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Obesity is a global epidemic that contributes to a number of health complications including cardiovascular disease, type 2 diabetes, cancer and neuropsychiatric disorders. Pharmacotherapeutic strategies to treat obesity are urgently needed. Research over the past two decades has increased substantially our knowledge of central and peripheral mechanisms underlying homeostatic energy balance. Homeostatic mechanisms involve multiple components including neuronal circuits, some originating in hypothalamus and brain stem, as well as peripherally-derived satiety, hunger and adiposity signals that modulate neural activity and regulate eating behavior. Dysregulation of one or more of these homeostatic components results in obesity. Coincident with obesity, reward mechanisms that regulate hedonic aspects of food intake override the homeostatic regulation of eating. In addition to functional interactions between homeostatic and reward systems in the regulation of food intake, homeostatic signals have the ability to alter vulnerability to drug abuse. Regarding the treatment of obesity, pharmacological monotherapies primarily focus on a single protein target. FDA-approved monotherapy options include phentermine (Adipex-P®), orlistat (Xenical®), lorcaserin (Belviq®) and liraglutide (Saxenda®). However, monotherapies have limited efficacy, in part due to the recruitment of alternate and counter-regulatory pathways. Consequently, a multi-target approach may provide greater benefit. Recently, two combination products have been approved by the FDA to treat obesity, including phentermine/topiramate (Qsymia®) and naltrexone/bupropion (Contrave®). The current review provides an overview of homeostatic and reward mechanisms that regulate energy balance, potential therapeutic targets for obesity and current treatment options, including some candidate therapeutics in clinical development. Finally, challenges in anti-obesity drug development are discussed. [ABSTRACT FROM AUTHOR]

Past research with the spontaneously hypertensive rat (SHR) model of attention deficit/hyperactivity disorder showed that adolescent methylphenidate treatment enhanced cocaine abuse risk in SHR during adulthood. The acquisition of cocaine self-administration was faster, and cocaine dose–response functions were shifted upward under fixed-ratio and progressive ratio schedules compared to adult SHR that received adolescent vehicle treatment or to control strains that received adolescent methylphenidate treatment. The current study determined if extending treatment beyond adolescence would ameliorate long-term consequences of adolescent methylphenidate treatment on cocaine abuse risk in adult SHR. Treatments (vehicle or 1.5 mg/kg/day oral methylphenidate) began on postnatal day 28. Groups of male SHR were treated with vehicle during adolescence and adulthood, with methylphenidate during adolescence and vehicle during adulthood, or with methylphenidate during adolescence and adulthood. The group receiving adolescent-only methylphenidate was switched to vehicle on P56. Cocaine self-administration began on postnatal day 77, and groups receiving methylphenidate during adolescence and adulthood were treated either 1-h before or 1-h after daily sessions. At baseline under a fixed-ratio 1 schedule, cocaine self-administration (2 h sessions; 0.3 mg/kg unit dose) did not differ among the four treatment groups. Under a progressive ratio schedule (4.5 h maximum session length; 0.01–1.0 mg/kg unit doses), breakpoints for self-administered cocaine in SHR receiving the adult methylphenidate treatment 1-h pre-session were not different from the vehicle control group. However, compared to the vehicle control group, breakpoints for self-administered cocaine at the 0.3 and 1.0 mg/kg unit doses were greater in adult SHR that received adolescent-only methylphenidate or received methylphenidate that was continued into adulthood and administered 1-h post-session. These findings suggest that extending methylphenidate treatment beyond adolescence does not ameliorate explicitly the long-term consequences of adolescent methylphenidate treatment. Pre-session methylphenidate may mask temporarily the detection of an increase in cocaine self-administration following chronic methylphenidate treatment. [ABSTRACT FROM AUTHOR]

Abstract: Tobacco dependence is the most preventable cause of death and is a chronic, relapsing disorder in which compulsive tobacco use persists despite known negative health consequences. All currently available cessation agents (nicotine, varenicline and bupropion) have limited efficacy and are associated with high relapse rates, revealing a need for more efficacious, alternative pharmacotherapies. The major alkaloid in tobacco, nicotine, activates nicotinic receptors (nAChRs) which increase brain extracellular dopamine producing nicotine reward leading to addiction. nAChRs are located primarily presynaptically and modulate synaptic activity by regulating neurotransmitter release. Subtype-selective nAChR antagonists that block reward-relevant mesocorticolimbic and nigrostriatal dopamine release induced by nicotine may offer advantages over current therapies. An innovative approach is to provide pharmacotherapies which are antagonists at nAChR subtypes mediating nicotine evoked dopamine release. In addition, providing multiple medications with a wider array of targets and mechanisms should provide more treatment options for individuals who are not responsive to the currently available pharmacotherapies. This review summarizes the currently available smoking cessation therapies and discusses emerging potential therapeutic approaches employing pharmacological agents which act as antagonists at nicotinic receptors. [Copyright &y& Elsevier]

Abstract: A series of lobelane homologues has been synthesized and evaluated for their [3H]DTBZ binding affinity at the vesicular monoamine transporter-2 (VMAT2). The structure–activity relationships (SAR) indicate that for retention of binding affinity at VMAT2, the lengths of the methylene linkers should be no shorter than one methylene unit at C-6 of the piperidine ring, and no shorter than two methylene units at C-2 of the piperidine ring. These results indicate that the intramolecular distances between the piperidine ring and two phenyl rings in lobelane analogues are an important criterion for retention of high affinity at VMAT2. [Copyright &y& Elsevier]

Abstract: A general entry into symmetrical 1,5-disubstituted granatanines that involves an alkylative ring-closure on a 2,6-bis enolate piperidine intermediate is described. [Copyright &y& Elsevier]

Abstract: Heterologous expression systems have increased the feasibility of developing selective ligands to target nicotinic acetylcholine receptor (nAChR) subtypes. However, the α6 subunit, a component in nAChRs that mediates some of the reinforcing effects of nicotine, is not easily expressed in systems such as the Xenopus oocyte. Certain aspects of α6-containing receptor pharmacology have been studied by using chimeric subunits containing the α6 ligand-binding domain. However, these chimeras would not be sensitive to an α6-selective channel blocker; therefore we developed an α6 chimera (α4/6) that has the transmembrane and intracellular domains of α6 and the extracellular domain of α4. We examined the pharmacological properties of α4/6-containing receptors and other important nAChR subtypes, including α7, α4β2, α4β4, α3β4, α3β2, and α3β2β3, as well as receptors containing α6/3 and α6/4 chimeras. Our data show that the absence or presence of the β4 subunit is an important factor for sensitivity to the ganglionic blocker mecamylamine, and that dihydro-β-erythroidine is most effective on subtypes containing the α4 subunit extracellular domain. Receptors containing the α6/4 subunit are sensitive to α-conotoxin PIA, while receptors containing the reciprocal α4/6 chimera are insensitive. In experiments with novel antagonists of nicotine-evoked dopamine release, the α4/6 chimera indicated that structural rigidity was a key element of compounds that could result in selectivity for noncompetitive inhibition of α6-containing receptors. Our data extend the information available on prototypical nAChR antagonists, and establish the α4/6 chimera as a useful new tool for screening drugs as selective nAChR antagonists. [Copyright &y& Elsevier]

Abstract: Limitations in efficacy and high relapse rates of currently available smoking cessation agents reveal the need for more efficacious pharmacotherapies. One strategy is to develop subtype-selective nicotinic receptor (nAChR) antagonists that inhibit nicotine-evoked dopamine (DA) release, the primary neurotransmitter involved in nicotine reward. Simple alkylation of the pyridino N-atom converts nicotine from a potent agonist into a potent antagonist. The classical antagonists, hexamethonium and decamethonium, differentiate between peripheral nAChR subtypes. Using a similar approach, we interconnected varying quaternary ammonium moieties with a lipophilic linker to provide N,N′-bis-nicotinium analogs, affording a lead compound, N,N′-dodecyl-1,12-diyl-bis-3-picolinium dibromide (bPiDDB), which inhibited nicotine-evoked DA release and decreased nicotine self-administration. The current work describes a novel compound, 1-(3-picolinium)-12-triethylammonium-dodecane dibromide (TMPD), a hybrid of bPiDDB and decamethonium. TMPD completely inhibited (IC50 =500nM) nicotine-evoked DA release from superfused rat striatal slices, suggesting that TMPD acts as a nAChR antagonist at more than one subtype. TMPD (1μM) inhibited the response to acetylcholine at α3β4, α4β4, α4β2, and α1β1ɛδ receptors expressed in Xenopus oocytes. TMPD had a 2-fold higher affinity than choline for the blood–brain barrier choline transporter, suggesting brain bioavailability. TMPD did not inhibit hyperactivity in nicotine sensitized rats, but significantly and specifically decreased nicotine self-administration. Together, the results suggest that TMPD may have the ability to reduce the rewarding effect of nicotine with minimal side effects, a pharmacological profile indicative of potential clinical utility for the treatment of tobacco dependence. [Copyright &y& Elsevier]

Abstract: A series of tropane derivatives has been synthesized as lobelane analogues and evaluated for their binding affinity at the vesicular monoamine transporter-2 (VMAT2), and at α4β2* and α7* nicotinic acetylcholine receptors. The trop-2-ene analogues 4a and 4b exhibited good affinity and high selectivity for VMAT2. [Copyright &y& Elsevier]

Abstract: A series of lobelane analogues has been synthesized and their structure–activity relationships at the vesicular monoamine transporter-2 (VMAT2) have been evaluated. The most potent analogues in this series were the cis-2,6-piperidino analogues, 25b, 27b, 28b, and 30b, with K i values ranging from 430 to 580nM. [Copyright &y& Elsevier]

N-n-Alkylpicolinium and N,N′-alkyl-bis-picolinium analogues were assessed in nicotinic receptor (nAChR) assays. The most potent and subtype-selective analogue, N,N′-dodecyl-bis-picolinium bromide (bPiDDB), inhibited nAChRs mediating nicotine-evoked [3H]dopamine release (IC50=5 nM; Imax of 60%), and did not interact with α4β2* or α7* nAChRs. bPiDDB represents the current lead compound for development as a tobacco use cessation agent. [Copyright &y& Elsevier]

A series of bis-nicotinium, bis-pyridinium, bis-picolinium, bis-quinolinium and bis-isoquinolinium compounds was evaluated for their binding affinity at nicotinic acetylcholine receptors (nAChRs) using rat brain membranes. N,N′-Decane-1,12-diyl-bis-nicotinium diiodide (bNDI) exhibited the highest affinity for [3H]nicotine binding sites (Ki=330 nM), but did not inhibit [3H]methyllycaconitine binding (Ki >100 μM), indicative of an interaction with α4β2*, but not α7* receptor subtypes, respectively. Also, bNDI inhibited (IC50=3.76 μM) nicotine-evoked 86Rb+ efflux from rat thalamic synaptosomes, indicating antagonist activity at α4β2* nAChRs. N,N′-Dodecane-1,12-diyl-bis-quinolinium dibromide (bQDDB) exhibited highest affinity for [3H]methyllycaconitine binding sites (Ki=1.61 μM), but did not inhibit [3H]nicotine binding (Ki>100 μM), demonstrating an interaction with α7*, but not α4β2* nAChRs. Thus, variation of N-n-alkyl chain length together with structural modification of the azaaromatic quaternary ammonium moiety afforded selective antagonists for the α4β2* nAChR subtype, as well as ligands with selectivity at α7* nAChRs. [Copyright &y& Elsevier]

Lobeline, an alkaloidal constituent of Lobelia inflata LINN., has a long history of therapeutic usage ranging from emetic and respiratory stimulant to tobacco smoking cessation agent. Although classified as both an agonist and an antagonist at nicotinic receptors, lobeline has no structural resemblance to nicotine, and structure–function relationships do not suggest a common pharmacophore. Lobeline inhibits nicotine-evoked dopamine release and [3H]nicotine binding, thus acting as a potent antagonist at both α3β2* and α4β2* neuronal nicotinic receptor subtypes. However, lobeline does not release dopamine from its presynaptic terminal, but appears to induce the metabolism of dopamine intraneuronally. Reevaluation of the mechanism by which lobeline alters dopamine function reveals that its primary mechanism is inhibition of dopamine uptake and promotion of dopamine release from the storage vesicles within the presynaptic terminal, via an interaction with the tetrabenazine-binding site on the vesicular monoamine transporter (VMAT2). Thus, lobeline appears to perturb the fundamental mechanisms of dopamine storage and release. Based on its neurochemical mechanism, the ability of lobeline to functionally antagonize the neurochemical and behavioral effects of the psychostimulants amphetamine and methamphetamine was examined. Lobeline was found to inhibit the amphetamine-induced release of dopamine in vitro, and amphetamine-induced hyperactivity, drug discrimination, and self-administration. However, lobeline does not support self-administration in rats, suggesting a lack of addiction liability. Thus, lobeline may reduce the abuse liability of these psychostimulants. The development of lobeline and lobeline analogs with targeted selectivity at VMAT2 represents a novel class of therapeutic agents having good potential as efficacious treatments for methamphetamine abuse. [Copyright &y& Elsevier]

Abstract: An efficient synthesis of cis-2,6-di-(2-quinolylpiperidine) has been developed. The key steps involve Wittig reaction of N-Cbz-protected cis-piperidine-2,6-dicarboxaldehyde (3) with 2-(triphenylphosphinyl-methyl)quinoline bromide (4) and sequential removal of the N-Cbz group and double bond reduction. This synthetic procedure provides an efficient preparation for this useful norlobelane analogue. [Copyright &y& Elsevier]

Abstract: Expeditious syntheses of cis-1-methyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo-[3,2h]isoquinoline/[2,3-f]quinoline have been developed. The syntheses started with commercially available materials and afforded excellent overall yields in straightforward steps. Intramolecular azomethine ylide-alkene [3+2] cycloaddition is the key step in the construction of these pyrroloisoquinoline and pyrroloquinoline scaffolds. This route is much more atom-economic than those reported in the literature and is appropriate for scale-up synthesis. [Copyright &y& Elsevier]

Research using zebrafish (Danio rerio) has begun to provide novel information in many fields, including the behavioral pharmacology of drug use and misuse. There have been limited studies on the effects of methamphetamine in adult zebrafish and the parameters of exposure (dose, test session length) have not been well-documented. Behavior following drug exposure is generally measured during relatively short sessions (6–10 min is common) in a novel tank environment. Many procedural variables (isolation, netting, novel tank) elicit anxiety-like behavior that is most apparent during the initial portion of a test session. This anxiety-like behavior might mask the initial effects of methamphetamine. During longer test sessions, these anxiety-like responses would be expected to habituate and drug effects should become more apparent. To test this idea, we measured several locomotor activity responses for 50-min following a range of methamphetamine doses (0.1–3.0 mg/L via immersion in methamphetamine solution). Methamphetamine failed to alter swimming velocity, distance travelled, or freezing time. In contrast, methamphetamine produced a dose-dependent decrease in time spent in the bottom of the tank, an increase in the number of visits to the top of the tank, and an increase in the number of transitions along the sides of the tank. The effects of methamphetamine were apparent 10–20 min following exposure and generally persisted throughout the session. These findings indicate that longer test sessions are required to measure methamphetamine-induced changes in behavior in zebrafish, as has been shown in other laboratory animals. The results also suggest that anxiety-like responses associated with various procedural aspects (netting, isolation, novel test apparatus) likely interfere with the ability to observe many behavioral effects of methamphetamine in zebrafish. Based on the current results, habituation to testing procedures to reduce anxiety-like behaviors is recommended in determining the effects of methamphetamine in zebrafish. • Effects of methamphetamine administered via immersion emerge after 10–15 min. • Effects of methamphetamine persist throughout the 50-min session. • Higher concentrations of methamphetamine are anxiogenic. • An optimal concentration of methamphetamine via immersion is 0.3 mg/L. [ABSTRACT FROM AUTHOR]

The Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a central regulator of learning and memory, which poses a problem for targeting it therapeutically. Indeed, our study supports prior conclusions that long-term interference with CaMKII signaling can erase pre-formed memories. By contrast, short-term pharmacological CaMKII inhibition with the neuroprotective peptide tatCN19o interfered with learning in mice only mildly and transiently (for less than 1 h) and did not at all reverse pre-formed memories. These results were obtained with =500-fold of the dose that protected hippocampal neurons from cell death after a highly clinically relevant pig model of transient global cerebral ischemia: ventricular fibrillation followed by advanced life support and electrical defibrillation to induce the return of spontaneous circulation. Of additional importance for therapy development, our preliminary cardiovascular safety studies in mice and pig did not indicate any concerns with acute tatCN19o injection. Taken together, although prolonged interference with CaMKII signaling can erase memory, acute short-term CaMKII inhibition with tatCN19o did not cause such retrograde amnesia that would pose a contraindication for therapy. [ABSTRACT FROM AUTHOR]

[Display omitted] Previous research has demonstrated therapeutic potential for VMAT2 inhibitors in rat models of methamphetamine use disorder. Here, we report on the neurochemical and behavioral effects of 1-(2-methoxyphenethyl)-4-phenethypiperazine (JPC-141), a novel analog of lobelane. JPC-141 potently inhibited (Ki = 52 nM) [3H]dopamine uptake by VMAT2 in striatal vesicles with 50 to 250-fold greater selectivity for VMAT2 over dopamine, norepinephrine and serotonin plasmalemma transporters. Also, JPC-141 was 57-fold more selective for inhibiting VMAT2 over [3H]dofetilide binding to hERG channels expressed by HEK293, suggesting relatively low potential for cardiotoxicity. When administered in vivo to rats , JPC-141 prevented the METH-induced reduction in striatal dopamine content when given either prior to or after a high dose of METH, suggesting a reduction in METH-induced dopaminergic neurotoxicity. In behavioral assays, JPC-141 decreased METH-stimulated locomotor activity in METH-sensitized rats at doses of JPC-141 which did not alter locomotor activity in the saline control group. Moreover, JPC-141 specifically decreased iv METH self-administration at doses that had no effect on food-maintained responding. These findings support the further development of VMAT2 inhibitors as pharmacotherapies for individuals with methamphetamine use disorder. [ABSTRACT FROM AUTHOR]

We have previously shown that quinolyl moieties are attractive structural replacements for the phenyl groups in lobelane. These quinolyl analogues had improved water-solubility over lobelane and retained the potent vesicular monoamine transporter-2 (VMAT-2) inhibitory properties of the parent compound, with quinlobelane ( 4 ) exhibiting potent inhibition of uptake at VMAT-2 ( K i = 51 nM). However, the VMAT-2 inhibitory properties of quinolyl analogues of norlobelane, which is equipotent with lobeline as an inhibitor of [ 3 H]dopamine (DA) uptake at VMAT-2, have not been reported. In the current communication, we describe the synthesis of some novel des -methyl quinolyl analogues of lobelane that exhibit greater affinity ( K i = 178–647 nM) for the dihydrotetrabenazine binding site located on VMAT-2 compared with lobelane ( K i = 970 nM), norlobelane ( K i = 2310 nM) and quinlobelane ( K i = 2640 nM). The most potent compounds, 14 and 15 , also exhibited inhibition of [ 3 H]DA uptake at VMAT-2 ( K i = 42 nM) which was comparable to both lobelane ( K i = 45 nM) and norlobelane ( K i = 43 nM). Results reveal that binding affinity at VMAT-2 serves as an accurate predictor of inhibition of the function of VMAT-2 for the majority of these analogues. These novel analogues are under consideration for further development as treatments for methamphetamine abuse. [ABSTRACT FROM AUTHOR]

Abstract: Replacing the phenyl groups in the structure of the VMAT2 inhibitor, lobelane with either pyridyl, quinolyl or indolyl groups affords novel analogues with improved water solubility. The synthetic methodologies reported herein also underscore the paucity of hydrogenation methods that offer selectivity in the synthesis of the different classes of heteroaromatic lobelane analogues. The quinolyl group was the only replacement for the phenyl group in lobelane that retained VMAT2 inhibition. [Copyright &y& Elsevier]

Abstract: Current smokers express the desire to quit. However, the majority find it difficult to remain abstinent. As such, research efforts continually seek to develop more effective treatment. One such area of research involves the interoceptive stimulus effects of nicotine as either a discriminative stimulus in an operant drug discrimination task, or more recently as a conditional stimulus (CS) in a discriminated goal-tracking task. The present work investigated the potential role nicotinic acetylcholine receptors play in the CS effects of nicotine (0.4mg/kg) using antagonists with differential selectivity for β2*, α7*, α6β2*, and α3β4* receptors. Methyllycaconitine (MLA) had no effect on nicotine-evoked conditioned responding. Mecamylamine and dihydro-β-erythroidine (DHβE) dose-dependently blocked responding evoked by the nicotine CS. In a time-course assessment of mecamylamine and DHβE, each blocked conditioned responding when given 5min before testing and still blocked conditioned responding when administered 200min before testing. Two novel bis-picolinium analogs (N, N′-(3, 3′-(dodecan-1,12-diyl)-bis-picolinium dibromide [bPiDDB], and N, N′-(decan-1,10-diyl)-bis-picolinium diiodide [bPiDI]) did not block nicotine-evoked conditioned responding. Finally, pretreatment with low dose combinations of mecamylamine, dextromethorphan, and/or bupropion was used to target α3β4* receptors. No combination blocked conditioned responding evoked by the training dose of nicotine. However, a combination of mecamylamine and dextromethorphan partially blocked nicotine-evoked conditioned responding to a lower dose of nicotine (0.1mg/kg). These results indicate that β2* and potentially α3β4* nicotinic acetylcholine receptors play a role in the CS effects of nicotine and are potential targets for the development of nicotine cessation aids. [Copyright &y& Elsevier]

Abstract: Evidence indicates that monoaminergic neurotransmitter transporters are promiscuous, transporting substrates other than their cognate neurotransmitters. For example, serotonin is transported by the dopamine transporter (DAT) under conditions in which serotonin transporter (SERT) activity is eliminated (e.g., pharmacological inhibition). We performed a kinetic analysis of [3H]serotonin uptake in rat striatal synaptosomes (expressing DAT and SERT) and hippocampal synaptosomes (expressing SERT, but not DAT). Nonspecific [3H]serotonin uptake was defined as the amount of uptake remaining in the presence of fluoxetine (10μM) or paroxetine (0.05μM). In hippocampal synaptosomes, K m and V max values for [3H]serotonin uptake did not differ whether fluoxetine or paroxetine was used to define nonspecific uptake. However, in striatal synaptosomes, both K m and V max values for [3H]serotonin uptake were greater when fluoxetine, rather than paroxetine, was used to define nonspecific uptake. These data suggest that, at the concentrations employed, fluoxetine inhibits serotonin uptake at both DAT and SERT, whereas paroxetine only inhibits serotonin uptake at SERT. Thus, when DAT is inhibited by GBR 12909, kinetic parameters for serotonin uptake via SERT in striatum are not different from those obtained in hippocampus. These findings have important implications regarding the analysis of monoaminergic reuptake in brain regions exhibiting heterogeneous transporter expression. [Copyright &y& Elsevier]

A series of N,N-disubstituted piperazines were prepared and evaluated for binding to α4β2* and α7* neuronal nicotinic acetylcholine receptors using rat striatum and whole brain membrane preparations, respectively. This series of compounds exhibited selectivity for α4β2* nAChRs and did not interact with the α7* nAChRs subtype. The most potent analogues were compounds 8b and 8f (Ki=32 μM). Thus, linking together a pyridine π-system and a cyclic amine moiety via a piperazine ring affords compounds with low affinity, but good selectivity for α4β2* nicotinic receptors. [Copyright &y& Elsevier]

• At baseline, rats had higher demand intensity and lower elasticity for sucrose compared to saccharin. • After 8-weeks of the high-fat diet, OP rats had significantly greater weight gain and lower demand elasticity for sucrose and saccharin and higher demand intensity for saccharin. • The changes in sucrose and saccharin elasticity suggest that DIO-induced changes in food-related behavior are associated with changes in reward processes. • The changes in demand intensity for saccharin suggest that demand intensity, as a measure of 'set point', is not directly linked to metabolic processes. • The current study shows that microeconomic theory and demand analysis is able to isolate independent aspects of diet-induced reward changes related to caloric and non-caloric reinforcers. Although hormonal and metabolic factors are well known to influence obesity, recent evidence suggests that obesity may be influenced also by changes in reward sensitivity akin to that seen in other 'reward pathologies', like substance use disorders. The current study sought to isolate changes in reward that may occur after the onset of diet-induced obesity by characterizing the economic demand for caloric (sucrose) and non-caloric (saccharin) reinforcers in a preclinical model of diet-induced obesity (DIO). We utilized economic demand analysis to measure baseline demand intensity (Q 0) and demand elasticity (α) for sucrose and saccharin reinforcers in rats. After baseline measures were collected, rats were assigned randomly to a high-fat (HF) diet or low-fat (LF) control diet. After 8-weeks of diet exposure, HF rats were divided into obesity-resistant (OR) or obesity-prone (OP) groups based on weight after the 8-week HF diet exposure. Post-DIO demand data for each reinforcer were reassessed. At baseline, rats had higher demand intensity and lower elasticity for sucrose compared to saccharin. After 8-weeks of the high-fat diet, OP rats had significantly greater weight gain and lower demand elasticity for sucrose and saccharin and higher demand intensity for saccharin. The changes in sucrose and saccharin elasticity suggest that DIO-induced changes in food-related behavior are associated with changes in reward processes. The changes in demand intensity for saccharin suggest that demand intensity, as a measure of 'set point', is not directly linked to metabolic processes. The current study shows that microeconomic theory and demand analysis is able to isolate independent aspects of diet-induced reward changes related to caloric and non-caloric reinforcers. [ABSTRACT FROM AUTHOR]