D. Matthew Walentiny, Ph.D.
- Virginia Commonwealth University, 2011
- Behavioral pharmacology of drugs of abuse
- Preclinical testing of candidate medications for substance abuse disorders
My research efforts are centered on understanding the ways in which drugs of abuse can modify or control behaviors. In particular, I am interested in studying how drugs can elicit or alter reward-like behaviors in rodents to better understand abuse-related phenomena in humans. One method I use for that objective is intracranial self-stimulation (ICSS). In this procedure, electrodes are implanted into a brain region implicated in reward function (medial forebrain bundle) and subjects are allowed to press a lever in a test chamber for electrical stimulations. ICSS supports stable levels of responding that we can manipulate with a number of variables, including drug treatments and the intensity or frequency of the current administered as reinforcement. In general, drugs that are abused by humans tend to increase responding for stimulation of the mesolimbic dopamine pathway. In contrast, drugs or conditions that produce dysphoric effects in humans (e.g., antipsychotic medications such as haloperidol or drug withdrawal) typically decrease such responding. We can therefore apply this methodology to study the abuse potential of novel drugs or evaluate candidate medications for their ability to reverse drug-induced alterations in ICSS.
A second key technique used in my lab to interrogate abuse-related effects of drugs is drug discrimination, an assay thought to model the subjective effects produced by drugs. A drug discrimination procedure typically involves associating the effects of a “training drug” with reinforcement when pressing one of two levers in a test chamber, and associating the effects of the drug’s vehicle with pressing that is reinforced on the opposite lever. When training is complete, subjects primarily press only the injection-associated lever, and they then can be tested with novel compounds. The degree to which a test compound directs responding to the same lever associated with the training drug enables inferences to how likely the two drugs are producing similar subjective effects. Like ICSS, this procedure can be utilized to compare abuse liability of novel drugs to known drugs of abuse or to evaluate potential treatments for substance abuse disorders, and is particularly valuable for identifying the neural mechanism(s) underlying these processes.
Walentiny DM, Vann RE, Mahadevan A, Kottani R, Gujjar R, Wiley JL (2013) Novel 3-substituted rimonabant analogues lack Delta(9)-tetrahydrocannabinol-like abuse-related behavioural effects in mice. Br J Pharmacol 169:10–20.
Walentiny DM, Gamage TF, Warner JA, Nguyen TK, Grainger DB, Wiley JL, Vann RE (2011) The endogenous cannabinoid anandamide shares discriminative stimulus effects with (9)-tetrahydrocannabinol in fatty acid amide hydrolase knockout mice. Eur J Pharmacol 656:63–67.
Walentiny DM, Vann RE, Warner JA, King LS, Seltzman HH, Navarro HA, Twine CEJ, Thomas BF, Gilliam AF, Gilmour BP, Carroll FI, Wiley JL. (2010) Kappa opioid mediation of cannabinoid effects of the potent hallucinogen, salvinorin A, in rodents. Psychopharmacology (Berl) 210:275–284.
Tobey KM, Walentiny DM, Wiley JL, Carroll FI, Damaj MI, Azar MR, Koob GF, George O, Harris LS, Vann RE (2012) Effects of the specific alpha4beta2 nAChR antagonist, 2-fluoro-3-(4-nitrophenyl) deschloroepibatidine, on nicotine reward-related behaviors in rats and mice. Psychopharmacology (Berl) 223:159–168.
Long JZ, Nomura DK, Vann RE, Walentiny DM, Booker L, Jin X, Burston JJ, Sim-Selley LJ, Lichtman AH, Wiley JL, Cravatt BF. (2009) Dual blockade of FAAH and MAGL identifies behavioral processes regulated by endocannabinoid crosstalk in vivo. Proc Natl Acad Sci U S A 106:20270–20275.