a-general-method-for-evaluating-deep-brain-stimulation-effects-on

A General Method for Evaluating Deep Brain Stimulation Effects on Intravenous Methamphetamine Self-Administration

Substance use disorders, particularly to methamphetamine, are devastating, relapsing diseases that disproportionally affect young people.  There is a need ...

Louisiana State University

For several years, our laboratory has investigated the role for the HPA axis in cocaine reinforcement. Two classes of drugs that we have studied include corticosterone synthesis inhibitors (e.g., metyrapone) and benzodiazepine receptor agonists (e.g., oxazepam). In the experiments described in this manuscript, we tested the effects of various doses of metyrapone and oxazepam against several doses of self-administered cocaine. Behavioral, endocrine and pharmacokinetic measures of the effects of the combination of metyrapone and oxazepam on cocaine reward are presented. Combinations of metyrapone and oxazepam at doses that produced no observable effects when administered separately significantly reduced cocaine self-administration without affecting food-maintained responding during the same sessions. Changes in pharmacokinetics or endocrine function do not appear to mediate these effects, suggesting a central mechanism of action. Therefore, although these drugs produce their effects through distinct mechanisms, an additive effect on cocaine self-administration is obtained when these drugs are administered together, suggesting that combinations of low doses of metyrapone and oxazepam may be useful in reducing cocaine seeking with a reduced incidence of unwanted side effects and a decreased potential for abuse.

Effects of the combination of metyrapone and oxazepam on cocaine and food self-administration in rats.

We have previously reported that pretreatment with benzodiazepines reduces intravenous cocaine self-administration in rats.

Alprazolam and oxazepam block the cue-induced reinstatement of extinguished cocaine seeking in rats.

Methamphetamine (MA) increases extracellular dopamine (DA) and at chronic high doses induces toxicity as indicated by decreased expression of tyrosine hydroxylase (TH) and dopamine transporter (DAT). Notably, rats will self-administer MA in escalating quantities producing such toxicity. However, the impact of MA at sub-toxic doses on DA regulation is not well established.

Biphasic dopamine regulation in mesoaccumbens pathway in response to non-contingent binge and escalating methamphetamine regimens in the Wistar rat.

M&eacute;thamph&eacute;tamine (MA) augmente extracellulaire dopamine (DA) et &agrave; des doses &eacute;lev&eacute;es chroniques induit une toxicit&eacute;, comme en t&eacute;moigne la diminution de l&#39;expression de la tyrosine hydroxylase (TH) et le transporteur de la dopamine (DAT). Notamment, des rats seront auto-administrer MA dans l&#39;escalade des quantit&eacute;s &agrave; produire cette toxicit&eacute;. Toutefois, l&#39;impact de MA sous-toxiques doses sur DA r&egrave;glement n&#39;est pas bien &eacute;tablie.

Biphasique r&egrave;glement de dopamine dans voie mesoaccumbens en r&eacute;ponse &agrave; la fr&eacute;n&eacute;sie non conditionnelles et d&#39;accumulation des sch&eacute;mas de m&eacute;thamph&eacute;tamine chez le rat Wistar.

Methamphetamin (MA) erh&ouml;ht die extrazellul&auml;re Dopamin (DA) und bei chronisch hohe Dosen induziert Toxizit&auml;t durch verminderte Expression von Tyrosin-Hydroxylase (TH) und Dopamin-Transporter (DAT). Insbesondere werden Ratten MA Selbstverwaltung, in steigenden Mengen produzieren solche Toxizit&auml;t. Die Auswirkungen der MA bei sub-toxic Dosen auf DA Verordnung ist jedoch nicht gut etabliert.

Biphasische Dopamin Verordnung Mesoaccumbens Weg als Reaktion auf nicht abh&auml;ngiges Binge und eskalierende Methamphetamin-Therapien bei Wistar-Ratten.

Metanfetamine (MA) aumenta la dopamina extracellulare (DA) e a dosi elevate croniche induce tossicit&agrave; come indicato dalla diminuita espressione di tirosina idrossilasi (TH) e trasportatore della dopamina (DAT). Auto-in particolare, ratti saranno somministrarsi MA di crescenti quantitativi di produzione di tali tossicit&agrave;. Tuttavia, l&#39;impatto di MA a dinamizzazione dosi DA regolamento non &egrave; ben consolidata.

Bifasico regolamento dopamina nel percorso mesoaccumbens in risposta a binge non contingente e regimi di metanfetamina nel ratto Wistar di escalation.

&#x7532;&#x57FA;&#x82EF;&#x4E19;&#x80FA; (MA) &#x589E;&#x52A0;&#x80DE;&#x5916;&#x591A;&#x5DF4;&#x80FA; (DA) &#x548C;&#x6162;&#x6027;&#x9AD8;&#x5242;&#x91CF;&#x8BF1;&#x4F7F;&#x6BD2;&#x6027;&#x964D;&#x4F4E;&#x8868;&#x8FBE;&#x7684;&#x916A;&#x6C28;&#x9178;&#x7F9F;&#x5316;&#x9176; (TH) &#x548C;&#x591A;&#x5DF4;&#x80FA;&#x8F6C;&#x8FD0;&#x86CB;&#x767D; (DAT) &#x6240;&#x793A;&#x3002;&#x503C;&#x5F97;&#x6CE8;&#x610F;&#x7684;&#x662F;&#xFF0C;&#x5927;&#x9F20;&#x4F1A;&#x4E0D;&#x65AD;&#x5347;&#x7EA7;&#xFF0C;&#x6279;&#x91CF;&#x751F;&#x4EA7;&#x8FD9;&#x79CD;&#x6BD2;&#x6027;&#x81EA;&#x6211;&#x9A6C;&#x3002;&#x7136;&#x800C;&#xFF0C;&#x9A6C; sub-toxic DA &#x8C03;&#x8282;&#x5242;&#x91CF;&#x7684;&#x5F71;&#x54CD;&#x4E0D;&#x662F;&#x884C;&#x4E4B;&#x6709;&#x6548;&#x7684;&#x3002;

&#x53CC; &#x76F8; &#x591A; &#x5DF4;&#x80FA; &#x8C03;&#x63A7; mesoaccumbens &#x901A;&#x8DEF; &#x5728; &#x56DE;&#x5E94; &#x975E; &#x7279; &#x9063; &#x961F; &#x72C2;&#x6F6E; &#x548C; &#x4E0D;&#x65AD; &#x5347;&#x7EA7; &#x7684; &#x7532;&#x57FA; &#x5B89;&#x975E; &#x4ED6; &#x660E; &#x5728; &#x5927;&#x9F20; &#x7684; &#x6CBB;&#x7597; &#x65B9;&#x6848; &#x3002;

&#x30E1;&#x30BF;&#x30F3;&#x30D5;&#x30A7;&#x30BF;&#x30DF;&#x30F3; (MA) &#x306F;&#x3001;&#x7D30;&#x80DE;&#x5916;&#x30C9;&#x30D1;&#x30DF;&#x30F3; (DA) &#x3092;&#x5897;&#x52A0;&#x3057;&#x3001;&#x6162;&#x6027;&#x306E;&#x9AD8;&#x7528;&#x91CF;&#x3067;&#x30C1;&#x30ED;&#x30B7;&#x30F3;&#x6C34;&#x9178;&#x5316;&#x9175;&#x7D20; (TH) &#x3068;&#x30C9;&#x30FC;&#x30D1;&#x30DF;&#x30F3; &#x30C8;&#x30E9;&#x30F3;&#x30B9;&#x30DD;&#x30FC;&#x30BF;&#x30FC; (DAT) &#x306E;&#x6E1B;&#x5C11;&#x306E;&#x5F0F;&#x306B;&#x3088;&#x3063;&#x3066;&#x793A;&#x3055;&#x308C;&#x308B;&#x6BD2;&#x6027;&#x3092;&#x8A98;&#x5C0E;&#x3057;&#x307E;&#x3059;&#x3002;&#x7279;&#x306B;&#x3001;&#x30E9;&#x30C3;&#x30C8;&#x306F;&#x305D;&#x306E;&#x3088;&#x3046;&#x306A;&#x6BD2;&#x6027;&#x306E;&#x751F;&#x7523;&#x91CF;&#x3092;&#x30A8;&#x30B9;&#x30AB;&#x30EC;&#x30FC;&#x30C8;&#x3067; MA &#x81EA;&#x5DF1;&#x7BA1;&#x7406;&#x3055;&#x308C;&#x307E;&#x3059;&#x3002;&#x3057;&#x304B;&#x3057;&#x3001;MA &#x306E;&#x5F71;&#x97FF; DA &#x898F;&#x5236;&#x4E0A;&#x306E;&#x4F4E;&#x7528;&#x91CF;&#x3067;&#x306F;&#x3088;&#x304F;&#x78BA;&#x7ACB;&#x3055;&#x308C;&#x305F;&#x3067;&#x306F;&#x3042;&#x308A;&#x307E;&#x305B;&#x3093;&#x3002;

&#x975E;&#x968F;&#x4F34;&#x3069;&#x3093;&#x3061;&#x3083;&#x3093;&#x9A12;&#x304E;&#x3068; Wistar &#x30E9;&#x30C3;&#x30C8;&#x306E;&#x30E1;&#x30BF;&#x30F3;&#x30D5;&#x30A7;&#x30BF;&#x30DF;&#x30F3;&#x306E;&#x30EC;&#x30B8;&#x30E1;&#x30F3;&#x3092;&#x30A8;&#x30B9;&#x30AB;&#x30EC;&#x30FC;&#x30C8;&#x306E;&#x5FDC;&#x7B54;&#x306B;&#x304A;&#x3051;&#x308B; mesoaccumbens &#x7D4C;&#x8DEF;&#x306B;&#x304A;&#x3051;&#x308B;&#x4E8C;&#x76F8;&#x6027;&#x30C9;&#x30FC;&#x30D1;&#x30DF;&#x30F3;&#x898F;&#x5236;&#x3002;

&#xBA54; &#xB2F4; &#xD398;&#xD0C0; &#xBBFC; (MA) &#xC138;&#xD3EC; &#xC678; &#xB3C4;&#xD30C;&#xBBFC; (DA) &#xC99D;&#xAC00; &#xD558; &#xACE0; &#xB9CC;&#xC131; &#xB192;&#xC740; &#xBCF5;&#xC6A9;&#xB7C9;&#xC5D0;&#xC11C; &#xB3C5;&#xC131; &#xD2F0;&#xB85C;&#xC2E0; hydroxylase (TH) &#xBC0F; &#xB3C4;&#xD30C;&#xBBFC; &#xC804;&#xC1A1; (DAT)&#xC758; &#xAC10;&#xC18C; &#xC2DD;&#xC5D0; &#xC758;&#xD574; &#xD45C;&#xC2DC; &#xB41C; &#xB300;&#xB85C; &#xC720;&#xB3C4; &#xD55C;&#xB2E4;. &#xD2B9;&#xD788;, &#xC950; &#xAC19;&#xC740; &#xB3C5;&#xC131;&#xC744; &#xC0DD;&#xC0B0; &#xD558;&#xB294; &#xC218;&#xB7C9;&#xC744; &#xACE0;&#xC870;&#xC5D0; MA &#xBCF5;&#xC6A9;&#xD560; &#xAC83;&#xC785;&#xB2C8;&#xB2E4;. &#xADF8;&#xB7EC;&#xB098;, &#xB2E4; &#xB808; &#xADE4; &#xB808;&#xC774; &#xC158;&#xC5D0; sub-toxic &#xBCF5;&#xC6A9; &#xC2DC; &#xC5C4;&#xB9C8;&#xC758; &#xC601;&#xD5A5; &#xC798; &#xC124;&#xB9BD; &#xB418;&#xC9C0; &#xC54A;&#xC2B5;&#xB2C8;&#xB2E4;.

&#xD30C;&#xACAC;&#xC774; &#xC544;&#xB2CC; &#xC0C1; &#xC2B5; &#xACE0; &#xBA54; &#xB2F4; &#xD398;&#xD0C0; &#xBBFC; regimens Wistar rat&#xC5D0; &#xACE0;&#xC870;&#xC5D0; &#xB300; &#xD55C; &#xC751;&#xB2F5; mesoaccumbens &#xD1B5;&#xB85C;&#xC5D0;&#xC11C; &#xB098;&#xC544;&#xC84C;&#xB2E4; &#xB3C4;&#xD30C;&#xBBFC; &#xADDC;&#xC81C;.

Metanfetamina (MA) aumenta la dopamina extracelular (DA) y en altas dosis cr&oacute;nica induce toxicidad seg&uacute;n lo indicado por la expresi&oacute;n disminuida de la tirosina hidroxilasa (TH) y el transportador de dopamina (DAT). En particular, las ratas autoadministrarse MA en crecientes cantidades de producci&oacute;n de dicha toxicidad. Sin embargo, el impacto de MA en dosis sub-t&oacute;xicos en DA regulaci&oacute;n no es reconocido.

Reglamento de dopamina bif&aacute;sica en camino de mesoaccumbens en respuesta a la borrachera no contingentes y reg&iacute;menes de metanfetamina en la rata Wistar en aumento.

We have previously reported that combining low doses of oxazepam and metyrapone (OX/MET) reduces intravenous cocaine self-administration without affecting stress-hormone levels. We hypothesized that the combination of OX/MET would also inhibit the reinstatement of cocaine or methamphetamine seeking induced by the presentation of a conditioned reinforcer and that stress hormone levels would not be influenced by this treatment.

Combinations of oxazepam and metyrapone attenuate cocaine and methamphetamine cue reactivity.

Although scientists have been investigating the neurobiology of psychomotor stimulant reward for many decades, there is still no FDA-approved treatment for cocaine or methamphetamine abuse. Research in our laboratory has focused on the relationship between stress, the subsequent activation of the hypothalamic-pituitary-adrenal (HPA) axis, and psychomotor stimulant reinforcement for almost 30 years. This research has led to the development of a combination of low doses of the cortisol synthesis inhibitor, metyrapone, and the benzodiazepine, oxazepam, as a potential pharmacological treatment for cocaine and other substance use disorders. In fact, we have conducted a pilot clinical trial that demonstrated that this combination can reduce cocaine craving and cocaine use. Our initial hypothesis underlying this effect was that the combination of metyrapone and oxazepam reduced cocaine seeking and taking by decreasing activity within the HPA axis. Even so, doses of the metyrapone and oxazepam combination that consistently reduced cocaine taking and seeking did not reliably alter plasma corticosterone (or cortisol in the pilot clinical trial). Furthermore, subsequent research has demonstrated that this drug combination is effective in adrenalectomized rats, suggesting that these effects must be mediated above the level of the adrenal gland. Our evolving hypothesis is that the combination of metyrapone and oxazepam produces its effects by increasing the levels of neuroactive steroids, most notably tetrahydrodeoxycorticosterone, in the medial prefrontal cortex and amygdala. Additional research will be necessary to confirm this hypothesis and may lead to the development of improved and specific pharmacotherapies for the treatment of psychomotor stimulant use.

The combination of metyrapone and oxazepam for the treatment of cocaine and other drug addictions.

Investigation of the role of stress in cocaine addiction has yielded an efficacious combination of metyrapone and oxazepam, hypothesized to decrease relapse to cocaine use by reducing stress-induced craving. However, recent data suggest an extra-adrenal role for metyrapone in mediating stress- and addiction-related behaviors. The interactions between the physiological stress response and cocaine self-administration were characterized in rodents utilizing surgical adrenalectomy and pharmacological treatment. Male Wistar rats were trained to self-administer cocaine (0.25mg/kg/infusion) and food pellets under a concurrent alternating fixed-ratio schedule of reinforcement. Surgical removal of the adrenal glands resulted in a significant decrease in plasma corticosterone and a consequent increase in ACTH, as expected. However, adrenalectomy did not significantly affect ongoing cocaine self-administration. Pretreatment with metyrapone, oxazepam and their combinations in intact rats resulted in a significant decrease in cocaine-reinforced responses. These same pharmacological treatments were still effective in reducing cocaine- and food-reinforced responding in adrenalectomized rats. The results of these experiments demonstrate that adrenally-derived steroids are not necessary to maintain cocaine-reinforced responding in cocaine-experienced rats. These results also demonstrate that metyrapone may produce effects outside of the adrenal gland, presumably in the central nervous system, to affect cocaine-related behaviors.

The extra-adrenal effects of metyrapone and oxazepam on ongoing cocaine self-administration.

Previous research has demonstrated a complicated role for stress and HPA axis activation in potentiating various cocaine-related behaviors in preclinical models of drug dependence. However, the investigation of several antiglucocorticoid therapies has yielded equivocal results in reducing cocaine-related behaviors, possibly because of varying mechanisms of actions. Specifically, research suggests that metyrapone (a corticosterone synthesis inhibitor) may reduce cocaine self-administration in rats via a nongenomic, extra-adrenal mechanism without altering plasma corticosterone. In the current experiments, male rats were trained to self-administer cocaine infusions and food pellets in a multiple, alternating schedule of reinforcement. Metyrapone pretreatment dose-dependently decreased cocaine self-administration as demonstrated previously. Pharmacological inhibition of neurosteroid production by finasteride had significant effects on cocaine self-administration, regardless of metyrapone pretreatment. However, metyrapone's effects on cocaine self-administration were significantly attenuated with bicuculline pretreatment, suggesting a role for GABA-active neurosteroids in cocaine-reinforced behaviors. In vitro binding data also confirmed that metyrapone does not selectively bind to GABA-related proteins. The results of these experiments support the hypothesis that metyrapone may increase neurosteroidogenesis to produce effects on cocaine-related behaviors.

Role of GABA-active neurosteroids in the efficacy of metyrapone against cocaine addiction.

In rodents, the behavioral and neurochemical effects resulting from the pharmacological blockade of the hypothalamo-pituitary-adrenal (HPA) axis are unclear. Metyrapone, a corticosterone synthesis inhibitor, has been demonstrated to reduce cocaine-related behaviors, especially in a low-dose combination with oxazepam, a benzodiazepine. Although this combination therapy (MET/OX) also reduces drug-taking and drug-seeking behaviors in both rodents and cocaine-dependent humans, these effects are not correlated with plasma glucocorticoid levels. In this brief report, we present data demonstrating that this MET/OX combination enhances brain levels of the GABA-active steroid metabolites, tetrahydrodeoxycorticosterone (THDOC) and allopregnanolone. Male rats, trained to self-administer cocaine or that received yoked-saline infusions, were pretreated with MET/OX, at doses that reduced cocaine-motivated responding, or vehicle. Allopregnanolone and THDOC were measured using liquid chromatography-mass spectroscopy (LC-MS/MS) in the prefrontal cortex and amygdala in the brains from these rats. THDOC levels were enhanced following MET/OX pretreatment in both brain regions, regardless of cocaine self-administration experience. However, allopregnanolone was selectively enhanced in the rats that self-administered cocaine, but not in rats in the yoked-saline group. Thus, the MET/OX combination increased neurosteroid content in brain regions important for drug addiction. These neurosteroids have been shown to reduce cocaine-related behaviors and may contribute to the behavioral effects of MET/OX combination therapy.

A therapeutic combination of metyrapone and oxazepam increases brain levels of GABA-active neurosteroids and decreases cocaine self-administration in male rats.

Article	Year
Effects of the combination of metyrapone and oxazepam on cocaine and food self-administration in rats. Pharmacology, biochemistry, and behavior\| PubMed ID: 18692521	2008
Alprazolam and oxazepam block the cue-induced reinstatement of extinguished cocaine seeking in rats. Psychopharmacology\| PubMed ID: 18797849	2009
Biphasic dopamine regulation in mesoaccumbens pathway in response to non-contingent binge and escalating methamphetamine regimens in the Wistar rat. Psychopharmacology\| PubMed ID: 21523347	2011
Combinations of oxazepam and metyrapone attenuate cocaine and methamphetamine cue reactivity. Drug and alcohol dependence\| PubMed ID: 23896309	2013
The combination of metyrapone and oxazepam for the treatment of cocaine and other drug addictions. Advances in pharmacology (San Diego, Calif.)\| PubMed ID: 24484984	2014
The extra-adrenal effects of metyrapone and oxazepam on ongoing cocaine self-administration. Brain research\| PubMed ID: 24887642	2014
Role of GABA-active neurosteroids in the efficacy of metyrapone against cocaine addiction. Behavioural brain research\| PubMed ID: 24959859	2014
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\| PubMed ID: 26003946	2015

Glenn F. Guerin

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