Although we have demonstrated a role for stress and the subsequent activation of the HPA axis in the etiology of cocaine reward and that drugs affecting central responses to stress and the HPA axis could be used to reduce drug seeking and drug taking (see below), additional research indicated that these effects might also be mediated above the level of the adrenal glands. In particular, we determined that not only were the effects of metyrapone and oxazepam maintained in adrenalectomized rats, these effects actually appeared to be enhanced in these animals. These data indicated that central mechanisms might be involved. Metyrapone inhibits 11β-hydroxylase, which is encoded by the CYP11B1 gene, and results in reduced levels of corticosterone (cortisol). Benzodiazepines can also inhibit 11β-hydroxylase under certain conditions. The CYP11B1 gene is found in tissues outside the adrenal gland, including the brain, which is a major site of extra-adrenal corticosterone production since corticosterone can be synthesized de novo from cholesterol in the central nervous system. When 11β-hydroxylase activity is inhibited, this shifts the cholesterol pathway away from the synthesis of corticosterone and toward the production of neuroactive steroids (neurosteroids) such as allopregnanolone and allotetrahydrodoc (TH-DOC).  In a novel series of experiments we demonstrated that the combination of metyrapone and oxazepam increased neurosteroid levels in the medial prefrontal cortex and amygdala.

 

Current research in this area also includes investigations of agonists for the translocator protein (18 kD) since oxazepam also binds to this TSPO protein. Preliminary data suggest that the TSPO agonist Ro5-4864 reduces methamphetamine seeking in rats. A better understanding of the mechanisms underlying these effects may lead to the development of novel treatments for methamphetamine addiction.

Spence, A.L., Guerin, G.F., and Goeders, N.E. The differential effects of alprazolam and oxazepam on methamphetamine self-administration in rats. Drug Alcohol Depend. 166:209-217, 2016. PMID: 27485488.

Schmoutz, C.D., Runyon, S.P., and Goeders N.E. Effects of Inhibitory GABA-Active Neurosteroids on Cocaine Seeking and Cocaine Taking in Rats. Psychopharmacology (Berl), 231:3391-400, 2014.  PMID: 24398823.

Guerin, G.F., Schmoutz, C.D., and Goeders, N.E. The Extra-Adrenal Effects of Metyrapone and Oxazepam on Ongoing Cocaine Self-Administration.  Brain Research, 1575:45-54, 2014.  PMID: 24887642.

Schmoutz, C.D., Guerin, G.F., and Goeders, N.E.  Role of GABA-Active Neurosteroids in the Efficacy of Metyrapone against Cocaine Addiction. Behavioural Brain Research, 271:269-76. 2014. PMID: 24959859.

Schmoutz, C.D., Guerin, G.F., Runyon, S.P., Dhungana, S., and Goeders, N.E. A Therapeutic Combination of Metyrapone and Oxazepam Increases Brain Levels of GABA-Active Neurosteroids and Decreases Cocaine Self-Administration in Male Rats. Behavioural Brain Research, 108–111, 2015. PMID: 26003946.

Spence, A.L., Guerin, G.F., Goeders, N.E. Differential Modulation of the Discriminative Stimulus Effects of Methamphetamine and Cocaine by Alprazolam and Oxazepam in Male and Female Rats. Neuropharmacology, 146-157, 2015. PMID: 26541330.

 

This work laid the groundwork for the translational research cited above. Since we had demonstrated that stress played a major role in the etiology of cocaine reward, these studies were designed to determine the effects of drugs that affect responses to stress (e.g., benzodiazepines) and/or the activation of the HPA axis (e.g., cortisol synthesis inhibitors and CRF receptor antagonists) on cocaine seeking and cocaine taking in rats.  We determined that benzodiazepines and corticosterone (cortisol) synthesis inhibitors might be the most promising candidates for the development of new pharmacotherapies for the treatment of cocaine addiction in rats.  However, these types of drugs have their drawbacks. Benzodiazepines have the potential for abuse and corticosterone synthesis inhibitors may produce adrenal insufficiency, which would limit their usefulness as candidates for treatment. These concerns might be mitigated, however, by using lower doses of the drugs. We therefore further hypothesized that we might be able to produce a comparable effect if we combined drugs that altered the response to stress and/or HPA axis activity and administered them at doses that were ineffective when delivered as individual agents. Through work conducted over more than 10 years, we determined that the administration of a combination of the corticosterone synthesis inhibitor, metyrapone, and the benzodiazepine, oxazepam, at does that were ineffective when administered singly, was effective in reducing cocaine and methamphetamine taking and seeking without affecting food-maintained responding.  This drug combination was also independently demonstrated to reduce nicotine self-administration in rats.  Finally, in the pilot clinical trial cited above, the combination of metyrapone and oxazepam was demonstrated in reduce cocaine craving and cocaine taking in human cocaine users. Several patents have been filed, and clinical trials conducted under an IND from the FDA are currently underway through Embera based on this research.

Goeders, N.E. and Guerin, G. F.  Effects of the Combination of Metyrapone and Oxazepam on Cocaine and Food Self-Administration in Rats.  Pharmacology, Biochemistry and Behavior, 91(1): 181-189, 2008. PMID: 18692521.

Goeders, N.E., Cohen, A., Fox, B.S., Azar, M.R., George, O., and Koob, G.F.  Effects of the Combination of Metyrapone and Oxazepam on Intravenous Nicotine Self-Administration in Rats.  Psychopharmacology (Berl), 223(1): 17-25, 2012. PMID: 22418732.

Keller, C.M., Cornett, E.M., Guerin, G.F., and Goeders, N.E.  Combinations of Oxazepam and Metyrapone Attenuate Cocaine and Methamphetamine Cue Reactivity.  Drug and Alcohol Dependence, 133(2): 405-412, 2013. PMID: 23896309.

Goeders, N.E., Guerin, G. F., and Schmoutz, C.D.  The Combination of Metyrapone and Oxazepam for the Treatment of Cocaine and Other Drug Addictions.  Advances in Pharmacology, 69:419-479, 2014.  PMID: 24484984.

 

We had previously demonstrated that cocaine affected receptors in the central nervous system related to stress and anxiety, including benzodiazepine and CRF receptor binding. Thus, it was logical to hypothesize that environmental factors that also affected these receptors (e.g., environmental stress) might also be involved in the behavioral effects of the drug. These studies were therefore designed to explore the role for stress and the subsequent activation of the hypothalamo-pituitary-adrenal (HPA) axis in cocaine reinforcement. Although a potential role for stress and anxiety (self-medication) in drug use had been postulated from clinical research (i.e., interviews), we established that uncontrollable (but not controllable) stress increased the reinforcing efficacy of cocaine and that this effect on the etiology of cocaine reward was related to an activation of the HPA axis. Thus, we began to unravel the mechanisms mediating the ability of stress to promote the relapse to drug use.

Goeders, N.E. and Guerin, G.F.  Non-Contingent Electric Footshock Facilitates the Acquisition of Intravenous Cocaine Self-Administration in Rats.  Psychopharmacology (Berl), 114(1):63-70, 1994.  PMID: 7846208.

Goeders, N.E. and Guerin, G.F.  Role for Corticosterone in Intravenous Cocaine Self-Administration in Rats.  Neuroendocrinology, 64(5): 337-348, 1996.  PMID: 8930934.

Mantsch, J.R., Saphier, D. and Goeders, N.E.  Corticosterone Facilitates the Acquisition of Cocaine Self-Administration in Rats: Opposite Effects of the Type II Glucocorticoid Receptor Agonist Dexamethasone.  Journal of Pharmacology and Experimental Therapeutics, 287(1): 72-80, 1998.  PMID: 9765324.

Goeders, N.E.  Stress and Cocaine Addiction.  (Perspectives in Pharmacology)  Journal of Pharmacology and Experimental Therapeutics, 301(3):785-789, 2002.  PMID: 12023504.

 

Studies had reported that some of the psychological effects of cocaine use in humans, including during withdrawal, were associated with anxiety and depression.  These studies were therefore initiated to determine the effects of cocaine on benzodiazepine and CRF receptor binding. We found that cocaine altered benzodiazepine and CRF receptor binding, especially in dopamine-rich brain regions.  These data indicated that the anxiety and depression associated with cocaine use may result from the direct effects of the drug on these binding sites.  These data also led to the follow-up studies reported in the contributions to science that are described below.

Goeders, N.E. and Kuhar, M.J.  Chronic Cocaine Administration Induces Opposite Changes in Dopamine Receptors in the Striatum and Nucleus Accumbens.  Alcohol and Drug Research, 7(4):207-216, 1987.  PMID: 2950865.

Goeders, N., Bell, V., Guidroz, A. and McNulty, M.  Dopaminergic Involvement in the Cocaine-Induced Up-Regulation of Benzodiazepine Receptors in the Rat Striatum.  Brain Research, 515(1-2): 1-8, 1990.  PMID: 2162715.

Goeders, N.E., Bienvenu, O.J. and De Souza, E.B.  Chronic Cocaine Administration Alters Corticotropin-Releasing-Factor Receptors in the Rat Brain.  Brain Research, 531(1-2): 322-328, 1990.  PMID: 1963104.

Goeders, N.E.  Cocaine Differentially Affects Benzodiazepine Receptors in Discrete Regions of the Rat Brain: Persistence and Potential Mechanisms Mediating These Effects.  Journal of Pharmacology and Experimental Therapeutics, 259(2): 574-581, 1991.  PMID: 1658304.

 

While the mesolimbic dopamine system was thought to play a role in cocaine reward, little attention had been paid to the medial prefrontal cortex (MPC) in the early 1980s. These experiments were designed to determine sites in the central nervous system that would support responding leading to the intracranial injection of pmol concentrations of cocaine into various brain regions.  We demonstrated that cocaine would maintain responding when cocaine was delivered into the MPC but not into the nucleus accumbens or ventral tegmental area.  These were the first demonstrations indicating a role for the MPC in cocaine reward.

Goeders, N.E. and Smith, J.E.  Cortical Dopaminergic Involvement in Cocaine Reinforcement.  Science, 19; 221(4612):773-755, 1983, PMID: 6879176.

Goeders, N.E., Dworkin, S.I. and Smith, J.E.   Neuropharmacological Assessment of Cocaine Self-Administration into the Medial Prefrontal Cortex.  Pharmacology, Biochemistry and Behavior, 24:1429-1440, 1986.

Goeders, N.E. and Smith, J.E.  Reinforcing Properties of Cocaine in the Medial Prefrontal Cortex:  Primary Action on Presynaptic Dopaminergic Terminals.  Pharmacology, Biochemistry and Behavior, 25(1):191-199, 1986.  PMID: 3018792.

Goeders, N.E. and Smith, J.E.  Intracranial Cocaine Self-Administration into the Medial Prefrontal Cortex Increases Dopamine Turnover in the Nucleus Accumbens.  Journal of Pharmacology and Experimental Therapeutics, 265(2): 592-600, 1993.  PMID: 8496810.