Abraham Zangen: photo

Abraham Zangen

Depression and Addiction in the Brain Reward System

Tel: (972-8) 934-4415
Fax: (972-8) 934-4131
e-mail: a.zangen@weizmann.ac.il

Current and Future Research

Mood-altering drugs have become an unavoidable part of the modern landscape. Whether they come in the form of medically-supervised anti-depressants, or as illegal substances obtained on the street, these drugs affect emotions by altering neurochemical and electrophysiological activities of the brain. Impaired function of the brain reward system is implicated in both depression and addiction, and these two states have documented comorbidity. The neurochemical changes induced in the brain as a result of these two conditions can be viewed as an expression of brain plasticity. Our lab studies focus on these two alterations in the reward system: depression and addiction. Our main goal is the study of the mechanisms by which the brain reward system affects mood and motivation by using animal models for depression and addiction. In addition we seek to develop new methods to examine neuronal processes at the root of depressive behavior and drug addiction, thereby finding new treatments for these devastating disorders.

  • Addiction represents the pathological usurpation of neural processes that normally serve reward-related learning, resulting in a strong habitual memory. Therefore we use Intracranial Electrical Stimulation in rats and Transcranial Magnetic Stimulation in humans to try and disrupt the addictive memory trace, before it becomes a permanent feature of the neuronal terrain. We have found that electrical stimulation of major reward pathways in the lateral hypothalamus or prefrontal cortex (PFC) and basolateral amygdala reduces drug-seeking behavior in animal models. Additionally, TMS to the dorsolateral PFC appeared to have a similar effect in humans; it reduced cigarette consumption and cue-induced craving. Hence, stimulating reward-related brain regions might be a novel strategy for normalizing neuronal adaptations induced by repeated drug use and thereby treating addiction.

  • In the world of drug abuse, the recovering addict is in a constant state of conflict, wherein he or she must choose between the rewarding effects of the drug, and the negative consequences of renewed drug use (relapse). Despite dedicated and innovative work using animal models, many studies of relapse seem to fall short of paralleling relapse in humans. Thus, we created a conflict model of cue-induced relapse in rats that approximates the human condition. We imitate the negative consequences using an electric barrier that administers a slight shock when crossed to access the drug, after presentation of a drug-associated cue. Our model seems to be particularly useful in examining individual differences in relapse, as a variety of individual differences in lever-responding were observed.

  • In-vivo electrophysiological recording allows us to further examine plasticity-related alterations in the function of the brain reward system that are critically involved in depressive behavior and drug addiction. We examine modifications in the ventral subiculum-nucleus accumbens (vSub-NAc) pathway, which is implicated in processing of contextual information and motivational function by recording evoked potentials in the NAc in response to stimulation of vSub of the hippocampus in anesthetized animals. The patterned input obtained suggests that the same information coming from the hippocampus can be subjected to different processing within the NAc. In response to paired-pulse stimulation and high frequency stimulation protocols, the vSub-NAc pathway demonstrates short-term plasticity. However, this pathway in naive rats is not amenable to long-term potentiation (LTP). Surprisingly, LTP can be induced following recovery from an acute cocaine injection but not following a saline injection. This suggests that a single cocaine exposure induces long-term metaplasticity in this pathway.

  • Alterations in the brain reward pathway persist in depression, evidenced by altered levels of brain derived neurotrophic factor (BDNF). Despite the established association between reduced BDNF levels and neurogenesis in the hippocampus and depression, it is not known whether reduced BDNF levels can directly precipitate depressive behavior, or are merely a side effect of depression. Moreover, the specific brain sites in which BDNF is critical to depressive behavior are unknown, and direct evidence of neurogenesis impairment due to local reduction in BDNF levels does not exist in-vivo. We were recently able to demonstrate that a reduction in BDNF expression in specific hippocampal subregions is not only associated with, but actually causes depressive behavior and reduced neurogenesis, by inducing BDNF knockdown in specific hippocampal subregions of rat brains. Moreover we anticipate that these findings and the anatomical regions of interest we have defined will direct future research towards understanding the pathophysiology of depression, and provide a target for more novel antidepressant intervention.

  • There are many factors that can cause, intensify, or ameliorate depressive symptoms, and this illness is thought to result from a combination of genetic and environmental factors. In order to study the genetic factors of depressive behavior under controlled conditions we are establishing a novel animal model for depression based on selective breeding for depressive phenotypes. Three different rat lines have been established in our lab by selective breading for depressive (DRL), normal (NRL) or motivated (MRL) behaviors, as measured by a battery of computerized behavioral tests. We are now testing the 10th generation and have found most aspects of motivation and hedonia to be hereditary in our model. We have found that electroconvulsive therapy, but not a standard antidepressant drug (desipramine) normalizes depressive behavior as well as BDNF levels in DRL rats. We believe that this new model for drug resistant depression will be useful in future studies of the genetic basis of depressive behavior.

  • A key factor in the environmental component of depression is chronic stress. Exposure to chronic mild stress (CMS) is known to induce anhedonia in adult animals, and is associated with the development of depression in humans. We have recently characterized the behavioral effects of CMS in young and adult animals and measured markers for alterations in neuronal plasticity induced by chronic stress. We found that CMS induced anhedonia in adult but not in young animals, and decreased BDNF levels and neurogenesis in the hippocampus of adult rats, but increased BDNF levels and neurogenesis in young rats. Therefore, chronic stress exerts substantially different neurochemical effects in young and adult animals, and this may explain our novel findings on the behavioral resilience of young animals to chronic stress.

  • To enhance neuroplasticity in the CMS model, we use brain stimulation to test for behavioral and neurochemical outcomes. We test whether sub-convulsive stimulation using intracranial electrical stimulation (ICS) of reward-related brain sites, such as the prelimbic cortex (PLC) or NAC, can induce antidepressant effects in a widely-used rat model for depressive behavior (CMS). Repeated ICS of either the NAC or the ventral, but not the dorsal, PLC reverses the main behavioral deficit and the reduction of hippocampal BDNF levels, induced by CMS. Our study implicates the ventral PLC and the NAC in the pathophysiology of depressive behavior and suggests that ICS of these regions can induce an antidepressant effect similar to ECT, without the cognitive impairment caused by the convulsive treatment.

  • Currently, one of our innovative projects involves the development and use of Deep Transcranial Magnetic Stimulation in humans to treat a host of behavioral disorders, including depression and addiction. We developed a novel coil design for stimulation of reward-related regions in the human brain and proved the ability of our approach to safely stimulate deep brain regions. Deep TMS produces directed electromagnetic fields that can induce excitation or inhibition of neurons deep inside the brain. The treatment is non-invasive, with no significant side effects, no systemic effect (in contrast to drugs), and no need of hospitalization or anesthesia. Consistent with our animal studies using brain stimulation in the CMS model, we found Deep TMS of the PFC to exert potent antidepressant effects on patients not previously responsive to antidepressant drugs in two different studies. Our work will further enrich our knowledge of brain reward pathways and will be of paramount importance in designing novel treatments for depression and addiction.

    List of Publications
    1. Zangen A., Overstreet D.H. and Yadid G. (1997) High serotonin and 5-hydroxyindoleacetic acid levels in limbic brain regions in a rat model of depression: Normalization by chronic antidepressant treatment. J. Neurochem.69:2477-2483.
    2. Zangen A., Herzberg U., Vogel Z. and Yadid G. (1998) Nociceptive stimulus induces release of endogenous beta-endorphin in the brain. Neuroscience 85:659-662.
    3. Serova L., Sabban E., Zangen A., Overstreet D.H. and Yadid G. (1998) Altered gene expression for catecholamine biosynthetic enzymes and stress response in rat genetic model of depression. Mol. Brain Res. 63:133-138.
    4. Zangen A. and Shainberg A. (1997) Thiamine deficiency in cardiac cells in culture. Biochem. Pharmacol. 54:575-582.
    5. Zangen A., Botzer D., Zangen R. and Shainberg A. (1998) Furosemide and digoxin inhibit thiamine uptake in cardiac cells. Eur. J. Pharmacol. 361:151-155.
    6. Zangen A., Overstreet D.H. and Yadid G. (1999) Increased catecholamine levles in specific brain regions of a rat model of depression: Normalization by chronic antidepressant treatment. Brain Res. 824:243-250.
    7. Zangen A., Nakash R. and Yadid G. (1999) Serotonin-mediated increases in extracellular beta-endorphin levels in the brain: A microdialysis study. J. Neurochem. 73:2569-2574.
    8. Yadid G., Nakash R., Deri I., Grin T., Kinor N., Gispan I. and Zangen A. (2000) Elucidation of the neurobiology of depression: Insights from a novel genetic animal model. Prog. Neurobiol. 62:353-378.
    9. Yadid G., Zangen A., Dmitrochenko A., Overstreet D.H. and Zohar J. (2000) Screening for new antidepressants with fast onset and long lasting action. Drug Dev. Res. 50:392-399.
    10. Yadid G., Zangen A., Herzberg U., Nakash R. and Sagen J. (2000) Alterations in endogenous brain beta-endorphin release by adrenal medullary transplants in the spinal cord. Neuropsychopharmacol. 23:709-716.
    11. Yadid G., Overstreet D.H. and Zangen A. (2001) Limbic dopaminergic adaptation to a stressful stimulus in a rat model of depression. Brain Res. 896:43-47.
    12. Zangen A., Nakash R., Overstreet D.H. and Yadid G. (2001) Association between depressive behavior and absence of serotonin-dopamine interaction in the nucleus accumbens. Psychopharmacology 155:434-439.
    13. Shir Y., Zeltser R., Vatine J., Carmi G., Belfer I., Zangen A., Overstreet D.H. and Seltzer Z. (2001) Correlation of intact sensibility and neuropathic pain-related behaviors in rats. Pain 90:75-82.
    14. Woods A. and Zangen A. (2001) Direct chemical interaction between dynorphin and excitatory amino acids. Neurochem. Res. 26:395-400.
    15. Zangen A., Ikemoto S., Zadina J.E. and Wise R.A. (2002) Rewarding and psychomotor stimulant effects of endomorphin-1: Anteroposterior differences within the ventral tegmental area and lack of effect in nucleus accumbens. J. Neurosci. 22:7225-7233.
    16. Zangen A., Roth Y. and Hallett M. (2002) A Coil Design for Transcranial Magnetic Stimulation of Deep Brain Regions. J. Clin Neurophysiol, 19:361-370.
    17. Greenwell T., Zangen A., Martin-Schild S., Gerall A.A., Wise R.A. and Zadina J.E., (2002) Endomorphin-1 and -2 immunoreactive cells in the hypothalamus are labeled by fluorogold injections to the ventral tegmental area. J. Comp. Neurol.454:320-328.
    18. Zangen A., Nakash R., Overstreet D.H. and Yadid G. (2002) Impaired response of beta-endorphin to serotonin stimulation in a rat model of depression. Neuroscience 110:389-393.
    19. Zangen A. and Hyodo K. (2002) Transcranial magnetic stimulation induces increasesin extracellular levels of dopamine and glutamate in the nucleus accumbens. Neuroreport, 13:2401-2405.
    20. Roth-Deri I., Zangen A., Aleli M., Goelman R.G., Peled G., Nakash R., Gispan-Herman I., Shaham Y. and Yadid G. (2003) Involvement of beta-endorphin in cocaine reinforcement. J. Neurochem. 84: 930-938.
    21. Zangen A. and Shalev U. (2003) Nucleus accumbens beta-endorphin levels are not elevated by brain stimulation reward but do increase with extinction. Eur J Neurosci. 17:1067-1072.
    22. Roth-Deri I., Zangen A., Aleli M., Goelman R.G., Peled G., Nakash R., Gispan-Herman I., Shaham Y. and Yadid G. (2003) Involvement of beta-endorphin in cocaine reinforcement. J. Neurochem. 84: 930-938.
    23. Ikemoto S., Witkin B.M., Zangen A and Wise R.A. (2004) Rewarding effects of AMPA administration into the supramammillary or posterior hypothalamic nuclei but not the ventral tegmental area. J Neurosci. 24:5758-5765.
    24. Solinas M., Zangen A., Thiriet N and Goldberg S.R. (2004) beta-Endorphin elevations in the ventral tegmental area regulate the discriminative effects of Delta-9-tetrahydrocannabinol. Eur J. Neurosci. 19:3183-3192.
    25. Zangen A., Y. Roth and Hallett M (2005) Transcranial Magnetic Stimulation of Deep Brain Regions: Evidence for Efficacy of the H-Coil. Clin. Neurophysiol. 116:775-9.
    26. Gersner R, Dar DE, Shabat-Simon M. and Zangen A. (2005) Behavioral analysis during the forced swim test using a joystick device. J. Neurosci. Meth 143:117-21.
    27. Butovsky E, Juknat A, Goncharov I, Elbaz J, Eilam R, Zangen A and Vogel Z (2005) In vivo up-regulation of brain-derived neurotrophic factor in specific brain areas by chronic exposure to Delta-tetrahydrocannabinol. J Neurochem. 93:802-11.
    28. Butovsky E, Juknat A, Elbaz J, Shabat-Simon M, Eilam R, Zangen A, Altstein M and Vogel Z. (2006) Chronic exposure to Delta(9)-tetrahydrocannabinol downregulates oxytocin and oxytocin-associated neurophysin in specific brain areas. Mol Cell Neurosci. 31:795-804.
    29. 29. Dar DE and Zangen A. (2006) Recent advances in selective mu-opioid ligands as evaluated in animal models. CMS-CNS 6, 1-14.
    30. Zangen A., Solinas M., Ikemoto S, Goldberg SR. and Wise R.A. (2006) Two brain sites for cannabinoid reward. J. Neurosci. 26:4901-4907.
    31. Roth Y., Amir A., Levkovitz Y. and Zangen A. (2007) Three-Dimensional Distribution of the Electric Field Induced in the Brain by Transcranial Magnetic Stimulation Using Figure-8 and Deep H-Coils. J Clin Neurophysiol. 24:31-38.
    32. Cooper A, Barnea-Ygael N, Levy D, Shaham Y and Zangen A. (2007) A conflict rat model of cue-induced relapse to cocaine seeking. Psychopharmacology. (2007) Jun 9 194:117-25.
    33. Levkovit Y, Roth Y, Eran E, Yoram Y, Sheer A and Zangen A. (2007) Deep Transcranial Magnetic Stimulation - a randomized controlled safety and cognitive study. Clin. Neurophysiol, 118; 2730-2744.
    34. Salvador R, Miranda PC, Roth Y and Zangen A. (2007) High-permeability core coils for transcranial magnetic stimulation of deep brain regions. IEEE Eng Med Biol Soc. 1:6652-5.
    35. Levy D., Shabat-Simon M, Shalev U., Cooper A and Zangen A. (2007) Repeated electrical stimulation of reward-related brain regions reduces cocaine seeking and alters glutamate receptor levels. J. Neurosci, 27; 14179-89.

    Book Chapters

    • Roth Y and Zangen A. (2006) Transcranial magnetic stimulation of deep brain regions. Biomedical Engineering Fundamentals (ed. Joseph D. Bronzino) chapter 37 pp 1-25 (CRC Press, Taylor & Francis 3rd ed., 2006).
    • Roth Y, Padberg F and Zangen A. (2007) Transcranial magnetic stimulation of deep brain regions: Principles and methods. In Marcolin M, Padberg F (eds.): Transcranial stimulation as treatment in mental disorders. Advances in Biological Psychiatry vol. 23 (2007) Karger Publishers Zhrich, Switzerland

    Patented Inventions
    • Coil for Transcranial Magnetic Stimulation of Deep Brain Regions. A PCT international application was filed by the NIH on 10/19/2001. The NIH (DHHS) Ref. No. is E-223-00/0 (First inventor: Abraham Zangen). Approved May 2007.
    • Continuation: Improved focalization of deep transcranial magnetic stimulation using time summation. A PCT international application was filed, June 2007.

    Research Support

    • NIDA/NIH (Abraham Zangen - PI) A conflict model of relapse to drug use.
    • Israel Science Foundation (ISF) (Abraham Zangen - PI) Role of Brain Derived Neurotrophic Factor (BDNF) within the Brain Reward System in Depressive Behavior. Evaluation by Localized BDNF Silencing.
    • Rosenzweig-Coopersmith Foundation (Abraham Zangen - PI) The brain reward system in depression and addiction.
    • Israel Anti-Drug association (Abraham Zangen -PI). Transcranial Magnetic Stimulation as a novel approach to study and treat addiction.