Doctor of Philosophy, Albany Medical Coll Of Union Univ (2015)
Bachelor of Science, S.U.N.Y. State University at Albany (2008)
Robert Malenka, Postdoctoral Faculty Sponsor
Current Research and Scholarly Interests
I am broadly interested in understanding how neuromodulatory systems (particularly those that use dopamine) govern long-term changes in neural signaling, anxiety behaviors, and reward-associated behaviors. I also have a strong interest in the biophysics and pharmacology of GABA type A receptors and how signaling at these receptors modulates brain circuitry. I primarily use optogenetics, electrophysiology, and rodent behavioral assays to address critical questions in these areas.
Robert Malenka, (7/13/2015)
Distinct neural mechanisms for the prosocial and rewarding properties of MDMA.
Science translational medicine
2019; 11 (522)
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
A Critical Role for the Globus Pallidus in Cocaine-Triggered Plasticity Revealed Byrabies Activity Screen
ELSEVIER SCIENCE INC. 2018: S235–S236
View details for Web of Science ID 000433001900009
Native System and Cultured Cell Electrophysiology for Investigating Anesthetic Mechanisms.
Methods in enzymology
2018; 602: 301–38
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
Rabies screen reveals GPe control of cocaine-triggered plasticity.
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
- Mutagenesis and computational docking studies support the existence of a histamine binding site at the extracellular beta 3+beta 3-interface of homooligomeric beta 3 GABA(A) receptors NEUROPHARMACOLOGY 2016; 108: 252-263
Dopamine Directly Modulates GABA(A) Receptors
JOURNAL OF NEUROSCIENCE
2015; 35 (8): 3525-3536
Dopamine is a critical neuromodulator that activates GPCRs in mammals or ligand-gated ion channels in invertebrates. The present study demonstrates that dopamine (0.1-10 mm) exerts novel, opposing effects on different populations of mammalian (rat) GABAA receptors. Using whole-cell patch-clamp electrophysiology, we observed direct dopamine-mediated inhibition of tonic-level (1 μm) GABA-evoked currents in untransfected striatal neurons that could be recapitulated in HEK293 cells containing α1β3 or α1β2γ2 subunits. Surprisingly, direct activation by dopamine was seen in the absence of GABA with α1β2γ2, α5β3γ2, or α1β3γ2 transfections. This activity was also present in α1β3γ2 receptors containing a mutant β3 subunit (H267A [(Z)β3]) insensitive to trace levels of inhibitory Zn(2+). Dopamine activation required β and γ subunits but not α subunits ((Z)β3γ2 EC50 value, 660 μm). Dopamine activity was fully blocked by picrotoxin but not GABAA competitive antagonists, and was strongly correlated with spontaneous receptor activity. We also report opposing effects of bicuculline and gabazine, such that bicuculline surprisingly activated non-α-containing (β3γ2) GABAA receptors, whereas gabazine suppressed spontaneous activity in these receptors. Our results suggest that dopamine may directly inhibit GABAA receptors that are both immediately adjacent to dopamine release sites in the striatum and activated by tonic GABA. Furthermore, synaptic/phasic release of dopamine may directly enhance signaling at some spontaneously active noncanonical GABAA receptors that lack α subunits.
View details for DOI 10.1523/JNEUROSCI.4390-14.2015
View details for Web of Science ID 000350738800023
View details for PubMedID 25716851
Antinociceptive activity of CC44, a biotinylated improgan congener
EUROPEAN JOURNAL OF PHARMACOLOGY
2013; 714 (1-3): 464-471
Improgan, a non-opioid, antinociceptive drug, activates descending analgesic circuits following brain administration, but the improgan receptor remains unidentified. Since biotinylation of drugs can enhance drug potency or facilitate discovery of new drug targets, a biotinylated congener of improgan (CC44) and several related compounds were synthesized and tested for antinociceptive activity. In rats and mice, intracerebroventricular (i.c.v.) administration of CC44 produced dose-dependent reductions in thermal nociceptive (tail flick and hot plate) responses, with 5-fold greater potency than improgan. CC44 also robustly attenuated mechanical (tail pinch) nociception in normal rats and mechanical allodynia in a spinal nerve ligation model of neuropathic pain. Similar to the effects of improgan, CC44 antinociception was reversed by the GABAA agonist muscimol (consistent with activation of analgesic circuits), and was resistant to the opioid antagonist naltrexone (implying a non-opioid mechanism). Also like improgan, CC44 produced thermal antinociception when microinjected into the rostral ventromedial medulla (RVM). Unlike improgan, CC44 (i.c.v.) produced antinociception which was resistant to antagonism by the cannabinoid CB1 antagonist/inverse agonist rimonabant. CC44 was inactive in mice following systemic administration, indicating that CC44 does not penetrate the brain. Preliminary findings with other CC44 congeners suggest that the heteroaromatic nucleus (imidazole), but not the biotin moiety, is required for CC44's antinociceptive activity. These findings demonstrate that CC44 is a potent analgesic compound with many improgan-like characteristics. Since powerful techniques are available to characterize and identify the binding partners for biotin-containing ligands, CC44 may be useful in searching for new receptors for analgesic drugs.
View details for DOI 10.1016/j.ejphar.2013.06.041
View details for Web of Science ID 000323601100060
View details for PubMedID 23834775