Amphetamine Blocks Long-Term Synaptic Depression in the Ventral Tegmental Area

Journal of Neuroscience - Tập 20 Số 15 - Trang 5575-5580 - 2000
Susan Jones1, Johanna L. Gutlerner1, Julie A. Kauer1
1Department of Neurobiology, Duke University School of Medicine, Durham, North Carolina 27710

Tóm tắt

The mesolimbic dopamine system is essential for reward-seeking behavior, and drugs of abuse are thought to usurp the normal functioning of this pathway. A growing body of evidence suggests that glutamatergic synapses on dopamine neurons in the ventral tegmental area (VTA) are modified during exposure to addictive drugs, producing sensitization, a progressive augmentation in the rewarding properties of psychostimulant drugs with repeated exposure. We have tested the hypothesis that psychostimulant exposure interferes with the synaptic plasticity of glutamatergic inputs to the VTA. We find that excitatory synapses onto VTA dopamine neurons exhibit long-term depression (LTD) in response to low-frequency stimulation and modest depolarization. LTD in the VTA is NMDA receptor-independent but is dependent on intracellular Ca2+and can be induced by driving Ca2+into the dopamine neuron. Brief exposure to amphetamine entirely blocks LTD at glutamatergic synapses in the VTA, by releasing endogenous dopamine that acts at D2 dopamine receptors. The block of LTD is selective, because amphetamine has no effect on hippocampal LTD. The LTD we have discovered in the VTA is likely to be an important component of excitatory control of the reward pathway; amphetamine will inhibit LTD, removing this normal brake on the glutamatergic drive to dopamine neurons. This effect of amphetamine represents an important mechanism by which normal function of the brain reward system may be impaired during substance abuse.

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Tài liệu tham khảo

10.1146/annurev.ne.19.030196.002253

10.1523/JNEUROSCI.19-10-03723.1999

Bunney BS Aghajanian GK (1975) Evidence for drug actions on both pre- and postsynaptic catecholamine receptors in the CNS. in Pre- and postsynaptic receptors, eds Usdin E Bunney WE (Dekker, New York), pp 89–122.

Carbone, 1989, Modulation of Ca channels in peripheral neurons., Ann NY Acad Sci, 1560, 346, 10.1111/j.1749-6632.1989.tb24114.x

Cardozo, 1995, Voltage-dependent calcium channels in rat midbrain dopamine neurons: modulation by dopamine and GABAB receptors., J Neurophysiol, 74, 1137, 10.1152/jn.1995.74.3.1137

10.1002/(SICI)1098-2396(19990315)31:4<256::AID-SYN3>3.0.CO;2-E

10.1038/289537a0

10.1016/S0896-6273(00)80102-6

10.1073/pnas.89.10.4363

10.1038/27919

10.1523/JNEUROSCI.16-01-00274.1996

10.1038/260258a0

10.1111/j.1749-6632.1988.tb42096.x

10.1016/0306-4522(83)90135-5

10.1523/JNEUROSCI.04-11-02866.1984

10.1523/JNEUROSCI.09-10-03463.1989

10.1113/jphysiol.1992.sp019136

10.1523/JNEUROSCI.19-22-09780.1999

Kalivas, 1993, Involvement of NMDA receptor stimulation in the ventral tegmental area and amygdala in behavioral sensitization to cocaine., J Pharmacol Exp Ther, 267, 486

Kalivas, 1998, Repeated cocaine administration alters extracellular glutamate in the ventral tegmental area., J Neurochem, 70, 1497, 10.1046/j.1471-4159.1998.70041497.x

10.1016/0165-0173(91)90007-U

Kalivas, 1988, Amphetamine injection into the ventral mesencephalon sensitizes rats to peripheral amphetamine and cocaine., J Pharmacol Exp Ther, 245, 1095

10.1177/026988119801200107

10.1016/0168-0102(93)90056-V

10.1016/0024-3205(89)90045-3

10.1016/0165-6147(92)90060-J

10.1016/S0306-4522(97)00654-4

10.1523/JNEUROSCI.19-05-01698.1999

10.1007/s002130050844

10.1146/annurev.ne.18.030195.001535

10.1016/0896-6273(92)90248-C

10.1523/JNEUROSCI.16-23-07478.1996

10.1523/JNEUROSCI.18-04-01270.1998

10.1523/JNEUROSCI.19-04-01437.1999

Overton, 1999, Long-term potentiation at excitatory amino acid synapses on midbrain dopamine neurons., NeuroReport, 10, 221, 10.1097/00001756-199902050-00004

10.1016/0006-8993(95)01460-8

10.1016/0165-0173(93)90013-P

10.1016/0006-8993(94)90858-3

Schultz, 1998, Predictive reward signal of dopamine neurons., J Neurophysiol, 80, 1, 10.1152/jn.1998.80.1.1

10.1111/j.1476-5381.1994.tb13138.x

10.3109/07853899809029938

10.1016/0006-8993(91)90731-A

Stack, 1991, Dopamine actions on calcium currents, potassium currents and hormone release in rat melanotrophs., J Physiol (Lond), 439, 37, 10.1113/jphysiol.1991.sp018655

10.1007/BF02246961

10.1073/pnas.95.25.15026

10.1523/JNEUROSCI.20-15-05581.2000

10.1016/0006-8993(94)01439-O

Vezina, 1993, Amphetamine administered to the ventral tegmental area but not to the nucleus accumbens sensitizes rats to systemic morphine: lack of conditioned effects., Brain Res, 516, 99, 10.1016/0006-8993(90)90902-N

White, 1996, Synaptic regulation of mesocorticolimbic dopamine neurons., Annu Rev Neurosci, 16, 405, 10.1146/annurev.ne.19.030196.002201

10.1016/S0376-8716(98)00072-6

White, 1995, Repeated administration of cocaine or amphetamine alters neuronal responses to glutamate in the mesoaccumbens dopamine system., J Pharmacol Exp Ther, 273, 445

10.1146/annurev.ne.19.030196.001535

10.1037/0033-295X.94.4.469

10.1146/annurev.ps.40.020189.001203

10.1016/S0301-0082(97)00051-8

10.1046/j.1471-4159.1999.0731529.x

10.1016/0306-4522(95)00248-H

10.1046/j.1471-4159.1999.0720479.x

Xue, 1996, Acute and repeated systemic amphetamine administration: effects on extracellular glutamate, aspartate, and serine levels in rat ventral tegmental area and nucleus accumbens., J Neurochem, 67, 352, 10.1046/j.1471-4159.1996.67010352.x

Yan, 1997, D2 dopamine receptors reduce N-type Ca2+ currents in rat neostriatal cholinergic interneurons through a membrane-delimited, protein-kinase-C-insensitive pathway., J Neurophysiol, 77, 1003, 10.1152/jn.1997.77.2.1003

Zhang, 1997, Increased responsiveness of ventral tegmental area dopamine neurons to glutamate after repeated administration of cocaine or amphetamine is transient and selectively involves AMPA receptors., J Pharmacol Exp Ther, 281, 699

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Journal of Neuroscience

Tập 20 Số 15

5575-5580

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