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Decreased activity of rat A10 dopamine neurons following withdrawal from repeated cocaine
European Journal of Pharmacolo~,% 218 (1992) 171 - 173 4": 1992 Elsevier Science Publishers B.V. All rights reserved 01114-2999/92/$05.00
EJP 21087
Short communication
Decreased activity of rat AIO dopamine neurons following withdrawa from repeated cocaine J a n i c c M. A c k e r m a n a n d F r a n c i s J. W h i t e Neuropsychopharmacoh~A3" Laboratory, Department of P~ychiatry, Wayne State Unil'ersity School of Medicine. l.afa.vette ('linic, 951 E. l.afa~'et Detroit, MI 48207, USA Received 6 April 1992, acccpted 19 May 1992
Electrophysiologieal techniqucs were uscd to detcrminc the basal activity of AI0 dopaminc (DA) neurons in the rat vcn tegmcntal area after a 10-14 da~, withdrawal from repcated cocaine treatment (10.0 mg/kg i.p. twice daily for 14 days). number of Sl~mtaneously activc AI0 DA cclls was significantly dccreascd (42%) in the cocaine-treated rats. This dccrc; activity may underlie the diminished basal levels of synaptic DA within the nucleus accumbcns previously rcporteq cocaine-withdrawn rats and may account for anhcdonia, anergia and cocaine craving reported by withdrawn cocaine addict' Cocainc; Dopaminc neurons; Withdrawal: Ventral tegmental area; Elcctrophysiology
1, Introduction The mcsoaccumbcns dopamincrgic system, consisting of A I 0 dopamine (DA) neuronal projections from the ventral tegmental area (VTA) to the nucicus accumbens, is involved in both the rewarding and locomotor-stimulating effects of cocaine (sec White, 1990; Kalivas and Stewart, 1991 for recent reviews). This pathway is also thought to play an essential role in the dcvelopment and expression of behavioral scnsitization to cocaine following prior long-term exposure to the drug. Therefore, it is not suprising that many functional aspects of this system are altered by repeated cocaine administration (Kalivas and Stcwart, 1991). Elcctrophysiological experiments have demonstrated that immediatlcy after the discontinuation of repeatcd cocaine trcatment, significant increases occur in the number of spontaneously active A10 DA cells in the VTA and in their basal firing rates, effects which are due to an initial decrease in the sensitivity of impulseregulating somatodendritic autoreceptors on these neurons (Henry et al., 1989; Ackerman and White, 1990). When rats are withdrawn from such treatment for 10 days, thc sensitivity of these autoreceptors returns to normal (Ackcrman and White, 1990). How-
Correspondence to: F.J. White, Neuropsychopharmacology Laboratory, Lafayette Clinic, 951 E. Lafayette, Detroit, MI 48207, USA.
Tel. 1.313.256 9011, fax 1.313.256 9025.
ever, it is not known whether the incrcased spo neous activity within this neuronal population per: during withdrawal. The prcscnt study addressed issue by determining the number of spontaneously tivc A I 0 DA cells and their basal firing rates follo~ a 10-14-day withdrawal from chronic cocainc admJ tration.
2. Materials and methods Male, S p r a g u e - D a w l c y rats (200-350 g, Hat were housed two per cage, in a colony under cons temperature (21-23°C) and humidity (40-50%) c 12-h l i g h t / d a r k schedule. Rats were injected i.p m l / k g ) with either 10 m g / k g cocaine HCI (n = 8 saline vehicle (n -- 10) twice daily (at 09:00 and 17:0 tor 14 days. Following treatment, a withdrawal pc of 10-14 days was allowed prior to testing. As previously detailed (Henry et al., 1989), stanc extracellularsingle-unit recording t e c h n i q u e s w e r e t to count the number of spontaneously active A I 0 cells per track in choral hydrate (400 m g / k g anesthetized rats. Briefly, single-barrel glass electro (in vitro impedance of 2.8 to 3.2 M.f2 at 135 Hz) v passed 12 times through the V T A in the dorsal-ver direction from 6.0 to 8.5 mm below the cortical surf The initial track in each rat was located 3.0 mm a rior (A) to lambda and 0.4 mm lateral (L) t o midline; the final track was located 3.4 mm A and
172
TABLE 1 Spontaneous activity of A10 DA neurons in the rat VTA following 10-14 days withdrawal from 14 days of repeated treatment with either ccv,:aine (10 m g / k g i.p. twice daily) or saline. The number of AI0 DA cells per descending electrode track (12 tracks) and the mean firing rate of all spontaneously active DA cells in the VTA of each rat were used to calculate mean (_+S.E.)values for the cocaine and saline (control) groups. N = number of rats in each group,
Saline ('ocaine
N
Cells/track
Firing rate
10 8
1.39_+ 0.1(1 0.81 + 0.07 ~'
4.51 ± 0.22 4.57 _+0.41
" P < 0.001, Student's t-test (two-tailed, independent samples),
mm L. Each track was separated by 0.2 mm. Each spontaneously active DA neuron was recorded for 3 - 6 min to determine its basal firing rate.
3. Results As shown in table 1, the number of spontaneously active A I 0 DA neurons was significantly decreased (42%) in cocaine-treated rats as compared to control rats following a 10-14-day withdrawal period. The firing rates of the DA cells did not differ between the two groups,
4. Discussion This study has demonstrated a significant decrease in the number of spontaneously active A10 DA cells in the rat VTA after a 10-14-day withdrawal from repeated cocaine administration. The reduced activity of VTA DA cells suggests decreased transmission in the mesoaceumbens pathway and a resultant reduction in both somatodendritic and nerve terminal DA release, Previous studies have provided considerable support for this suggestion. For example, following a 2-3-week withdrawal from repeated cocaine treatment, both K +and amphetamine-stimulated DA release from rat VTA slices are decreased (Kalivas and Duffy, 1988). Similarly, in vivo microdialysis studies have found significant reductions in basal levels of extracellular DA in the nucleus accumbens following either a 7-day (38%, Robertson ct al., 1991) or a 10-day (54%, Parsons et al., 1991) withdrawal from repeated cocaine treatment. Finally, there is a decrease in the binding of [3H]mazindol, a ligand which labels the DA transporter, within the nucleus accumbens of rats withdrawn from repeated cocaine for 10 days, an effect which may result from diminshed synaptic levels of DA (Sharpe et al., 1991). The present findings suggest that the diminished basal levels of synaptic DA within the
nucleus accumbens of cocaine withdrawn rats may SUit from a reduced number of active A10 DA cell: the VTA. The mechanism by which withdrawal from r e p e a cocaine treatment causes a reduction in the numbc~ spontaneously active VTA DA cells is unknown. " fact that the basal firing rates of the remaining a c A10 DA neurons were similar to those observed control rats is consistent with our earlier report t autorcceptor sensitivity, which plays a role in cont ling discharge rate, is normal at this time period withdrawal (Ackerman and White, 1990), and indic~ that autoreceptor supersensitivity cannot account the observed decrease in active DA neurons. It thc fore seems likely that alterations in specific cond tanccs a n d / o r in afferent inputs to VTA DA cells h occurred. Such changes might involve either a decrc or increase (e.g. depolarization inactivation) in exc tory transmission or an increase in inhibitory t~_ Future studies will address the mechanism respons: for the decrease in active DA cells. Whatever the mechanism(s) underlying the inact tion of a subpopulation of VTA DA ceils during caine withdrawal, this and related findings indic that shortly after the cessation of cocaine treatm (1-3 days), DA cells arc hyperactive (Henry et 1989) but hyporesponsive to cocaine administrati i.e. there is a reduced ability of cocaine to enha synaptic DA levels (Kalivas and Stewart, 1991), whet following longer periods of withdrawal (7-14), they hypoactive (present findings, Parsons et al., 1t Robertson et al., 1991), but hyperrcsponsive to eoc~ administration (Akimoto et al., 1989; Kalivas and St art, 1991). While the increased responsiveness of neurons to cocaine during withdrawal appears to involved in behavioral sensitization to cocaine, it r be that the decreased basal activity of the mesoacc~ bens DA system is involved in the phenomena anhedonia, anergia and cocaine craving which characteristic of the middle and late phases of coc~ withdrawal in humans (Gawin, 1991).
Acknowledgements We thank Vernice Davis for technical assistance. "[his study supported by UIISPHS Grants DA-04093 and MH-40832 to F.
References Ackerman, J.M. and F.J. White, 1990, AI0 somatodendritic dopm autoreceptor sensitivity following withdrawal from repeatec caine treatment, Neurosci. Lett. 117, 181. Akimoto, K., T. Hamamura and S. Otsuki, 1989, Subchronic toe treatment enhances cocaine-induced dopamine efflux, studie
in vivo intracerebra[ dialysis, Brain Res. 490, 339.
Gawin, F.II., 1991, Cocaine addiction: psychology and neurophysiology, Science 251, 1580. tlenry, D.J., M.A. Green and F.J. White, 1989, Electrophysiological effects of cocaine in the mesoaccumbens dopamine system: Repeated administration, J. Pharmacol. Exp. Ther. 251,839. Kalivas, P.W. and P. Duff'y, 1988, Effects of daily cocaine and morphine treatment on somatodendritic and terminal field dopamine release, J..Neurochem. 50, 1498. Kalivas, P.W. and J. Stewart, 1991, Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity, Brain Res. Rev. 16, 223. Parsons, L.H., A.D. Smith and J.B. Justice, Jr., 1991, Basal cxtraccl-
lular dopamine is decreased in the rat nucleus accumbcns d~ abstinence from chronic cocaine, Synapse 9, 60. Robertson, M.W., C.A. Leslie and J.P. Bennett, Jr., 1991, App~ synaptic dopamine deficiency induced by withdrawal from ch cocaine treatment, Brain Rcs. 538, 337. Sharpe, L.G., N.S. Pilotte, W.M. Mitchell and E.B. Dc Sot,za, Withdrawal of repeated cocaine decreases autoradiogr~ [3H]mazindol-labelling of dopamine transporter in rat nu accumbens, Eur. J. Pharmacol. 203, 141. White, F.J., 1990, Electrophysiological basis of the reinforcing ct of cocaine, Bchav. Pharmacol. 1,303.
EJP 21087
Short communication
Decreased activity of rat AIO dopamine neurons following withdrawa from repeated cocaine J a n i c c M. A c k e r m a n a n d F r a n c i s J. W h i t e Neuropsychopharmacoh~A3" Laboratory, Department of P~ychiatry, Wayne State Unil'ersity School of Medicine. l.afa.vette ('linic, 951 E. l.afa~'et Detroit, MI 48207, USA Received 6 April 1992, acccpted 19 May 1992
Electrophysiologieal techniqucs were uscd to detcrminc the basal activity of AI0 dopaminc (DA) neurons in the rat vcn tegmcntal area after a 10-14 da~, withdrawal from repcated cocaine treatment (10.0 mg/kg i.p. twice daily for 14 days). number of Sl~mtaneously activc AI0 DA cclls was significantly dccreascd (42%) in the cocaine-treated rats. This dccrc; activity may underlie the diminished basal levels of synaptic DA within the nucleus accumbcns previously rcporteq cocaine-withdrawn rats and may account for anhcdonia, anergia and cocaine craving reported by withdrawn cocaine addict' Cocainc; Dopaminc neurons; Withdrawal: Ventral tegmental area; Elcctrophysiology
1, Introduction The mcsoaccumbcns dopamincrgic system, consisting of A I 0 dopamine (DA) neuronal projections from the ventral tegmental area (VTA) to the nucicus accumbens, is involved in both the rewarding and locomotor-stimulating effects of cocaine (sec White, 1990; Kalivas and Stewart, 1991 for recent reviews). This pathway is also thought to play an essential role in the dcvelopment and expression of behavioral scnsitization to cocaine following prior long-term exposure to the drug. Therefore, it is not suprising that many functional aspects of this system are altered by repeated cocaine administration (Kalivas and Stcwart, 1991). Elcctrophysiological experiments have demonstrated that immediatlcy after the discontinuation of repeatcd cocaine trcatment, significant increases occur in the number of spontaneously active A10 DA cells in the VTA and in their basal firing rates, effects which are due to an initial decrease in the sensitivity of impulseregulating somatodendritic autoreceptors on these neurons (Henry et al., 1989; Ackerman and White, 1990). When rats are withdrawn from such treatment for 10 days, thc sensitivity of these autoreceptors returns to normal (Ackcrman and White, 1990). How-
Correspondence to: F.J. White, Neuropsychopharmacology Laboratory, Lafayette Clinic, 951 E. Lafayette, Detroit, MI 48207, USA.
Tel. 1.313.256 9011, fax 1.313.256 9025.
ever, it is not known whether the incrcased spo neous activity within this neuronal population per: during withdrawal. The prcscnt study addressed issue by determining the number of spontaneously tivc A I 0 DA cells and their basal firing rates follo~ a 10-14-day withdrawal from chronic cocainc admJ tration.
2. Materials and methods Male, S p r a g u e - D a w l c y rats (200-350 g, Hat were housed two per cage, in a colony under cons temperature (21-23°C) and humidity (40-50%) c 12-h l i g h t / d a r k schedule. Rats were injected i.p m l / k g ) with either 10 m g / k g cocaine HCI (n = 8 saline vehicle (n -- 10) twice daily (at 09:00 and 17:0 tor 14 days. Following treatment, a withdrawal pc of 10-14 days was allowed prior to testing. As previously detailed (Henry et al., 1989), stanc extracellularsingle-unit recording t e c h n i q u e s w e r e t to count the number of spontaneously active A I 0 cells per track in choral hydrate (400 m g / k g anesthetized rats. Briefly, single-barrel glass electro (in vitro impedance of 2.8 to 3.2 M.f2 at 135 Hz) v passed 12 times through the V T A in the dorsal-ver direction from 6.0 to 8.5 mm below the cortical surf The initial track in each rat was located 3.0 mm a rior (A) to lambda and 0.4 mm lateral (L) t o midline; the final track was located 3.4 mm A and
172
TABLE 1 Spontaneous activity of A10 DA neurons in the rat VTA following 10-14 days withdrawal from 14 days of repeated treatment with either ccv,:aine (10 m g / k g i.p. twice daily) or saline. The number of AI0 DA cells per descending electrode track (12 tracks) and the mean firing rate of all spontaneously active DA cells in the VTA of each rat were used to calculate mean (_+S.E.)values for the cocaine and saline (control) groups. N = number of rats in each group,
Saline ('ocaine
N
Cells/track
Firing rate
10 8
1.39_+ 0.1(1 0.81 + 0.07 ~'
4.51 ± 0.22 4.57 _+0.41
" P < 0.001, Student's t-test (two-tailed, independent samples),
mm L. Each track was separated by 0.2 mm. Each spontaneously active DA neuron was recorded for 3 - 6 min to determine its basal firing rate.
3. Results As shown in table 1, the number of spontaneously active A I 0 DA neurons was significantly decreased (42%) in cocaine-treated rats as compared to control rats following a 10-14-day withdrawal period. The firing rates of the DA cells did not differ between the two groups,
4. Discussion This study has demonstrated a significant decrease in the number of spontaneously active A10 DA cells in the rat VTA after a 10-14-day withdrawal from repeated cocaine administration. The reduced activity of VTA DA cells suggests decreased transmission in the mesoaceumbens pathway and a resultant reduction in both somatodendritic and nerve terminal DA release, Previous studies have provided considerable support for this suggestion. For example, following a 2-3-week withdrawal from repeated cocaine treatment, both K +and amphetamine-stimulated DA release from rat VTA slices are decreased (Kalivas and Duffy, 1988). Similarly, in vivo microdialysis studies have found significant reductions in basal levels of extracellular DA in the nucleus accumbens following either a 7-day (38%, Robertson ct al., 1991) or a 10-day (54%, Parsons et al., 1991) withdrawal from repeated cocaine treatment. Finally, there is a decrease in the binding of [3H]mazindol, a ligand which labels the DA transporter, within the nucleus accumbens of rats withdrawn from repeated cocaine for 10 days, an effect which may result from diminshed synaptic levels of DA (Sharpe et al., 1991). The present findings suggest that the diminished basal levels of synaptic DA within the
nucleus accumbens of cocaine withdrawn rats may SUit from a reduced number of active A10 DA cell: the VTA. The mechanism by which withdrawal from r e p e a cocaine treatment causes a reduction in the numbc~ spontaneously active VTA DA cells is unknown. " fact that the basal firing rates of the remaining a c A10 DA neurons were similar to those observed control rats is consistent with our earlier report t autorcceptor sensitivity, which plays a role in cont ling discharge rate, is normal at this time period withdrawal (Ackerman and White, 1990), and indic~ that autoreceptor supersensitivity cannot account the observed decrease in active DA neurons. It thc fore seems likely that alterations in specific cond tanccs a n d / o r in afferent inputs to VTA DA cells h occurred. Such changes might involve either a decrc or increase (e.g. depolarization inactivation) in exc tory transmission or an increase in inhibitory t~_ Future studies will address the mechanism respons: for the decrease in active DA cells. Whatever the mechanism(s) underlying the inact tion of a subpopulation of VTA DA ceils during caine withdrawal, this and related findings indic that shortly after the cessation of cocaine treatm (1-3 days), DA cells arc hyperactive (Henry et 1989) but hyporesponsive to cocaine administrati i.e. there is a reduced ability of cocaine to enha synaptic DA levels (Kalivas and Stewart, 1991), whet following longer periods of withdrawal (7-14), they hypoactive (present findings, Parsons et al., 1t Robertson et al., 1991), but hyperrcsponsive to eoc~ administration (Akimoto et al., 1989; Kalivas and St art, 1991). While the increased responsiveness of neurons to cocaine during withdrawal appears to involved in behavioral sensitization to cocaine, it r be that the decreased basal activity of the mesoacc~ bens DA system is involved in the phenomena anhedonia, anergia and cocaine craving which characteristic of the middle and late phases of coc~ withdrawal in humans (Gawin, 1991).
Acknowledgements We thank Vernice Davis for technical assistance. "[his study supported by UIISPHS Grants DA-04093 and MH-40832 to F.
References Ackerman, J.M. and F.J. White, 1990, AI0 somatodendritic dopm autoreceptor sensitivity following withdrawal from repeatec caine treatment, Neurosci. Lett. 117, 181. Akimoto, K., T. Hamamura and S. Otsuki, 1989, Subchronic toe treatment enhances cocaine-induced dopamine efflux, studie
in vivo intracerebra[ dialysis, Brain Res. 490, 339.
Gawin, F.II., 1991, Cocaine addiction: psychology and neurophysiology, Science 251, 1580. tlenry, D.J., M.A. Green and F.J. White, 1989, Electrophysiological effects of cocaine in the mesoaccumbens dopamine system: Repeated administration, J. Pharmacol. Exp. Ther. 251,839. Kalivas, P.W. and P. Duff'y, 1988, Effects of daily cocaine and morphine treatment on somatodendritic and terminal field dopamine release, J..Neurochem. 50, 1498. Kalivas, P.W. and J. Stewart, 1991, Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity, Brain Res. Rev. 16, 223. Parsons, L.H., A.D. Smith and J.B. Justice, Jr., 1991, Basal cxtraccl-
lular dopamine is decreased in the rat nucleus accumbcns d~ abstinence from chronic cocaine, Synapse 9, 60. Robertson, M.W., C.A. Leslie and J.P. Bennett, Jr., 1991, App~ synaptic dopamine deficiency induced by withdrawal from ch cocaine treatment, Brain Rcs. 538, 337. Sharpe, L.G., N.S. Pilotte, W.M. Mitchell and E.B. Dc Sot,za, Withdrawal of repeated cocaine decreases autoradiogr~ [3H]mazindol-labelling of dopamine transporter in rat nu accumbens, Eur. J. Pharmacol. 203, 141. White, F.J., 1990, Electrophysiological basis of the reinforcing ct of cocaine, Bchav. Pharmacol. 1,303.