Brandon S. Bentzley

Economic demand predicts addiction-like behavior and therapeutic efficacy of oxytocin in the rat

Significance Cocaine addiction is a major public health problem with no current pharmacotherapy approved by the US Food and Drug Administration. To accelerate discovery of treatments, we developed an animal model based on economics. Economics allows mathematical alignment of animal and human behavior, permitting more confident predictions of efficacy in addicts. Although economic models are strongly associated with addiction severity in humans, they have not yet been shown to be a marker of addiction in rats. In this report, we confirm that economic demand is strongly associated with addiction-like behavior in rats, and can predict the efficacy of a promising addiction therapy. Our findings indicate that this economic approach can be used to accelerate the development of novel addiction therapies. Development of new treatments for drug addiction will depend on high-throughput screening in animal models. However, an addiction biomarker fit for rapid testing, and useful in both humans and animals, is not currently available. Economic models are promising candidates. They offer a structured quantitative approach to modeling behavior that is mathematically identical across species, and accruing evidence indicates economic-based descriptors of human behavior may be particularly useful biomarkers of addiction severity. However, economic demand has not yet been established as a biomarker of addiction-like behavior in animals, an essential final step in linking animal and human studies of addiction through economic models. We recently developed a mathematical approach for rapidly modeling economic demand in rats trained to self-administer cocaine. We show here that economic demand, as both a spontaneous trait and induced state, predicts addiction-like behavior, including relapse propensity, drug seeking in abstinence, and compulsive (punished) drug taking. These findings confirm economic demand as a biomarker of addiction-like behavior in rats. They also support the view that excessive motivation plays an important role in addiction while extending the idea that drug dependence represents a shift from initially recreational to compulsive drug use. Finally, we found that economic demand for cocaine predicted the efficacy of a promising pharmacotherapy (oxytocin) in attenuating cocaine-seeking behaviors across individuals, demonstrating that economic measures may be used to rapidly identify the clinical utility of prospective addiction treatments.

The behavioral economics of drug self-administration: A review and new analytical approach for within-session procedures

RationaleBehavioral–economic demand curve analysis offers several useful measures of drug self-administration. Although generation of demand curves previously required multiple days, recent within-session procedures allow curve construction from a single 110-min cocaine self-administration session, making behavioral–economic analyses available to a broad range of self-administration experiments. However, a mathematical approach of curve fitting has not been reported for the within-session threshold procedure.ObjectivesWe review demand curve analysis in drug self-administration experiments and provide a quantitative method for fitting curves to single-session data that incorporates relative stability of brain drug concentration.MethodsSprague–Dawley rats were trained to self-administer cocaine, and then tested with the threshold procedure in which the cocaine dose was sequentially decreased on a fixed ratio-1 schedule. Price points (responses/mg cocaine) outside of relatively stable brain cocaine concentrations were removed before curves were fit. Curve-fit accuracy was determined by the degree of correlation between graphical and calculated parameters for cocaine consumption at low price (Q0) and the price at which maximal responding occurred (Pmax).ResultsRemoving price points that occurred at relatively unstable brain cocaine concentrations generated precise estimates of Q0 and resulted in Pmax values with significantly closer agreement with graphical Pmax than conventional methods.ConclusionThe exponential demand equation can be fit to single-session data using the threshold procedure for cocaine self-administration. Removing data points that occur during relatively unstable brain cocaine concentrations resulted in more accurate estimates of demand curve slope than graphical methods, permitting a more comprehensive analysis of drug self-administration via a behavioral–economic framework.

Orexin-1 receptor signaling increases motivation for cocaine-associated cues.

The orexin/hypocretin system is involved in multiple cocaine addiction processes that involve drug‐associated environmental cues, including cue‐induced reinstatement of extinguished cocaine seeking and expression of conditioned place preference. However, the orexin system does not play a role in several behaviors that are less cue‐dependent, such as cocaine‐primed reinstatement of extinguished cocaine seeking and low‐effort cocaine self‐administration. We hypothesized that cocaine‐associated cues, but not cocaine alone, engage signaling at orexin‐1 receptors (OX1Rs), and this cue‐engaged OX1R signaling increases motivation for cocaine. Motivation for cocaine was measured in Sprague–Dawley rats with behavioral‐economic demand curve analysis after pretreatment with the OX1R antagonist SB‐334867 (SB) or vehicle with and without light + tone cues. Demand for cocaine was higher when cocaine‐associated cues were present, and SB only reduced cocaine demand in the presence of these cues. We then investigated whether cocaine demand was linked to the cued reinstatement of cocaine seeking, as both procedures are partially driven by cocaine‐associated cues in an orexin‐dependent manner. SB blocked cue‐induced reinstatement behavior, and baseline demand predicted SB efficacy with the largest effect in high‐demand animals, i.e. animals with the greatest cue‐dependent behavior. We conclude that OX1R signaling increases the reinforcing efficacy of cocaine‐associated cues but not that of cocaine alone. This supports our view that orexin plays a prominent role in the ability of conditioned cues to activate motivational responses.

Oxytocin Acts in Nucleus Accumbens to Attenuate Methamphetamine Seeking and Demand

BACKGROUND Evidence indicates that oxytocin, an endogenous peptide well known for its role in social behaviors, childbirth, and lactation, is a promising addiction pharmacotherapy. We employed a within-session behavioral-economic (BE) procedure in rats to examine oxytocin as a pharmacotherapy for methamphetamine (meth) addiction. The BE paradigm was modeled after BE procedures used to assess motivation for drugs in humans with addiction. The same BE variables assessed across species have been shown to predict later relapse behavior. Thus, the translational potential of preclinical BE studies is particularly strong. METHODS We tested the effects of systemic and microinfused oxytocin on demand for self-administered intravenous meth and reinstatement of extinguished meth seeking in male and female rats using a BE paradigm. Correlations between meth demand and meth seeking were assessed. RESULTS Female rats showed greater demand (i.e., motivation) for meth compared with male rats. In both male and female rats, meth demand predicted reinstatement of meth seeking, and systemic oxytocin decreased demand for meth and attenuated reinstatement to meth seeking. Oxytocin was most effective at decreasing meth demand and seeking in rats with the strongest motivation for drug. Finally, these effects of systemic oxytocin were mediated by actions in the nucleus accumbens. CONCLUSIONS Oxytocin decreases meth demand and seeking in both sexes, and these effects depend on oxytocin signaling in the nucleus accumbens. Overall, these data indicate that development of oxytocin-based therapies may be a promising treatment approach for meth addiction in humans.

Individual differences in orexin-I receptor modulation of motivation for the opioid remifentanil

Orexin‐1 receptors (Ox1Rs) have been implicated in the motivation for drugs of abuse. Here, we utilized a within‐session behavioral‐economics threshold procedure to screen for individual differences in economic demand for the ultra‐short‐acting opioid remifentanil and to test whether antagonism of Ox1Rs reduces remifentanil demand. The behavioral‐economics procedure revealed robust individual differences in free consumption of remifentanil (Q0 parameter; hedonic set point). Rats with low baseline Q0 (low takers) displayed high demand elasticity (α parameter; reduced responding as drug price increased indicating low motivation for drug), whereas subjects with a higher Q0 (high takers) exhibit low demand elasticity (low α) by continuing to self‐administer remifentanil despite increased cost (reflecting higher motivation for drug). In a punished responding paradigm utilizing footshock, subjects that were classified as high takers at baseline withstood twice as much shock as low takers to continue self‐administering remifentanil. Interestingly, Ox1R antagonism with SB‐334867 reduced Q0 and increased α in low takers but not in high takers. Similarly, the Ox1R antagonist attenuated cue‐induced, but not drug‐induced, reinstatement of remifentanil seeking in low takers but had no significant effect on reinstatement of drug seeking in high takers. Together, these data reveal a novel role of orexins in demand for remifentanil: Ox1Rs modulate demand in low takers but not in individuals that exhibit addictive‐like behaviors (high takers). Finally, the behavioral assays in this study can serve as a novel laboratory model for studying individual differences in opioid use disorders.

Influencing circadian and sleep-wake regulation for prevention and intervention in mood and anxiety disorders: what makes a good homeostat?

All living organisms depend on homeostasis, the complex set of interacting metabolic chemical reactions for maintaining life and well‐being. This is no less true for psychiatric well‐being than for physical well‐being. Indeed, a focus on homeostasis forces us to see how inextricably linked mental and physical well‐being are. This paper focuses on these linkages. In particular, it addresses the ways in which understanding of disturbed homeostasis may aid in creating classes of patients with mood and anxiety disorders based on such phenotypes. At the cellular level, we may be able to compensate for the inability to study living brain tissue through the study of homeostatic mechanisms in fibroblasts, pluripotent human cells, and mitochondria and determine how homeostasis is disturbed at the level of these peripheral tissues through exogenous stress. We also emphasize the remarkable opportunities for enhancing knowledge in this area that are offered by advances in technology. The study of human behavior, especially when combined with our greatly improved capacity to study unique but isolated populations, offers particularly clear windows into the relationships among genetic, environmental, and behavioral contributions to homeostasis.

Unilateral ultra-brief pulse electroconvulsive therapy for depression in Parkinson's disease

Electroconvulsive therapy (ECT) has demonstrated efficacy in treating core symptoms of Parkinsons disease (PD); however, widespread use of ECT in PD has been limited due to concern over cognitive burden. We investigated the use of a newer ECT technology known to have fewer cognitive side effects (right unilateral [RUL] ultra‐brief pulse [UBP]) for the treatment of medically refractory psychiatric dysfunction in PD.

Inhibiting subthalamic nucleus decreases cocaine demand and relapse: therapeutic potential.

Preclinical evidence indicates that inactivation of subthalamic nucleus (STN) may be effective for treating cocaine addiction, and therapies that target STN, e.g. deep brain stimulation, are available indicating that this may have clinical promise. Here, we assessed the therapeutic potential of STN inactivation using a translationally relevant economic approach that quantitatively describes drug‐taking behavior, and tested these results with drug‐seeking tasks. Economic demand for cocaine was assessed in rats (n = 11) using a within‐session threshold procedure in which cocaine price (responses/mg cocaine) was sequentially increased throughout the session. Cocaine demand was assessed in this manner immediately after bilateral microinfusions into STN of either vehicle (artificial cerebrospinal fluid) or the GABAA receptor agonist muscimol. A separate group of animals (n = 8) was tested for changes in cocaine seeking either during extinction or in response to cocaine‐associated cues. Muscimol‐induced inhibition of STN significantly attenuated cocaine consumption at high prices, drug seeking during extinction and cued reinstatement of cocaine seeking. In contrast, STN inhibition did not reduce cocaine consumption at low prices or locomotor activity. Thus, STN inactivation reduced economic demand for cocaine and multiple measures of drug seeking during extinction. In view of the association between economic demand and addiction severity in both rat and human, these results indicate that STN inactivation has substantial clinical potential for treatment of cocaine addiction.

Chemogenetic Manipulations of Ventral Tegmental Area Dopamine Neurons Reveal Multifaceted Roles in Cocaine Abuse

Ventral tegmental area (VTA) dopamine (DA) neurons perform diverse functions in motivation and cognition, but their precise roles in addiction-related behaviors are still debated. Here, we targeted VTA DA neurons for bidirectional chemogenetic modulation during specific tests of cocaine reinforcement, demand, and relapse-related behaviors, querying the roles of DA neuron inhibitory and excitatory G-protein signaling in these processes. Designer receptor stimulation of Gq-, but not Gs-signaling in DA neurons enhanced cocaine seeking via functionally distinct projections to forebrain limbic regions. In contrast, engaging inhibitory Gi/o signaling in DA neurons blunted cocaine’s reinforcing and priming effects, reduced stress-potentiated reinstatement, and altered cue-induced cocaine seeking strategy, but not the motivational impact of cocaine cues per se. Results demonstrate that DA neurons play several distinct roles in cocaine seeking, depending on behavioral context, G-protein signaling, and DA neuron efferent target, highlighting their multifaceted roles in addiction. Significance Statement G-protein coupled receptors are crucial modulators of VTA dopamine neuron activity, but how metabotropic signaling impacts dopamine’s complex roles in reward and addiction is poorly understood. Here, we bidirectionally modulate dopamine neuron G-protein signaling with DREADDs during a variety of cocaine seeking behaviors, revealing nuanced, pathway-specific roles in cocaine reward, effortful seeking, and relapse-like behaviors. Gq- and Gs-stimulation activated dopamine neurons, but only Gq stimulation robustly enhanced cocaine seeking. Gi/o inhibitory signaling altered the response strategy employed during cued reinstatement, and reduced some, but not all types of cocaine seeking. Results show that VTA dopamine neurons modulate numerous distinct aspects of cocaine addiction- and relapse-related behaviors, and indicate potential new approaches for intervening in these processes to treat addiction.

Optimization of epidural cortical stimulation for treatment-resistant depression

Major depressive disorder is debilitating and prevalent. Approximately 30% of patients do not respond to four antidepressant medications [1], and up to half of medication-resistant patients do not respond to electroconvulsive therapy (ECT) [2]. Epidural prefrontal cortical stimulation (EpCS), with electrodes implanted superficially to dura mater, has shown promise as a potential treatment for TRD [3,4] with early work informing the development of improved lead placement and programming methods [5,6]. However, investigations of brain stimulation for treatment of TRD have been marked by difficulty in establishing a systematic method of determining stimulation parameters [7], and the optimization of future attempts depends on an improved understanding of the causes for treatment failures. In a prior article in Brain Stimulationwe reported that in an open-label clinical trial 3 of 5 patients with TRD treated with bilateral EpCSof thedorsolateral prefrontal cortex (DLPFC) and frontopolar cortex (FPC) had sustained remission from TRD at 5-year followup [3,8]. This reportdetails a patientwho failed to remit at the5-year follow-up, but later achieved sustained remission after the electrical current of the device was raised to a sufficient level.