High affinity choline transport and acetylCoA production in brain and their roles in the regulation of acetylcholine synthesis

Jope, Richard S.

doi:10.1016/0165-0173(79)90009-2

Cited by 359 publications

(142 citation statements)

References 133 publications

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“…The nonspecific component was defined as binding in the presence of an excess concentration (10 mM) of unlabeled HC-3 and again, specific binding was expressed relative to membrane protein. Previous work has shown that developmental changes in HC-3 binding reflect almost exclusively a change in the total concentration of transporter sites (Zahalka et al, 1993); however, the interpretation of results of the present study, which relate to HC-3 binding as an index of synaptic activity (Cheney et al, 1989;Jope, 1979;Murrin, 1980;Navarro et al, 1989;Shelton et al, 1979;Simon et al, 1976;Zahalka et al, 1992Zahalka et al, , 1993, does not depend upon whether the change is specific to concentration or affinity.…”

Section: Assayscontrasting

confidence: 82%

Short-Term Adolescent Nicotine Exposure has Immediate and Persistent Effects on Cholinergic Systems: Critical Periods, Patterns of Exposure, Dose Thresholds

Abreu‐Villaça

Seidler

Qiao

et al. 2003

Neuropsychopharmacol

138

101

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In adolescents, the symptoms of nicotine dependence can appear well before the onset of habitual smoking. We investigated short-term nicotine exposure in adolescent rats for corresponding cholinergic alterations. Beginning on postnatal day 30, rats were given a 1-week regimen of nicotine infusions or twice-daily injections, at doses (0.6, 2, and 6 mg/kg/day) set to achieve plasma levels found in occasional to regular smokers. In the cerebral cortex, midbrain, and hippocampus, we assessed nicotinic cholinergic receptor (nAChR) binding, choline acetyltransferase (ChAT) activity, a constitutive marker for cholinergic nerve terminals, and [ 3 H]hemicholinium-3 (HC-3) binding to the high-affinity choline transporter, which responds to cholinergic synaptic stimulation. nAChR upregulation was observed with either administration route, even at the lowest dose; in the hippocampus, increases could be detected with as little as 2 days' treatment at 0.6 mg/kg/day. In the midbrain, upregulation was still significant even 1 month post-treatment. Adolescent nicotine treatment also produced lasting decrements in HC-3 binding that were separable from effects on ChAT, suggesting cholinergic synaptic impairment. Again, these effects were obtained at the lowest dose and remained significant 1 month post-treatment. Our results indicate that in adolescence, even a brief period of continuous or intermittent nicotine exposure, elicits lasting alterations in cholinergic systems in brain regions associated with nicotine dependence. As the effects are detected at exposures that produce plasma concentrations as little as one-tenth of those in regular smokers, the exquisite sensitivity of the adolescent brain to nicotine may contribute to the onset of nicotine dependence even in occasional smokers.

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Section: Assayscontrasting

confidence: 82%

Short-Term Adolescent Nicotine Exposure has Immediate and Persistent Effects on Cholinergic Systems: Critical Periods, Patterns of Exposure, Dose Thresholds

Abreu‐Villaça

Seidler

Qiao

et al. 2003

Neuropsychopharmacol

138

101

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“…With respect to sources of choline, pathways exist within the brain for the de novo synthesis of phosphatidylcholine from phosphatidylethanolamine (13), and the release of choline by the action of phospholipase D can support ACh synthesis (14). However, cytoplasmic synthesis of ACh is believed to depend predominantly on the acute uptake of extracellular choline across the presynaptic plasma membrane (12,15). Two major neuronal transport mechanisms for choline have been described: a Na ϩ -dependent, hemicholinium-3 (HC-3)-sensitive, high-affinity choline uptake (HACU; K m ϭ 1-5 M) process associated with cholinergic presynaptic terminals and a more ubiquitous mechanism of HC-3-insensitive, Na ϩ -independent, choline transport having a lower affinity for choline (K m Ϸ 100 M) (16,17).…”

mentioning

confidence: 99%

“…Within presynaptic terminals, ACh is synthesized from choline and acetyl-CoA by the enzyme choline acetyltransferase (ChAT) (9,10), and this ACh synthesis is thought to be limited by choline availability (11,12). With respect to sources of choline, pathways exist within the brain for the de novo synthesis of phosphatidylcholine from phosphatidylethanolamine (13), and the release of choline by the action of phospholipase D can support ACh synthesis (14).…”

mentioning

confidence: 99%

Lethal impairment of cholinergic neurotransmission in hemicholinium-3-sensitive choline transporter knockout mice

Ferguson

Bazalakova²,

Savchenko³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

151

137

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Presynaptic acetylcholine (ACh) synthesis and release is thought to be sustained by a hemicholinium-3-sensitive choline transporter (CHT). We disrupted the murine CHT gene and examined CHT؊͞؊ and ؉͞؊ animals for evidence of impaired cholinergic neurotransmission. Although morphologically normal at birth, CHT؊͞؊ mice become immobile, breathe irregularly, appear cyanotic, and die within an hour. Hemicholinium-3-sensitive choline uptake and subsequent ACh synthesis are specifically lost in CHT؊͞؊ mouse brains. Moreover, we observe a time-dependent loss of spontaneous and evoked responses at CHT؊͞؊ neuromuscular junctions. Consistent with deficits in synaptic ACh availability, we also observe developmental alterations in neuromuscular junction morphology reminiscent of changes in mutants lacking ACh synthesis. Adult CHT؉͞؊ mice overcome reductions in CHT protein levels and sustain choline uptake activity at wild-type levels through posttranslational mechanisms. Our results demonstrate that CHT is an essential and regulated presynaptic component of cholinergic signaling and indicate that CHT warrants consideration as a candidate gene for disorders characterized by cholinergic hypofunction.

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“…1). The rate-limiting step in the synthesis of acetylcholine (ACh) is the availability of choline in the cell (Jope 1979). Therefore, cholinergic cells possess a high-affinity choline transporter (HA-TS) on their terminals, in addition to the low-affinity choline transporter found on all neuronal cell types (Simon and Kuhar 1975;Okuda et al 2000).…”

Section: Neurochemisty Of Nicotinementioning

confidence: 99%

“…Therefore, cholinergic cells possess a high-affinity choline transporter (HA-TS) on their terminals, in addition to the low-affinity choline transporter found on all neuronal cell types (Simon and Kuhar 1975;Okuda et al 2000). ACh is actively synthesized via choline acetyltransferase (ChAT), which is located in the presynaptic nerve terminals near synaptic vesicles (Jope 1979). Because this enzyme is exclusive to the synthesis of ACh, it is a reliable marker of cholinergic neurons (Eckenstein and Sofroniew 1983).…”

Section: Neurochemisty Of Nicotinementioning

confidence: 99%

Translational Research in Nicotine Dependence

Turner

Gold

Schnoll

et al. 2013

Cold Spring Harbor Perspectives in Medicine

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Nicotine addiction accounts for 4.9 million deaths each year. Furthermore, although smoking represents a significant health burden in the United States, at present there are only three FDA-approved pharmacotherapies currently on the market: (1) nicotine replacement therapy, (2) bupropion, and (3) varenicline. Despite this obvious gap in the market, the complexity of nicotine addiction in addition to the increasing cost of drug development makes targeted drug development prohibitive. Furthermore, using combinations of mouse and human studies, additional treatments could be developed from off-the-shelf, currently approved medication lists. This article reviews translational studies targeting manipulations of the cholinergic system as a viable therapeutic target for nicotine addiction.

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High affinity choline transport and acetylCoA production in brain and their roles in the regulation of acetylcholine synthesis

Cited by 359 publications

References 133 publications

Short-Term Adolescent Nicotine Exposure has Immediate and Persistent Effects on Cholinergic Systems: Critical Periods, Patterns of Exposure, Dose Thresholds

Short-Term Adolescent Nicotine Exposure has Immediate and Persistent Effects on Cholinergic Systems: Critical Periods, Patterns of Exposure, Dose Thresholds

Lethal impairment of cholinergic neurotransmission in hemicholinium-3-sensitive choline transporter knockout mice

Translational Research in Nicotine Dependence

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