Boris Heifets

All Publications

• Hallucinogens in Mental Health: Preclinical and Clinical Studies on LSD, Psilocybin, MDMA, and Ketamine. The Journal of neuroscience : the official journal of the Society for Neuroscience De Gregorio, D., Aguilar-Valles, A., Preller, K. H., Heifets, B. D., Hibicke, M., Mitchell, J., Gobbi, G. 2020

  Abstract

  A revamped interest in the study of hallucinogens has recently emerged, especially with regard to their potential application in the treatment of psychiatric disorders. In the last decade, a plethora of preclinical and clinical studies have confirmed the efficacy of ketamine in the treatment of depression. More recently, emerging evidence has pointed out the potential therapeutic properties of psilocybin and LSD, as well as their ability to modulate functional brain connectivity. Moreover, MDMA, a compound belonging to the family of entactogens, has been demonstrated to be useful to treat post-traumatic stress disorders. In this review, the pharmacology of hallucinogenic compounds is summarized by underscoring the differences between psychedelic and nonpsychedelic hallucinogens as well as entactogens, and their behavioral effects in both animals and humans are described. Together, these data substantiate the potentials of these compounds in treating mental diseases.

  View details for DOI 10.1523/JNEUROSCI.1659-20.2020

  View details for PubMedID 33257322

• Piercing the Ketamine Cloud ANESTHESIOLOGY Heifets, B. D. 2020; 133 (5): 970–72

  View details for DOI 10.1097/ALN.0000000000003562

  View details for Web of Science ID 000578753200006

  View details for PubMedID 32946552

• Brain-wide unbiased mapping of neuronal activity pinpoints ketamine's interaction with the opioid system in mice Ryskamp, D., Salgado, J., Barbosa, D. A., Heifets, B. D. LIPPINCOTT WILLIAMS & WILKINS. 2020: 415

  View details for Web of Science ID 000619264500195

• Amygdala-Midbrain Connections Modulate Appetitive and Aversive Learning. Neuron Steinberg, E. E., Gore, F., Heifets, B. D., Taylor, M. D., Norville, Z. C., Beier, K. T., Földy, C., Lerner, T. N., Luo, L., Deisseroth, K., Malenka, R. C. 2020

  Abstract

  The central amygdala (CeA) orchestrates adaptive responses to emotional events. While CeA substrates for defensive behaviors have been studied extensively, CeA circuits for appetitive behaviors and their relationship to threat-responsive circuits remain poorly defined. Here, we demonstrate that the CeA sends robust inhibitory projections to the lateral substantia nigra (SNL) that contribute to appetitive and aversive learning in mice. CeA→SNL neural responses to appetitive and aversive stimuli were modulated by expectation and magnitude consistent with a population-level salience signal, which was required for Pavlovian conditioned reward-seeking and defensive behaviors. CeA→SNL terminal activation elicited reinforcement when linked to voluntary actions but failed to support Pavlovian associations that rely on incentive value signals. Consistent with a disinhibitory mechanism, CeA inputs preferentially target SNL GABA neurons, and CeA→SNL and SNL dopamine neurons respond similarly to salient stimuli. Collectively, our results suggest that amygdala-nigra interactions represent a previously unappreciated mechanism for influencing emotional behaviors.

  View details for DOI 10.1016/j.neuron.2020.03.016

  View details for PubMedID 32294466

• Better living through chemistry: MDMA's prosocial mechanism as a starting point for improved therapeutics. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Heifets, B. D., Malenka, R. C. 2020

  View details for DOI 10.1038/s41386-020-00803-8

  View details for PubMedID 32792684

• A newly developed anesthetic based on a unique chemical core. Proceedings of the National Academy of Sciences of the United States of America Cayla, N. S., Dagne, B. A., Wu, Y., Lu, Y., Rodriguez, L., Davies, D. L., Gross, E. R., Heifets, B. D., Davies, M. F., MacIver, M. B., Bertaccini, E. J. 2019

  Abstract

  Intravenous anesthetic agents are associated with cardiovascular instability and poorly tolerated in patients with cardiovascular disease, trauma, or acute systemic illness. We hypothesized that a new class of intravenous (IV) anesthetic molecules that is highly selective for the slow type of gamma-aminobutyric acid type A receptor (GABAAR) could have potent anesthetic efficacy with limited cardiovascular effects. Through in silico screening using our GABAAR model, we identified a class of lead compounds that are N-arylpyrrole derivatives. Electrophysiological analyses using both an in vitro expression system and intact rodent hippocampal brain slice recordings demonstrate a GABAAR-mediated mechanism. In vivo experiments also demonstrate overt anesthetic activity in both tadpoles and rats with a potency slightly greater than that of propofol. Unlike the clinically approved GABAergic anesthetic etomidate, the chemical structure of our N-arylpyrrole derivative is devoid of the chemical moieties producing adrenal suppression. Our class of compounds also shows minimal to no suppression of blood pressure, in marked contrast to the hemodynamic effects of propofol. These compounds are derived from chemical structures not previously associated with anesthesia and demonstrate that selective targeting of GABAAR-slow subtypes may eliminate the hemodynamic side effects associated with conventional IV anesthetics.

  View details for DOI 10.1073/pnas.1822076116

  View details for PubMedID 31308218

• Disruptive Psychopharmacology. JAMA psychiatry Heifets, B. D., Malenka, R. C. 2019

  View details for DOI 10.1001/jamapsychiatry.2019.1145

  View details for PubMedID 31241740

• Rigorous Trial Design Is Essential to Understand the Role of Opioid Receptors in Ketamine's Antidepressant Effect JAMA PSYCHIATRY Heifets, B. D., Williams, N. R., Bentzley, B. S., Schatzberg, A. F. 2019; 76 (6): 657–58

  View details for DOI 10.1001/jamapsychiatry.2019.0766

  View details for Web of Science ID 000474836500016

• Attenuation of Anti-Suicidal Effects of Ketamine by Opioid Receptor Antagonism Williams, N., Heifets, B., Bentzley, B., Blasey, C., Sudheimer, K., Lyons, D., Schatzberg, A. ELSEVIER SCIENCE INC. 2019: S113

  View details for DOI 10.1016/j.biopsych.2019.03.284

  View details for Web of Science ID 000472661000271

• Rigorous Trial Design Is Essential to Understand the Role of Opioid Receptors in Ketamine's Antidepressant Effect. JAMA psychiatry Heifets, B. D., Williams, N. R., Bentzley, B. S., Schatzberg, A. F. 2019

  View details for PubMedID 31042274

• Rigorous Translational Models Are Key to Studying Ketamine's Antidepressant Mechanism: Response to Wang and Kaplin AMERICAN JOURNAL OF PSYCHIATRY Heifets, B. D., Williams, N. R., Blasey, C., Sudheimer, K., Rodriguez, C. I., Schatzberg, A. F. 2019; 176 (5): 412

  View details for DOI 10.1176/appi.ajp.2019.19010044r

  View details for Web of Science ID 000466364500015

• Rigorous Translational Models Are Key to Studying Ketamine's Antidepressant Mechanism: Response to Wang and Kaplin. The American journal of psychiatry Heifets, B. D., Williams, N. R., Blasey, C., Sudheimer, K., Rodriguez, C. I., Schatzberg, A. F. 2019; 176 (5): 412

  View details for PubMedID 31039633

• Interpreting Ketamine's Opioid Receptor Dependent Effect: Response to Sanacora AMERICAN JOURNAL OF PSYCHIATRY Heifets, B. D., Williams, N. R., Blasey, C., Sudheimer, K., Rodriguez, C. I., Schatzberg, A. F. 2019; 176 (3): 249–50

  View details for DOI 10.1176/appi.ajp.2018.18091061r

  View details for Web of Science ID 000462846900011

• Target Population, Dose, and Timing Considerations for Understanding Naltrexone's Subjective Effect: Response to Amiaz. The American journal of psychiatry Heifets, B. D., Williams, N. R., Blasey, C., Sudheimer, K., Rodriguez, C. I., Schatzberg, A. F. 2019; 176 (3): 251–52

  View details for PubMedID 30818989

• Interpreting Ketamine's Opioid Receptor Dependent Effect: Response to Sanacora. The American journal of psychiatry Heifets, B. D., Williams, N. R., Blasey, C., Sudheimer, K., Rodriguez, C. I., Schatzberg, A. F. 2019; 176 (3): 249–50

  View details for PubMedID 30818991

• Target Population, Dose, and Timing Considerations for Understanding Naltrexone's Subjective Effect: Response to Amiaz AMERICAN JOURNAL OF PSYCHIATRY Heifets, B. D., Williams, N. R., Blasey, C., Sudheimer, K., Rodriguez, C. I., Schatzberg, A. F. 2019; 176 (3): 251–52

  View details for DOI 10.1176/appi.ajp.2018.18111231r

  View details for Web of Science ID 000462846900013

• Distinct neural mechanisms for the prosocial and rewarding properties of MDMA. Science translational medicine Heifets, B. D., Salgado, J. S., Taylor, M. D., Hoerbelt, P., Cardozo Pinto, D. F., Steinberg, E. E., Walsh, J. J., Sze, J. Y., Malenka, R. C. 2019; 11 (522)

  Abstract

  The extensively abused recreational drug (±)3,4-methylenedioxymethamphetamine (MDMA) has shown promise as an adjunct to psychotherapy for treatment-resistant psychiatric disease. It is unknown, however, whether the mechanisms underlying its prosocial therapeutic effects and abuse potential are distinct. We modeled both the prosocial and nonsocial drug reward of MDMA in mice and investigated the mechanism of these processes using brain region-specific pharmacology, transgenic manipulations, electrophysiology, and in vivo calcium imaging. We demonstrate in mice that MDMA acting at the serotonin transporter within the nucleus accumbens is necessary and sufficient for MDMA's prosocial effect. MDMA's acute rewarding properties, in contrast, require dopaminergic signaling. MDMA's prosocial effect requires 5-HT1b receptor activation and is mimicked by d-fenfluramine, a selective serotonin-releasing compound. By dissociating the mechanisms of MDMA's prosocial effects from its addictive properties, we provide evidence for a conserved neuronal pathway, which can be leveraged to develop novel therapeutics with limited abuse liability.

  View details for DOI 10.1126/scitranslmed.aaw6435

  View details for PubMedID 31826983

• Attenuation of antidepressant and antisuicidal effects of ketamine by opioid receptor antagonism. Molecular psychiatry Williams, N. R., Heifets, B. D., Bentzley, B. S., Blasey, C., Sudheimer, K. D., Hawkins, J., Lyons, D. M., Schatzberg, A. F. 2019

  Abstract

  We recently reported that naltrexone blocks antidepressant effects of ketamine in humans, indicating that antidepressant effects of ketamine require opioid receptor activation. However, it is unknown if opioid receptors are also involved in ketamine's antisuicidality effects. Here, in a secondary analysis of our recent clinical trial, we test whether naltrexone attenuates antisuicidality effects of ketamine. Participants were pretreated with naltrexone or placebo prior to intravenous ketamine in a double-blinded crossover design. Suicidality was measured with the Hamilton Depression Rating Scale item 3, Montgomery-Åsberg Depression Rating Scale item 10, and Columbia Suicide Severity Rating Scale. In the 12 participants who completed naltrexone and placebo conditions, naltrexone attenuated the antisuicidality effects of ketamine on all three suicidality scales/subscales (linear mixed model, fixed pretreatment effect, p < 0.01). Results indicate that opioid receptor activation plays a significant role in the antisuicidality effects of ketamine.

  View details for DOI 10.1038/s41380-019-0503-4

  View details for PubMedID 31467392

• Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism Williams, N. R., Heifets, B. D., Blasey, C., Sudheimer, K., Pannu, J., Pankow, H., Hawkins, J., Birnbaum, J., Lyons, D. M., Rodriguez, C. I., Schatzberg, A. F. AMER PSYCHIATRIC PUBLISHING, INC. 2018: 1205–15

  View details for DOI 10.1176/appi.ajp.2018.18020138

  View details for Web of Science ID 000451749000012

• Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism. The American journal of psychiatry Williams, N. R., Heifets, B. D., Blasey, C., Sudheimer, K., Pannu, J., Pankow, H., Hawkins, J., Birnbaum, J., Lyons, D. M., Rodriguez, C. I., Schatzberg, A. F. 2018: appiajp201818020138

  Abstract

  OBJECTIVE: In addition to N-methyl-d-aspartate receptor antagonism, ketamine produces opioid system activation. The objective of this study was to determine whether opioid receptor antagonism prior to administration of intravenous ketamine attenuates its acute antidepressant or dissociative effects.METHOD: In a proposed double-blind crossover study of 30 adults with treatment-resistant depression, the authors performed a planned interim analysis after studying 14 participants, 12 of whom completed both conditions in randomized order: placebo or 50 mg of naltrexone preceding intravenous infusion of 0.5 mg/kg of ketamine. Response was defined as a reduction ≥50% in score on the 17-item Hamilton Depression Rating Scale (HAM-D) score on postinfusion day 1.RESULTS: In the interim analysis, seven of 12 adults with treatment-resistant depression met the response criterion during the ketamine plus placebo condition. Reductions in 6-item and 17-item HAM-D scores among participants in the ketamine plus naltrexone condition were significantly lower than those of participants in the ketamine plus placebo condition on postinfusion days 1 and 3. Secondary analysis of all participants who completed the placebo and naltrexone conditions, regardless of the robustness of response to ketamine, showed similar results. There were no differences in ketamine-induced dissociation between conditions. Because naltrexone dramatically blocked the antidepressant but not the dissociative effects of ketamine, the trial was halted at the interim analysis.CONCLUSIONS: The findings suggest that ketamine's acute antidepressant effect requires opioid system activation. The dissociative effects of ketamine are not mediated by the opioid system, and they do not appear sufficient without the opioid effect to produce the acute antidepressant effects of ketamine in adults with treatment-resistant depression.

  View details for PubMedID 30153752

• 5-HT release in nucleus accumbens rescues social deficits in mouse autism model. Nature Walsh, J. J., Christoffel, D. J., Heifets, B. D., Ben-Dor, G. A., Selimbeyoglu, A., Hung, L. W., Deisseroth, K., Malenka, R. C. 2018

  Abstract

  Dysfunction in prosocial interactions is a core symptom of autism spectrum disorder. However, the neural mechanisms that underlie sociability are poorly understood, limiting the rational development of therapies to treat social deficits. Here we show in mice that bidirectional modulation of the release of serotonin (5-HT) from dorsal raphe neurons in the nucleus accumbens bidirectionally modifies sociability. In a mouse model of a common genetic cause of autism spectrum disorder-a copy number variation on chromosome 16p11.2-genetic deletion of the syntenic region from 5-HT neurons induces deficits in social behaviour and decreases dorsal raphe 5-HT neuronal activity. These sociability deficits can be rescued by optogenetic activation of dorsal raphe 5-HT neurons, an effect requiring and mimicked by activation of 5-HT1b receptors in the nucleus accumbens. These results demonstrate an unexpected role for 5-HT action in the nucleus accumbens in social behaviours, and suggest that targeting this mechanism may prove therapeutically beneficial.

  View details for PubMedID 30089910

• KETAMINE'S ANTIDEPRESSANT EFFECT IS BLOCKED BY A MU-OPIOID RECEPTOR ANTAGONIST IN HUMANS AND MICE Heifets, B. D., Williams, N., Sudheimer, K., Pankow, H., Blasey, C., Lyons, D., Schatzberg, A. F. LIPPINCOTT WILLIAMS & WILKINS. 2018: 343

  View details for Web of Science ID 000460106500197

• Case Report of an Awake Craniotomy in a Patient With Eisenmenger Syndrome. A&A practice Heifets, B. D., Crawford, E., Jackson, E., Brodt, J., Jaffe, R. A., Burbridge, M. A. 2018; 10 (9): 219–22

  Abstract

  We present a detailed report of an awake craniotomy for recurrent third ventricular colloid cyst in a patient with severe pulmonary arterial hypertension in the setting of Eisenmenger syndrome, performed 6 weeks after we managed the same patient for a more conservative procedure. This patient has a high risk of perioperative mortality and may be particularly susceptible to perioperative hemodynamic changes or fluid shifts. The risks of general anesthesia induction and emergence must be balanced against the risks inherent in an awake craniotomy on a per case basis.

  View details for PubMedID 29708913

• Native System and Cultured Cell Electrophysiology for Investigating Anesthetic Mechanisms. Methods in enzymology Hoerbelt, P., Heifets, B. D. 2018; 602: 301–38

  Abstract

  Anesthetic agents interact with a variety of ion channels and membrane-bound receptors, often at agent-specific binding sites of a single protein. These molecular-level interactions are ultimately responsible for producing the clinically anesthetized state. Between these two scales of effect, anesthetic agents can be studied in terms of how they impact the physiology of neuronal circuits, individual neurons, and cells expressing individual receptor types. The acutely dissected hippocampal slice is one of the most extensively studied and characterized preparations of intact neural tissue and serves as a highly useful experimental model system to test hypotheses of anesthetic mechanisms. Specific agent-receptor interactions and their effect on excitable membranes can further be defined with molecular precision in cell-based expression systems. We highlight several approaches in these respective systems that we have used and that also have been used by many investigators worldwide. We emphasize economy and quality control, to allow an experimenter to carry out these types of studies in a rigorous and efficient manner.

  View details for PubMedID 29588037

• Fluid management concepts for severe neurological illness: an overview. Current opinion in anaesthesiology Heifets, B. D., Tanaka, P., Burbridge, M. A. 2018

  Abstract

  The acute care of a patient with severe neurological injury is organized around one relatively straightforward goal: avoid brain ischemia. A coherent strategy for fluid management in these patients has been particularly elusive, and a well considered fluid management strategy is essential for patients with critical neurological illness.In this review, several gaps in our collective knowledge are summarized, including a rigorous definition of volume status that can be practically measured; an understanding of how electrolyte derangements interact with therapy; a measurable endpoint against which we can titrate our patients' fluid balance; and agreement on the composition of fluid we should give in various clinical contexts.As the possibility grows closer that we can monitor the physiological parameters with direct relevance for neurological outcomes and the various complications associated with neurocritical illness, we may finally move away from static therapy recommendations, and toward individualized, precise therapy. Although we believe therapy should ultimately be individualized rather than standardized, it is clear that the monitoring tools and analytical methods used ought to be standardized to facilitate appropriately powered, prospective clinical outcome trials.

  View details for PubMedID 30015638

• Rabies screen reveals GPe control of cocaine-triggered plasticity. Nature Beier, K. T., Kim, C. K., Hoerbelt, P., Hung, L. W., Heifets, B. D., DeLoach, K. E., Mosca, T. J., Neuner, S., Deisseroth, K., Luo, L., Malenka, R. C. 2017

  Abstract

  Identification of neural circuit changes that contribute to behavioural plasticity has routinely been conducted on candidate circuits that were preselected on the basis of previous results. Here we present an unbiased method for identifying experience-triggered circuit-level changes in neuronal ensembles in mice. Using rabies virus monosynaptic tracing, we mapped cocaine-induced global changes in inputs onto neurons in the ventral tegmental area. Cocaine increased rabies-labelled inputs from the globus pallidus externus (GPe), a basal ganglia nucleus not previously known to participate in behavioural plasticity triggered by drugs of abuse. We demonstrated that cocaine increased GPe neuron activity, which accounted for the increase in GPe labelling. Inhibition of GPe activity revealed that it contributes to two forms of cocaine-triggered behavioural plasticity, at least in part by disinhibiting dopamine neurons in the ventral tegmental area. These results suggest that rabies-based unbiased screening of changes in input populations can identify previously unappreciated circuit elements that critically support behavioural adaptations.

  View details for PubMedID 28902833

• Case Report of an Awake Craniotomy in a Patient With Eisenmenger Syndrome. A & A case reports Heifets, B. D., Crawford, E., Jackson, E., Brodt, J., Jaffe, R. A., Burbridge, M. A. 2017

  Abstract

  We present a detailed report of an awake craniotomy for recurrent third ventricular colloid cyst in a patient with severe pulmonary arterial hypertension in the setting of Eisenmenger syndrome, performed 6 weeks after we managed the same patient for a more conservative procedure. This patient has a high risk of perioperative mortality and may be particularly susceptible to perioperative hemodynamic changes or fluid shifts. The risks of general anesthesia induction and emergence must be balanced against the risks inherent in an awake craniotomy on a per case basis.

  View details for DOI 10.1213/XAA.0000000000000664

  View details for PubMedID 29135526

• BEYOND KETAMINE FOR PSYCHIATRIC DISEASE: UNRAVELING THE MURINE NEURAL MECHANISMS OF THE EMPATHOGEN MDMA, A NOVEL, RAPID-ONSET SINGLE-SHOT CLINICAL THERAPY FOR POST-TRAUMATIC STRESS DISORDER Heifets, B. D., Taylor, M., Hung, L. W., Malenka, R. C. LIPPINCOTT WILLIAMS & WILKINS. 2016

  View details for Web of Science ID 000403582200157

• MDMA as a Probe and Treatment for Social Behaviors. Cell Heifets, B. D., Malenka, R. C. 2016; 166 (2): 269–72

  Abstract

  MDMA, better known as the recreational drug "ecstasy," is well known for stimulating a feeling of closeness and empathy in its users. We advocate that exploring its mechanism of action could lead to new treatments for psychiatric conditions characterized by impairments in social behavior.

  View details for PubMedID 27419864

• Chronic pain. Decreased motivation during chronic pain requires long-term depression in the nucleus accumbens. Science Schwartz, N., Temkin, P., Jurado, S., Lim, B. K., Heifets, B. D., Polepalli, J. S., Malenka, R. C. 2014; 345 (6196): 535-542

  Abstract

  Several symptoms associated with chronic pain, including fatigue and depression, are characterized by reduced motivation to initiate or complete goal-directed tasks. However, it is unknown whether maladaptive modifications in neural circuits that regulate motivation occur during chronic pain. Here, we demonstrate that the decreased motivation elicited in mice by two different models of chronic pain requires a galanin receptor 1-triggered depression of excitatory synaptic transmission in indirect pathway nucleus accumbens medium spiny neurons. These results demonstrate a previously unknown pathological adaption in a key node of motivational neural circuitry that is required for one of the major sequela of chronic pain states and syndromes.

  View details for DOI 10.1126/science.1253994

  View details for PubMedID 25082697

• HIPPOCAMPAL GABAERGIC FIELD POTENTIALS: A NOVEL HIGH THROUGHPUT SCREEN FOR GENERAL ANESTHETICS IN RAT Nie, J., Sharma, B., Maclver, B., Heifets, B. D. LIPPINCOTT WILLIAMS & WILKINS. 2014: S144

  View details for Web of Science ID 000209827600126

• IMPROVING DEEP BRAIN STIMULATION THROUGH TARGETED SYNAPTIC MODIFICATION Heifets, B. D., Deisseroth, K., Malenka, R., MacIver, B. LIPPINCOTT WILLIAMS & WILKINS. 2013: 159

  View details for Web of Science ID 000330441700136

• Acute Cardiovascular Toxicity of Low-Dose Intrathecal Ziconotide. Pain medicine (Malden, Mass.) Heifets, B. D., Smith, S. M., Leong, M. S. 2013

  View details for PubMedID 23855951

• Endocannabinoid Signaling and Long-Term Synaptic Plasticity ANNUAL REVIEW OF PHYSIOLOGY Heifets, B. D., Castillo, P. E. 2009; 71: 283-306

  Abstract

  Endocannabinoids (eCBs) are key activity-dependent signals regulating synaptic transmission throughout the central nervous system. Accordingly, eCBs are involved in neural functions ranging from feeding homeostasis to cognition. There is great interest in understanding how exogenous (e.g., cannabis) and endogenous cannabinoids affect behavior. Because behavioral adaptations are widely considered to rely on changes in synaptic strength, the prevalence of eCB-mediated long-term depression (eCB-LTD) at synapses throughout the brain merits close attention. The induction and expression of eCB-LTD, although remarkably similar at various synapses, are controlled by an array of regulatory influences that we are just beginning to uncover. This complexity endows eCB-LTD with important computational properties, such as coincidence detection and input specificity, critical for higher CNS functions like learning and memory. In this article, we review the major molecular and cellular mechanisms underlying eCB-LTD, as well as the potential physiological relevance of this widespread form of synaptic plasticity.

  View details for DOI 10.1146/annurev.physiol.010908.163149

  View details for Web of Science ID 000264489600014

  View details for PubMedID 19575681

• Interneuron activity controls endocannabinoid-mediated presynaptic plasticity through calcineurin PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Heifets, B. D., Chevaleyre, V., Castillo, P. E. 2008; 105 (29): 10250-10255

  Abstract

  Retrograde signaling by endocannabinoids (eCBs) mediates a widely expressed form of long-term depression at excitatory and inhibitory synapses (eCB-LTD), involving a reduction in neurotransmitter release. In the hippocampus, eCB-LTD occurs at interneuron (IN)-pyramidal cell (PC) synapses (I-LTD), and its induction requires a presynaptic reduction of cAMP/PKA signaling resulting from minutes of type 1 cannabinoid receptor (CB1R) activation. Although repetitive activity of glutamatergic synapses initiates the eCB mobilization required for I-LTD, it is unclear whether CB1R-containing GABAergic terminals are passive targets of eCBs or whether they actively contribute to induction. Here, we show that the minutes-long induction period for I-LTD may serve as a window to integrate associated spontaneous activity in the same IN receiving the retrograde eCB signal. Indeed, reducing spontaneous IN firing blocked I-LTD, which could be rescued with extra stimulation of inhibitory afferents. Moreover, cell pair recordings showed that a single IN expressed LTD onto a PC only if it was active during eCB signaling. Several methods of disrupting presynaptic Ca(2+) dynamics all blocked I-LTD, strongly suggesting that IN spikes regulate I-LTD by raising Ca(2+) at the nerve terminal. Finally, inhibiting the Ca(2+)-activated phosphatase, calcineurin, fully blocked I-LTD, but blocking another phosphatase did not. Our findings support a model where both CB1R signaling and IN activity shift the balance of kinase and phosphatase activity in the presynaptic terminal to induce I-LTD.

  View details for DOI 10.1073/pnas.0711880105

  View details for Web of Science ID 000257913200072

  View details for PubMedID 18632563

• Endocannabinoid-mediated long-term plasticity requires cAMP/PKA signaling and RIM1 alpha NEURON Chevaleyre, V., Heifets, B. D., Kaeser, P. S., Sudhof, T. C., Purpura, D. P., Castillo, P. E. 2007; 54 (5): 801-812

  Abstract

  Endocannabinoids (eCBs) have emerged as key activity-dependent signals that, by activating presynaptic cannabinoid receptors (i.e., CB1) coupled to G(i/o) protein, can mediate short-term and long-term synaptic depression (LTD). While the presynaptic mechanisms underlying eCB-dependent short-term depression have been identified, the molecular events linking CB1 receptors to LTD are unknown. Here we show in the hippocampus that long-term, but not short-term, eCB-dependent depression of inhibitory transmission requires presynaptic cAMP/PKA signaling. We further identify the active zone protein RIM1alpha as a key mediator of both CB1 receptor effects on the release machinery and eCB-dependent LTD in the hippocampus. Moreover, we show that eCB-dependent LTD in the amygdala and hippocampus shares major mechanistic features. These findings reveal the signaling pathway by which CB1 receptors mediate long-term effects of eCBs in two crucial brain structures. Furthermore, our results highlight a conserved mechanism of presynaptic plasticity in the brain.

  View details for DOI 10.1016/j.neuron.2007.05.020

  View details for Web of Science ID 000247329900012

  View details for PubMedID 17553427

• Regulation of regulators of G protein signaling mRNA expression in rat brain by acute and chronic electroconvulsive seizures JOURNAL OF NEUROCHEMISTRY Gold, S. J., Heifets, B. D., Pudiak, C. M., Potts, B. W., Nestler, E. J. 2002; 82 (4): 828-838

  Abstract

  G protein-coupled receptor (GPCR) signaling cascades may be key substrates for the antidepressant effects of chronic electroconvulsive seizures (ECS). To better understand changes in these signaling pathways, alterations in levels of mRNA's encoding regulators of G protein signaling (RGS) protein subtypes-2, -4, -7, -8 and -10 were evaluated in rat brain using northern blotting and in situ hybridization. In prefrontal cortex, RGS2 mRNA levels were increased several-fold 2 h following an acute ECS. Increases in RGS8 mRNA were of lesser magnitude (30%), and no changes were evident for the other RGS subtypes. At 24 h following a chronic ECS regimen, RGS4, -7, and -10 mRNA levels were reduced by 20-30%; only RGS10 was significantly reduced 24 h after acute ECS. Levels of RGS2 mRNA were unchanged 24 h following either acute or chronic ECS. In hippocampus, RGS2 mRNA levels were markedly increased 2 h following acute ECS. More modest increases were seen for RGS4 mRNA expression, whereas levels of the other RGS subtypes were unaltered. At 24 h following chronic ECS, RGS7, -8 and -10 mRNA levels were decreased in the granule cell layer, and RGS7 and -8 mRNA levels were decreased in the pyramidal cell layers. Only RGS8 and -10 mRNA levels were significantly reduced in hippocampus 24 h following an acute ECS. Paralleling neocortex, RGS2 mRNA content was unchanged in hippocampus 24 h following either acute or chronic ECS. In ventromedial hypothalamus, RGS4 mRNA content was increased 24 h following chronic ECS, whereas RGS7 mRNA levels were only increased 24 h following an acute ECS. The increased RGS4 mRNA levels in hypothalamus were significant by 2 h following an acute ECS. These studies demonstrate subtype-, time-, and region-specific regulation of RGS proteins by ECS, adaptations that may contribute to the antidepressant effects of this treatment.

  View details for Web of Science ID 000177369300011

  View details for PubMedID 12358788

• The effect of scopolamine in older rabbits tested in the 750 ms delay eyeblink classical conditioning procedure INTEGRATIVE PHYSIOLOGICAL AND BEHAVIORAL SCIENCE Woodruff-Pak, D. S., Green, J. T., Pak, J. T., Heifets, B., Pak, M. H. 2002; 37 (2): 103-113

  Abstract

  We investigated the effect of several doses of scopolamine in older rabbits that were trained for 20 days in the 750 ms delay eyeblink classical conditioning procedure. Our aim was to determine if the scopolamine-injected older rabbit would be a useful model for testing drugs for cognition enhancement in Alzheimer's disease (AD). A total of 39 rabbits with a mean age of 31 months received classical eyeblink conditioning with daily injections of 0.25, 0.75, or 1.5 mg/kg scopolamine hydrobromide or sterile saline vehicle. Doses of 0.75 and 1.5 mg/kg scopolamine significantly impaired acquisition, whereas acquisition was not significantly impaired with 0.25 mg/kg scopolamine. Results exhibit parallels in performance on delay eyeblink classical conditioning between scopolamine-treated older rabbits and human patients diagnosed with AD.

  View details for Web of Science ID 000177491000002

  View details for PubMedID 12186305

• Nefiracetam ameliorates associative learning impairment in the scopolamine-injected older rabbit. Medical science monitor Pak, J., Green, J., Heifets, B., Pak, M., Woodruff-Pak, D. 2002; 8 (4): BR105-12

  Abstract

  The cognition-enhancing drug, nefiracetam, is in Phase III clinical trials to treat memory impairment in Alzheimer's disease (AD). Nefiracetam ameliorates acquisition of delay eyeblink classical conditioning in older rabbits, a form of associative learning with striking behavioral and neurobiological similarities in rabbits and humans. In both species, delay eyeblink conditioning engages the septo-hippocampal cholinergic system and is disrupted when the cholinergic system is antagonized. Delay eyeblink classical conditioning is impaired in normal aging and severely disrupted in AD.To test further the efficacy of nefiracetam in an animal model that mimics some of the neurobiological and behavioral effects present in AD, we tested 56 older rabbits assigned to 7 treatment groups in the 750 ms delay eyeblink conditioning procedure. Older rabbits were injected with 1.5 mg/kg scopolamine to simulate disruption of the cholinergic system in AD. Three doses of nefiracetam (5, 10, or 15 mg/kg) were also injected in older rabbits receiving 1.5 mg/kg scopolamine. Control groups were treated with 1.5 mg/kg scopolamine + vehicle, vehicle alone, or explicitly unpaired presentations of conditioning stimuli and vehicle or 1.5 mg/kg scopolamine + 15 mg/kg nefiracetam.Rabbits injected with 1.5 mg/kg scopolamine alone were impaired, but a dose of 15 mg/kg nefiracetam reversed significantly the behavioral impairment.Nefiracetam had ameliorating effects on a task impaired in AD in an animal model of AD: older rabbits with cholinergic system antagonism.

  View details for PubMedID 11951055

• Chemical analysis of ecstasy pills JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Baggott, M., Heifets, B., Jones, R. T., Mendelson, J., Sferios, E., Zehnder, J. 2000; 284 (17): 2190-2190

  View details for Web of Science ID 000090052600026

  View details for PubMedID 11056589

• Anticonvulsant efficacy of N-methyl-D-aspartate antagonists against convulsions induced by cocaine JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Witkin, J. M., Gasior, M., Heifets, B., Tortella, F. C. 1999; 289 (2): 703-711

  Abstract

  Convulsions associated with cocaine abuse can be life threatening and resistant to standard emergency treatment. Cocaine (75 mg/kg, i. p.) produced clonic convulsions in approximately 90% of male, Swiss-Webster mice. A variety of clinically used antiepileptic agents did not significantly protect against cocaine convulsions (e. g., diazepam and phenobarbital). Anticonvulsants in clinical practice that did significantly protect against convulsion did so only at doses with significant sedative/ataxic effects (e.g., clonazepam and valproic acid). In contrast, functional N-methyl-D-aspartate (NMDA) antagonists all produced dose-dependent and significant protection against the convulsant effects of cocaine. Anticonvulsant efficacy was achieved by blockade of both competitive and noncompetitive modulatory sites on the NMDA receptor complex. Thus, competitive antagonists, ion-channel blockers, polyamine antagonists, and functional blockers of the strychnine-insensitive glycine modulatory site all prevented cocaine seizures. The role of NMDA receptors in the control of cocaine-induced convulsions was further strengthened by the positive correlation between the potencies of noncompetititve antagonists or competitive antagonists to block convulsions and their respective affinities for their specific binding sites on the NMDA receptor complex. Although some NMDA blockers produced profound behavioral side effects at efficacious doses (e.g., noncompetitive antagonists), others (e.g., some low-affinity channel blockers, some competitive antagonists, and glycine antagonists) demonstrated significant and favorable separation between their anticonvulsant and side effect profiles. The present results provide the most extensive evidence to date identifying NMDA receptor blockade as a potential strategy for the discovery of agents for clinical use in averting toxic sequelae from cocaine overdose. Given the literature suggesting a role for these drugs in other areas of drug abuse treatments, NMDA receptor antagonists sit in a unique position as potential therapeutic candidates.

  View details for Web of Science ID 000079857100013

  View details for PubMedID 10215643