TY - JOUR
T1 - Influence of neurotrophic factors on morphine- and cocaine-induced biochemical changes in the mesolimbic dopamine system
AU - Berhow, M. T.
AU - Russell, D. S.
AU - Terwilliger, R. Z.
AU - Beitner-Johnson, D.
AU - Self, D. W.
AU - Lindsay, R. M.
AU - Nestler, E. J.
N1 - Funding Information:
Acknowledgements--This work was funded by USPHS grants DA07359, DA08227 and DA00203, and by the Abraham Ribicoff Research Facilities of the Connecticut Mental Health Center, State of Connecticut Department of Mental Health. The authors would also like to thank Drs S. Weigand, R. S. Duman and M. Chao for valuable discussions and V. A. Vaidya and D. H. Wolf for their assistance in manuscript preparation.
PY - 1995/10
Y1 - 1995/10
N2 - Previous research has shown an increase in tyrosine hydroxylase in the ventral tegmental area following chronic morphine and chronic cocaine treatments. Chronic morphine treatment also increases levels of glial fibrillary acidic protein in this brain region. In the present study, we investigated the effects of infusing neurotropic factors (nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, neurotrophin-4 or ciliary neurotrophic factor) via midline intra-ventral tegmental area cannulae on these biochemical changes. Our studies examined the effects of neurotrophic factor infusion alone, neurotrophic factor infusion followed by morphine treatment, morphine treatment followed by neurotrophic factor infusion, and concurrent neurotrophic factor infusion and cocaine treatment. Brain-derived neurotrophic factor, which by itself tended to decrease tyrosine hydroxylase levels in the ventral tegmental area, prevented the characteristic increase in tyrosine hydroxylase following morphine and cocaine exposure and reversed the increase in rats pretreated with morphine. Neurotrophin-4 and neurotrophin-3 exerted similar effects. In addition, neurotrophin-4 prevented the morphine-induced increase in glial fibrillary acidic protein. In contrast, ciliary neurotrophic factor infusions alone resulted in an increase in tyrosine hydroxylase levels, with no additional increase induced by morphine or cocaine coadministration. Nerve growth factor alone had no effect on tyrosine hydroxylase or glial fibrillary acidic protein levels and did not affect morphine's ability to induce these proteins. We also looked at the effects of intra-ventral tegmental area infusion of neurotrophic factor on cAMP-dependent protein kinase and adenylyl cyclase activity in the nucleus accumbens, both of which are increased by chronic morphine or cocaine exposure. In general, regulation of cAMP-dependent protein kinase and adenylyl cyclase by neurotrophic factors paralleled effects seen in the ventral tegmental area. Intra-ventral tegmental area infusion of brain-derived neurotrophic factor (or neurotrophin-4) alone tended to decrease cAMP-dependent protein kinase and adenylyl cyclase activity in the nucleus accumbens and prevented the morphine-induced increases in these enzymes. These effects were not seen with ciliary neurotrophic factor or nerve growth factor. These studies demonstrate novel interactions within the ventral tegmental area, and its target the nucleus accumbens, between neurotrophic factors and drugs of abuse, which have potentially important implications for the pathophysiology and treatment of drug addiction.
AB - Previous research has shown an increase in tyrosine hydroxylase in the ventral tegmental area following chronic morphine and chronic cocaine treatments. Chronic morphine treatment also increases levels of glial fibrillary acidic protein in this brain region. In the present study, we investigated the effects of infusing neurotropic factors (nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, neurotrophin-4 or ciliary neurotrophic factor) via midline intra-ventral tegmental area cannulae on these biochemical changes. Our studies examined the effects of neurotrophic factor infusion alone, neurotrophic factor infusion followed by morphine treatment, morphine treatment followed by neurotrophic factor infusion, and concurrent neurotrophic factor infusion and cocaine treatment. Brain-derived neurotrophic factor, which by itself tended to decrease tyrosine hydroxylase levels in the ventral tegmental area, prevented the characteristic increase in tyrosine hydroxylase following morphine and cocaine exposure and reversed the increase in rats pretreated with morphine. Neurotrophin-4 and neurotrophin-3 exerted similar effects. In addition, neurotrophin-4 prevented the morphine-induced increase in glial fibrillary acidic protein. In contrast, ciliary neurotrophic factor infusions alone resulted in an increase in tyrosine hydroxylase levels, with no additional increase induced by morphine or cocaine coadministration. Nerve growth factor alone had no effect on tyrosine hydroxylase or glial fibrillary acidic protein levels and did not affect morphine's ability to induce these proteins. We also looked at the effects of intra-ventral tegmental area infusion of neurotrophic factor on cAMP-dependent protein kinase and adenylyl cyclase activity in the nucleus accumbens, both of which are increased by chronic morphine or cocaine exposure. In general, regulation of cAMP-dependent protein kinase and adenylyl cyclase by neurotrophic factors paralleled effects seen in the ventral tegmental area. Intra-ventral tegmental area infusion of brain-derived neurotrophic factor (or neurotrophin-4) alone tended to decrease cAMP-dependent protein kinase and adenylyl cyclase activity in the nucleus accumbens and prevented the morphine-induced increases in these enzymes. These effects were not seen with ciliary neurotrophic factor or nerve growth factor. These studies demonstrate novel interactions within the ventral tegmental area, and its target the nucleus accumbens, between neurotrophic factors and drugs of abuse, which have potentially important implications for the pathophysiology and treatment of drug addiction.
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U2 - 10.1016/0306-4522(95)00207-Y
DO - 10.1016/0306-4522(95)00207-Y
M3 - Article
C2 - 8545003
AN - SCOPUS:0029086255
SN - 0306-4522
VL - 68
SP - 969
EP - 979
JO - Neuroscience
JF - Neuroscience
IS - 4
ER -