optimal dose and time of 4 mg/kg, 90 min, increased the content of acetylcholine in the rat striatum by about 30% without affecting the acetylcholine content in other brain regions. Striatal choline acetyltransferase and acetylcholinesterase activities and sodium-dependent high affinity choline uptake were not affected by the in vivo administration or the in vitro incubation with even high amounts of the drug. The increase in striatal acetylcholine by bromocriptine was mediated through the dopaminergic system since pretreatment with pimozide or penfluridol, powerful dopamine receptor antagonists, completely prevented the effect while parachlorophenylaline and phenoxybenzene pretreatment were ineffective. The action of bromocriptine, differently from that of apomorphine, was also blocked upon inhibition of tyrosine hydroxylase by alphamethylparatyrosine, suggesting that intact catecholamine synthesis is necessary for the drug to act. The requirement of dopamine by bromocriptine was further indicated when no potentiation of the cholinergic response to bromocriptine occurred following induction of dopamine receptor supersensitivity by long-term 6-hydroxydopamine lesion of the nigroneostriatal pathway. On the other hand, evidence is presented to show that bromocriptine acts in synergism with dopamine as the latency period for the onset of bromocriptine's cholinergic action was significantly decreased when it was administered in combination with a subthreshold dose of L-dopa, the dopamine precursor. There also was no summation of bromocriptine's increase with apomorphine's increase in striatal acetylcholine content at supramaximal doses possibly indicating that the same population of intrastriatal cholinergic neurons is the common target of both drugs. It is proposed that bromocriptine exerts an inhibitory effect on the striatal cholinergic neurons through a stimulation of the dopaminergic system but, differently from apomorphine, it requires the presence of endogenous dopamine for its action.

Increase in rat striatal acetylcholine content by d-fenfluramine, a serotonin releaser

The anorectic agent, d-fenfluramine, maximally increased the acetylcholine content in the striatum by 50% at doses of 5–10 mg/kg. The action of the drug was completely prevented by treatments designed to interfere with serotonergic transmission (e.g., combined electrolytic lesion of the nucleus raphe medianus and dorsalis; pretreatments with methergoline, parachlorophenylalanine or fluoxetine). By contrast, interference with dopaminergic transmission (e.g., lesion of the nigrostriatal dopaminergic tract with 6-OHDA; pre-treatment with penfluridol) did not impede the action of d-fenfluramine. The administration of d-fenfluramine to animals given a supramaximal dose of apomorphine, 1.5 mg/kg, produced a summated increase in striatal acetylcholine. The data are consistent with the hypothesis that there may exist in the striatum different populations of cholinergic interneurons regulated by serotonin and dopamine, respectively.

Effect of carbamazepine on cholinergic parameters in rat brain areas

The action of the anti-epileptic drug, carbamazepine, was studied on the cholinergic tetrad (acetylcholine, choline, choline o-acetyltransferase and cholinesterase) in rat brain areas. The drug increased striatal acetylcholine starting at an intraperitoneal dose of 15 mg/kg. The maximal increase in striatal acetylcholine of 66% was produced at 25 mg/kg and the effect persisted for at least 120 min. This action was selective for the striatum, there being no effect in other brain regions encompassing the mesencephalon, diencephalon, cerebellum and hippocampus. The hemispheric residuum (after removal of the striatum and hippocampus) showed a 45% increase in acetylcholine but only at the highest dose used, 50 mg/kg. The choline level was decreased markedly in both the striatum and hemispheric residuum by carbamazepine at a dose of 25 mg/kg. Neither carbamazepine nor its metabolite, carbamazepine-10,11-epoxide affected striatal choline o-acetyltransferase or cholinesterase after in vitro incubation. The increase in striatal acetylcholine by carbamazepine was not mediated through the dopaminergic system, since pretreatment with pimozide, a powerful dopaminergic antagonist, did not prevent the effect. No tolerance to the action of carbamazepine on striatal acetylcholine was produced after chronic treatment with 25 mg/kg twice per day for 6 days.

Increase in striatal acetylcholine by picrotoxin in the rat: Evidence for a gabergic-dopaminergic-cholinergic link

Picrotoxin, 2 mg/kg i.p., a GABA receptor blocking agent, increased rat striatal acetylcholine content by approximately 70% without altering the levels of this amine in the cerebral hemispheres, mesencephalon, diencephalon, hippocampus and cerebellum. Striatal choline levels were concomitantly decreased by about 25%. This dose of picrotoxin also increased striatal homovanillic acid levels by about 30%, an effect which was not antagonized by pretreatment with the dopamine receptor stimulating agent, piribedil. Picrotoxin did not affect striatal choline-O-acetyltransferase or cholinesterase activity after in vitro incubation. The action of picrotoxin on striatal acetylcholine levels was partially antagonized by pimozide and completely blocked by alpha-methyl-para-tyrosine pretreatment while the intraventricular injection of 6-hydroxydopamine was without effect. Convulsions were not prevented by any of these treatments. The results are interpreted as follows: picrotoxin released dopamine through disinhibition of the dopaminergic neurons as a result of blockade of gabergic receptors. The increased dopaminergic activity inhibited cholinergic neurons and lead to an increase in acetylcholine content. The data thus provide evidence for a possible gabergic (inhibitory)—dopaminergic (inhibitory)-cholinergic link terminating in the striatum.

Decrease in rat striatal acetylcholine levels by some direct- and indirect-acting dopaminergic antagonists

Several direct- or indirect-acting dopamine receptor antagonists were found to decrease rat striatal acetylcholine levels. The maximum decrease of about 50% was produced by pimozide (0.5 mg/kg), by haloperidol (0.5 mg/kg) and by reserpine (2.5 mg/kg). The decreases in acetylcholine produced by pimozide and by haloperidol were found to be specific for the striatum and did not alter diencephalonic, mesencephalonic, cerebellar or hemispheric acetylcholine levels. Furthermore, these two drugs completely blocked the increase in striatal acetylcholine produced by the dopamine receptor agonist, apomorphine, and had no effect on striatal choline acetyltransferase and cholinesterase. These data suggest that haloperidol and pimozide act on the striatal cholinergic neurons through strong blockade of dopamine receptors. Reserpine presumably decreased striatal acetylcholine levels indirectly by depleting biogenic amines. Clozapine and 1-fenfluramine were unable to block the action of apomorphine, as was shown previously for chlorpromazine. It is thus suggested that these drugs are reversible dopamine receptor antagonists. Their weaker action in decreasing striatal acetylcholine may depend upon this property.

Increase in striatal acetylcholine levels [formula omitted] by piribedil a new dopamine receptor stimulant

Piribedil, (1–2″-pyrimidyl)-4-piperonyl piperazine), an agent proposed for the treatment of Parkinson's disease, was found to increase acetylcholine levels in the rat striatum and diencephalon but not in the mesencephalon, cerebellum or hemispheres. The effect was most marked in the striatum (greater than 100%) and long-lasting (at least 8 hours after a single administration of 60 mg/kg i.p.). Striatal choline levels were also increased by piribedil but did not parallel at all times and doses the effect on acetylcholine. Furthermore, choline levels were increased in all brain regions except the hemispheres. Striatal choline acetyltransferase and acetylcholinesterase were not affected by in vitro or in vivo treatment with even high doses of piribedil. α-Methyl-p-tyrosine was ineffective in blocking piribedil while pimozide, a blocker of dopamine receptors, completely antagonized the action of piribedil on striatal acetylcholine. It is concluded that piribedil produced the increase in striatal acetylcholine by directly stimulating dopamine receptors.