Peer-induced cocaine seeking in rats: Comparison to nonsocial stimuli and role of paraventricular hypothalamic oxytocin neurons.

The purpose of this study was to determine if social vs nonsocial cues (peer vs light/tone) can serve as discriminative stimuli to reinstate cocaine seeking. In addition, to assess a potential mechanism, an oxytocin (OT) promoter-linked hM3Dq DREADD was infused into the paraventricular nucleus of the hypothalamus to determine whether peer-induced cocaine seeking is decreased by activation of OT neurons. Male rats underwent twice-daily self-administration sessions, once with cocaine in the presence of one peer (S+) and once with saline in the presence of a different peer (S-). Another experiment used similar procedures, except the discriminative stimuli were nonsocial (constant vs flashing light/tone), with one stimulus paired with cocaine (S+) and the other paired with saline (S-). A third experiment injected male and female rats with OTp-hM3Dq DREADD or control virus into PVN and tested them for peer-induced reinstatement of cocaine seeking following clozapine (0.1 mg/kg). Although acquisition of cocaine self-administration was similar in rats trained with either peer or light/tone discriminative stimuli, the latency to first response was reduced by the peer S+, but not by the light/tone S+. In addition, the effect of the conditioned stimulus was overshadowed by the peer S+ but not by the light/tone S+. Clozapine blocked the effect of the peer S+ in rats receiving the OTp-hM3Dq DREADD virus, but not in rats receiving the control virus. These results demonstrate that a social peer can serve as potent trigger for drug seeking and that OT in PVN modulates peer-induced reinstatement of cocaine seeking.

Environmental enrichment and drug value: a behavioral economic analysis in male rats.

Rats raised in an enriched condition (EC) show decreased stimulant self-administration relative to rats reared in an isolated condition (IC). However, few studies have examined the behavioral mechanisms underlying this environment-induced difference in self-administration. Because economic demand for drugs of abuse predicts addiction-like behavior in both humans and animals, we applied a behavioral economic analysis to cocaine self-administration data in EC and IC rats. During cocaine self-administration, the dose decreased across blocks of trials (0.75-0.003 mg/kg/inf), which allowed for a determination of demand intensity and demand elasticity. Demand intensity did not differ between EC and IC rats; however, cocaine was more elastic in EC rats relative to IC rats (i.e. EC rats were less willing to respond for cocaine as the unit price increased). When EC rats were placed in an isolated condition, demand elasticity decreased, whereas elasticity increased for IC rats placed in an enriched condition. Additionally, we applied behavioral economic analyses to previously published self-administration data and found that our results replicate past findings with cocaine and methylphenidate. To determine if differences in demand elasticity are specific to drug reinforcement, a separate group of rats was tested in sucrose or saccharin self-administration. Results showed that sucrose and saccharin were more elastic in EC rats relative to IC rats, and demand intensity was lower for saccharin in EC rats relative to IC rats. Overall, drug and nondrug reinforcers are more elastic in EC rats, which may account for the protective effects of environmental enrichment against stimulant self-administration.

The role of glutamate signaling in incentive salience: second-by-second glutamate recordings in awake Sprague-Dawley rats.

The attribution of incentive salience to reward-predictive stimuli has been shown to be associated with substance abuse-like behavior such as increased drug taking. Evidence suggests that glutamate neurotransmission and sequential N-methyl-D-aspartate (NMDA) activation are involved in the attribution of incentive salience. Here, we further explore the role of second-by-second glutamate neurotransmission in the attribution of incentive salience to reward-predictive stimuli by measuring sign-tracking behavior during a Pavlovian conditioned approach procedure using ceramic-based microelectrode arrays configured for sensitive measures of extracellular glutamate in awake behaving Sprague-Dawley rats. Specifically, we show that there is an increase in extracellular glutamate levels in the prelimbic cortex (PrL) and the nucleus accumbens core (NAcC) during sign-tracking behavior to a food-predictive conditioned stimulus (CS+) compared to the presentation of a non-predictive conditioned stimulus (CS-). Furthermore, the results indicate greater increases in extracellular glutamate levels in the PrL compared to NAcC in response to the CS+, including differences in glutamate release and signal decay. Taken together, the present research suggests that there is differential glutamate signaling in the NAcC and PrL during sign-tracking behavior to a food-predictive CS+.

Differential stimulus control of drug-seeking: multimodal reinstatement.

In animal models of substance-use disorder, individuals that repeatedly self-administer drugs of abuse have long-lasting neuronal adaptations that do not occur ostensibly in control animals only exposed to natural reinforcers (e.g. food). Because any treatment for substance-use disorder will be given to individuals with drug-taking histories, adequate dissociation of the specific neurobehavioral mechanisms underlying drug reinforcement, natural reinforcement and their associated cue effects requires an experimental model that exposes individuals to both reinforcer conditions, along with their associated stimuli. Furthermore, contingent stimuli that reinforce drug seeking through second-order relationships may produce reinstatement of drug seeking through different neurobehavioral means than non-contingent exposure to stimuli that signal the availability of a drug reinforcer, effectively producing different modes of stimulus-induced reinstatement. Toward experimental isolation of the relationships mentioned, herein, we used a within-session multiple schedule of reinforcement containing both discriminative (SD ) and conditioned (CS) stimuli to study stimulus control of drug-taking and food-taking behavior, along with how these functionally distinct cues may differentially reinstate drug-seeking and food-seeking behavior within a single animal. We demonstrate specific stimulus control over drug and food taking; furthermore, we demonstrate that the same stimulus (i.e. cue light) operating as an SD or CS produced differential reinstatement of drug-taking and food-taking behavior. The results suggest that contingent CSs and non-contingent SD s produce reinstatement through different neurobehavioral processes and, within-session multiple schedules, can be used to study different modes of specific stimulus control over drug and food seeking in a single animal with both drug-taking and food-taking history.

Isolating the incentive salience of reward-associated stimuli: value, choice, and persistence.

Sign- and goal-tracking are differentially associated with drug abuse-related behavior. Recently, it has been hypothesized that sign- and goal-tracking behavior are mediated by different neurobehavioral valuation systems, including differential incentive salience attribution. Herein, we used different conditioned stimuli to preferentially elicit different response types to study the different incentive valuation characteristics of stimuli associated with sign- and goal-tracking within individuals. The results demonstrate that all stimuli used were equally effective conditioned stimuli; however, only a lever stimulus associated with sign-tracking behavior served as a robust conditioned reinforcer and was preferred over a tone associated with goal-tracking. Moreover, the incentive value attributed to the lever stimulus was capable of promoting suboptimal choice, leading to a significant reduction in reinforcers (food) earned. Furthermore, sign-tracking to a lever was more persistent than goal-tracking to a tone under omission and extinction contingencies. Finally, a conditional discrimination procedure demonstrated that sign-tracking to a lever and goal-tracking to a tone were dependent on learned stimulus-reinforcer relations. Collectively, these results suggest that the different neurobehavioral valuation processes proposed to govern sign- and goal-tracking behavior are independent but parallel processes within individuals. Examining these systems within individuals will provide a better understanding of how one system comes to dominate stimulus-reward learning, thus leading to the differential role these systems play in abuse-related behavior.

r-bPiDI, an α6ß2* Nicotinic Receptor Antagonist, Decreases Nicotine-Evoked Dopamine Release and Nicotine Reinforcement.

α6ß2* nicotinic acetylcholine receptors (nAChRs) expressed by dopaminergic neurons mediate nicotine-evoked dopamine (DA) release and nicotine reinforcement. α6ß2* antagonists inhibit these effects of nicotine, such that α6ß2* receptors serve as therapeutic targets for nicotine addiction. The present research assessed the neuropharmacology of 1,10-bis(3-methyl-5,6-dihydropyridin-1(2H)-yl)decane (r-bPiDI), a novel small-molecule, tertiary amino analog of its parent compound, N,N-decane-1,10-diyl-bis-3-picolinium diiodide (bPiDI). bPiDI was previously shown to inhibit both nicotine-evoked DA release and the reinforcing effects of nicotine. In the current study, r-bPiDI inhibition of [(3)H]nicotine and [(3)H]methyllycaconitine binding sites was evaluated to assess interaction with the recognition binding sites on α4ß2* and α7* nAChRs, respectively. Further, r-bPiDI inhibition of nicotine-evoked DA release in vitro in the absence and presence of α-conotoxin MII and following chronic in vivo nicotine administration were determined. The ability of r-bPiDI to decrease nicotine self-administration and food-maintained responding was also assessed. Results show that r-bPiDI did not inhibit [(3)H]nicotine or [(3)H]methyllycaconitine binding, but potently (IC50 = 37.5 nM) inhibited nicotine-evoked DA release from superfused striatal slices obtained from either drug naïve rats or from those repeatedly treated with nicotine. r-bPiDI inhibition of nicotine-evoked DA release was not different in the absence or presence of α-conotoxin MII, indicating that r-bPiDI acts as a potent, selective α6ß2* nAChR antagonist. Acute systemic administration of r-bPiDI specifically decreased nicotine self-administration by 75 %, and did not alter food-maintained responding, demonstrating greater specificity relative to bPiDI and bPiDDB, as well as the tertiary amino analog r-bPiDDB. The current work describes the discovery of r-bPiDI, a tertiary amino, α-conotoxin MII-like small molecule that acts as a potent and selective antagonist at α6ß2* nAChRs to specifically decrease nicotine self-administration in rats, thus, establishing r-bPiDI as a lead compound for development as a treatment for nicotine addiction.

Impacts of xylazine on fentanyl demand, body weight, and acute withdrawal in rats: A comparison to lofexidine.

The opioid use landscape has recently shifted to include xylazine, a veterinary anesthetic, as an adulterant in the fentanyl supply. The health impacts of xylazine as an emerging fentanyl adulterant has raised alarm regarding xylazine as a public health threat, warranting research on the impacts of xylazine on fentanyl's behavioral effects. No prior studies have evaluated the effects of xylazine on fentanyl consumption at various unit doses, fentanyl demand, or withdrawal as compared to the Food and Drug Administration-approved opioid withdrawal medication, lofexidine (Lucemyra®). This is important because lofexidine and xylazine are both adrenergic α2a (A2aR) agonists, however, lofexidine is not a noted fentanyl adulterant. Here we evaluated xylazine and lofexidine combined with self-administered fentanyl doses in male and female rats and evaluated fentanyl demand, body weight, and acute withdrawal. Consumption of fentanyl alone increased at various unit doses compared to saline. Xylazine but not lofexidine shifted fentanyl consumption downward at a number of unit doses, however, both lofexidine and xylazine suppressed fentanyl demand intensity as compared to a fentanyl alone control group. Further, both fentanyl + lofexidine and fentanyl + xylazine reduced behavioral signs of fentanyl withdrawal immediately following SA, but signs increased by 12 h only in the xylazine co-exposed group. Weight loss occurred throughout fentanyl SA and withdrawal regardless of group, although the xylazine group lost significantly more weight during the first 24 h of withdrawal than the other two groups. Severity of weight loss during the first 24 h of withdrawal was also correlated with severity of somatic signs of fentanyl withdrawal. Together, these results suggest that body weight loss may be an important indicator of withdrawal severity during acute withdrawal from the xylazine/fentanyl combination, warranting further translational evaluation.

Xylazine suppresses fentanyl consumption during self-administration and induces a unique sex-specific withdrawal syndrome that is not altered by naloxone in rats.

Prescription and illicit opioid use are a public health crisis, with the landscape shifting to fentanyl use. Since fentanyl is 100-fold more potent than morphine, its use is associated with a higher risk of fatal overdose that can be remediated through naloxone (Narcan) administration. However, recent reports indicate that xylazine, an anesthetic, is increasingly detected in accidental fentanyl overdose deaths. Anecdotal reports suggest that xylazine may prolong the fentanyl "high," alter the onset of fentanyl withdrawal, and increase resistance to naloxone-induced reversal of overdose. To date, no preclinical studies have evaluated the impacts of xylazine on fentanyl self-administration (SA; 2.5 µg/kg/infusion) or withdrawal to our knowledge. We established a rat model of xylazine/fentanyl co-SA and withdrawal and evaluated outcomes as a function of biological sex. When administered alone, chronic xylazine (2.5 mg/kg, intraperitoneal) induced unique sex-specific withdrawal symptomatology, whereby females showed delayed onset of signs and a possible enhancement of sensitivity to the motor-suppressing effects of xylazine. Xylazine reduced fentanyl consumption in both male and female rats regardless of whether it was experimenter-administered or added to the intravenous fentanyl product (0.05, 0.10, and 0.5 mg/kg/infusion) when compared to fentanyl SA alone. Interestingly, this effect was dose-dependent when self-administered intravenously. Naloxone (0.1 mg/kg, subcutaneous injection) did not increase somatic signs of fentanyl withdrawal, regardless of the inclusion of xylazine in the fentanyl infusion in either sex; however, somatic signs of withdrawal were higher across time points in females after xylazine/fentanyl co-SA regardless of naloxone exposure as compared to females following fentanyl SA alone. Together, these results indicate that xylazine/fentanyl co-SA dose-dependently suppressed fentanyl intake in both sexes and induced a unique withdrawal syndrome in females that was not altered by acute naloxone treatment. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Synthetic contraceptive hormones occlude the ability of nicotine to reduce ethanol consumption in ovary-intact female rats.

Rates of tobacco and alcohol use in women are rising, and women are more vulnerable than men to escalating tobacco and alcohol use. Many women use hormonal birth control, with the oral contraceptive pill being the most prevalent. Oral contraceptives contain both a progestin (synthetic progesterone) and a synthetic estrogen (ethinyl estradiol; EE) and are contraindicated for women over 35 years who smoke. Despite this, no studies have examined how synthetic contraceptive hormones impact this pattern of polysubstance use in females. To address this critical gap in the field, we treated ovary-intact female rats with either sesame oil (vehicle), the progestin levonorgestrel (LEVO; contained in formulations such as Alesse®), or the combination of EE+LEVO in addition to either undergoing single (nicotine or saline) or polydrug (nicotine and ethanol; EtOH) self-administration (SA) in a sequential use model. Rats preferred EtOH over water following extended EtOH drinking experience as well as after nicotine or saline SA experience, and rats undergoing only nicotine SA (water controls) consumed more nicotine as compared to rats co-using EtOH and nicotine. Importantly, this effect was occluded in groups treated with contraceptive hormones. In the sequential use group, both LEVO alone and the EE+LEVO combination occluded the ability of nicotine to decrease EtOH consumption. Interestingly, demand experiments suggest an economic substitute effect between nicotine and EtOH. Together, we show that chronic synthetic hormone exposure impacts nicotine and EtOH sequential use, demonstrating the crucial need to understand how chronic use of different contraceptive formulations alter patterns of polydrug use in women.

Environmental enrichment during development decreases intravenous self-administration of methylphenidate at low unit doses in rats.

Despite the efficacy and widespread use of methylphenidate (MPH) as a treatment modality for attention deficit hyperactivity disorder, clinical and preclinical findings indicate that it has abuse potential. Environmental enrichment reduces susceptibility to cocaine and amphetamine self-administration and decreases impulsive behavior, but its effects on MPH self-administration are unknown. The present experiments sought to determine the influence of environmental enrichment on MPH self-administration. Male rats were raised in an enriched condition (EC) or isolated condition (IC). They were trained to self-administer MPH (0.3 mg/kg/infusion) and then exposed to varying doses of MPH on either a fixed-ratio (experiment 1) or a progressive-ratio (experiment 2) schedule of reinforcement. EC rats earned significantly fewer infusions of MPH at low doses (0.03 and 0.056 mg/kg/infusion) compared with IC rats under both schedules; however, no differences were observed at high unit doses (0.1-1.0 mg/kg/infusion). During saline substitution at the end of MPH self-administration, EC rats also responded less for saline compared with IC rats, indicative of more rapid extinction. As with other stimulant drugs with different mechanisms of action, environmental enrichment during development protects against self-administration of MPH at low unit doses but not at high unit doses.

Ovarian Hormones Regulate Nicotine Consumption and Accumbens Glutamatergic Plasticity in Female Rats.

Women report greater cigarette cravings during the menstrual cycle phase with higher circulating levels of 17ß-estradiol (E2), which is metabolized to estrone (E1). Both E2 and E1 bind to estrogen receptors (ERs), which have been highly studied in the breast, uterus, and ovary. Recent studies have found that ERs are also located on GABAergic medium spiny neurons (MSNs) within the nucleus accumbens core (NAcore). Glutamatergic plasticity in NAcore MSNs is altered following nicotine use; however, it is unknown whether estrogens impact this neurobiological consequence. To test the effect of estrogen on nicotine use, we ovariectomized (OVX) female rats that then underwent nicotine self-administration acquisition and compared them to ovary-intact (sham) rats. The OVX animals then received either sesame oil (vehicle), E2, or E1+E2 supplementation for 4 or 20 d before nicotine sessions. While both ovary-intact and OVX females readily discriminated levers, OVX females consumed less nicotine than sham females. Further, neither E2 nor E1+E2 increased nicotine consumption back to sham levels following OVX, regardless of the duration of the treatment. OVX also rendered NAcore MSNs in a potentiated state following nicotine self-administration, which was reversed by 4 d of systemic E2 treatment. Finally, we found that E2 and E1+E2 increased ERα mRNA in the NAcore, but nicotine suppressed this regardless of hormone treatment. Together, these results show that estrogens regulate nicotine neurobiology, but additional factors may be required to restore nicotine consumption to ovary-intact levels.

meso-Transdiene analogs inhibit vesicular monoamine transporter-2 function and methamphetamine-evoked dopamine release.

Lobeline, a nicotinic receptor antagonist and neurotransmitter transporter inhibitor, is a candidate pharmacotherapy for methamphetamine abuse. meso-Transdiene (MTD), a lobeline analog, lacks nicotinic receptor affinity, retains affinity for vesicular monoamine transporter 2 (VMAT2), and, surprisingly, has enhanced affinity for dopamine (DA) and serotonin transporters [DA transporter (DAT) and serotonin transporter (SERT), respectively]. In the current study, MTD was evaluated for its ability to decrease methamphetamine self-administration in rats relative to food-maintained responding. MTD specifically decreased methamphetamine self-administration, extending our previous work. Classical structure-activity relationships revealed that more conformationally restricted MTD analogs enhanced VMAT2 selectivity and drug likeness, whereas affinity at the dihydrotetrabenazine binding and DA uptake sites on VMAT2 was not altered. Generally, MTD analogs exhibited 50- to 1000-fold lower affinity for DAT and were equipotent or had 10-fold higher affinity for SERT, compared with MTD. Representative analogs from the series potently and competitively inhibited [(3)H]DA uptake at VMAT2. (3Z,5Z)-3,5-bis(2,4-dichlorobenzylidene)-1-methylpiperidine (UKMH-106), the 3Z,5Z-2,4-dichlorophenyl MTD analog, had improved selectivity for VMAT2 over DAT and importantly inhibited methamphetamine-evoked DA release from striatal slices. In contrast, (3Z,5E)-3,5-bis(2,4-dichlorobenzylidene)-1-methylpiperidine (UKMH-105), the 3Z,5E-geometrical isomer, inhibited DA uptake at VMAT2, but did not inhibit methamphetamine-evoked DA release. Taken together, these results suggest that these geometrical isomers interact at alternate sites on VMAT2, which are associated with distinct pharmacophores. Thus, structural modification of the MTD molecule resulted in analogs exhibiting improved drug likeness and improved selectivity for VMAT2, as well as the ability to decrease methamphetamine-evoked DA release, supporting the further evaluation of these analogs as treatments for methamphetamine abuse.

Cue effects on methylphenidate self-administration in rats.

Associations between drugs and the stimuli paired with drugs have been proposed as primary factors in drug addiction and relapse. Previous research has found cues paired with drug infusions are important for many classes of drugs. The purpose of the present experiment was to determine if a cue light was necessary to engender reliable self-administration of methylphenidate (MPH), which is a widely prescribed drug for attention deficit hyperactivity disorder. Rats were given access to MPH (0.3 mg/kg/infusion) or saline for self-administration. Half of the rats in each group had infusions paired with a cue light, whereas the other half did not. Two additional groups of rats received MPH infusions noncontingently; one group's lever pressing turned on the cue light, and the other group's lever pressing had no consequence. Both MPH and the cue functioned as weak reinforcers on their own. The group that lever pressed for MPH paired with a cue light pressed significantly more for MPH than any other group, indicating that the cue and MPH had a synergistic effect on self-administration when combined. Taken together, these results indicate that MPH has reinforcing properties on its own, but that environmental cues also play an important role in enhancing MPH self-administration.

Strain differences in self-administration of methylphenidate and sucrose pellets in a rat model of attention-deficit hyperactivity disorder.

Despite its abuse potential, methylphenidate (MPH) is widely prescribed for treatment of attention-deficit hyperactivity disorder (ADHD). The purpose of the present study was to examine MPH self-administration in a rat model of ADHD. Experiment 1 examined the acquisition of MPH self-administration and assessed the MPH dose-effect curve in spontaneously hypertensive rats (SHR), an inbred rat model of ADHD, Wistar Kyotos (WKY), the progenitor strain for SHR, and Sprague-Dawley (SD), an outbred control strain. Experiment 2 replicated Experiment 1, but replaced MPH infusions with sucrose pellets. Initial acquisition of MPH self-administration was greater in SHR and SD than WKY. However, with extended training using an incrementing fixed ratio schedule SHR and WKY did not differ in responding for MPH using the training dose (0.3 mg/kg/infusion) or other unit doses, except that SHR showed greater responding than WKY at 0.1 mg/kg/infusion. SHR also showed greater acquisition and maintenance of sucrose-reinforced responding compared with both WKY and SD. Greater initial acquisition of MPH self-administration in SHR than WKY may not be due to a strain-specific difference in sensitivity to the reinforcing effect of MPH.

Quantifying value-based determinants of drug and non-drug decision dynamics.

RATIONALE: A growing body of research suggests that substance use disorder (SUD) may be characterized as disorders of decision making. However, drug choice studies assessing drug-associated decision making often lack more complex and dynamic conditions that better approximate contexts outside the laboratory and may lead to incomplete conclusions regarding the nature of drug-associated value. OBJECTIVES: The current study assessed isomorphic (choice between identical food options) and allomorphic (choice between remifentanil [REMI] and food) choice across dynamically changing reward probabilities, magnitudes, and differentially reward-predictive stimuli in male rats to better understand determinants of drug value. Choice data were analyzed at aggregate and choice-by-choice levels using quantitative matching and reinforcement learning (RL) models, respectively. RESULTS: Reductions in reward probability or magnitude independently reduced preferences for food and REMI commodities. Inclusion of reward-predictive cues significantly increased preference for food and REMI rewards. Model comparisons revealed that reward-predictive stimuli significantly altered the economic substitutability of food and REMI rewards at both levels of analysis. Furthermore, model comparisons supported the reformulation of reward value updating in RL models from independent terms to a shared, relative term, more akin to matching models. CONCLUSIONS: The results indicate that value-based quantitative choice models can accurately capture choice determinants within complex decision-making contexts and corroborate drug choice as a multidimensional valuation process. Collectively, the present study indicates commonalities in decision-making for drug and non-drug rewards, validates the use of economic-based SUD therapies (e.g., contingency management), and implicates the neurobehavioral processes underlying drug-associated decision-making as a potential avenue for future SUD treatment.

Remifentanil-food choice follows predictions of relative subjective value.

BACKGROUND: Preclinical studies into drug vs. nondrug choice have emerged to better model and investigate the neurobehavioral mechanisms underlying drug preference. Current literature has suggested that drugs of abuse have inherently low value, thus promoting food preference. Herein, we examined remifentanil vs. food choice to test both the relative value hypothesis and the 'direct effects' (pharmacological effects of drugs on alternative reinforcers) hypothesis of opioid preference. METHODS: Adult male rats were trained under two choice procedures (controlled vs. uncontrolled reinforcer frequency) for remifentanil vs. food choice. Furthermore, a series of procedural manipulations known to affect drug reinforcement were tested under both choice procedures. Using remifentanil self-administration data, pharmacokinetic profiles were calculated and analyzed to determine if opioid intake was related to opioid preference. RESULTS: Both choice procedures produced dose-dependent preference. Moreover, procedural manipulations produced comparable changes in remifentanil preference under both choice procedures. In addition, calculated pharmacokinetic data revealed that preference was dissociable from intake under the controlled reinforcer frequency choice procedure. CONCLUSIONS: When compared to the 'direct effects' hypothesis, remifentanil preference was better predicted by the relative value hypothesis, formalized in generalized matching. Use of a controlled reinforcer frequency schedule successfully removed the drug preference-intake confound found in most drug-choice procedures. Importantly, drug preference under the controlled reinforcer frequency schedule remained sensitive to procedural manipulations known to affect drug reinforcement. Thus, given that differential drug intake itself affects neurobiological measurements, future use of controlled reinforcer frequency schedules may help to better isolate the neurobehavioral mechanisms that mediate opioid preference.

Neuronal activity associated with cocaine preference: Effects of differential cocaine intake.

Differences in overall cocaine intake can directly affect neuroadaptations, and this relationship can make it difficult to interpret neurobiological changes seen in drug-choice studies, since drug intake varies between subjects. Herein, a choice procedure that controls for cocaine intake was utilized to explore if neuronal activity, measured as cFos expression in the orbitofrontal cortex (OFC) and nucleus accumbens (NAc), was reflective of preference. Results demonstrated that cFos expression, in both the OFC and NAc, was independent of cocaine preference when cocaine intake was kept constant across individuals. However, when cocaine intake was systematically varied, the expression of cFos associated with cocaine preference was related to overall cocaine intake in the OFC, but not the NAc. Altogether, these results demonstrate that cocaine intake during choice can affect neurobiological outcome measures; thus, the neurobehavioral mechanisms underlying cocaine preference may be better isolated when controlling for cocaine frequency and intake. In all, some caution is warranted when interpreting results from choice studies evaluating the neurobehavioral mechanisms that underlie drug preference when drug frequency and intake are uncontrolled, and future research is needed to determine the role of drug frequency and intake on neurobiological measures associated with drug choice.

Natural and synthetic estrogens specifically alter nicotine demand and cue-induced nicotine seeking in female rats.

Women have more difficulty maintaining smoking cessation than men, and experience greater withdrawal symptomatology as well as higher prevalence of relapse. Further, currently available treatments for smoking cessation, such as the nicotine patch and varenicline, have been shown to be less effective in women. Fluctuations in ovarian hormones across the menstrual cycle can affect craving and smoking relapse propensity. In addition, many women who smoke use some form of oral contraceptives, which most often contain ethinyl estradiol (EE), a synthetic, orally bio-available estrogen that is currently prescribed to women chronically and has been shown to alter smoking reward in women. The current study examined the impact of 17ß-estradiol (E2), the prominent endogenous form of the steroid hormone estrogen, as well as EE, on nicotine self-administration, demand, and reinstatement following ovariectomy (OVX) or sham surgery. OVX vehicle-treated female rats consumed less nicotine, had lower intensity of demand, and reinstated less compared to sham vehicle-treated female rats. OVX-E2 and OVX-EE treatment groups showed a rebound of nicotine intake later in training, and Q0 levels of consumption were partially rescued in both groups. Further, E2 but not EE reversed the abolishment of reinstated nicotine seeking induced by OVX. Taken together, these results demonstrate that natural and synthetic estrogens play a critical role in mediating the neurobehavioral effects of nicotine, and future studies are essential for our understanding of how synthetic hormones contained within oral contraceptives interact with smoking.

The novel pyrrolidine nor-lobelane analog UKCP-110 [cis-2,5-di-(2-phenethyl)-pyrrolidine hydrochloride] inhibits VMAT2 function, methamphetamine-evoked dopamine release, and methamphetamine self-administration in rats.

Both lobeline and lobelane attenuate methamphetamine self-administration in rats by decreasing methamphetamine-induced dopamine release via interaction with vesicular monoamine transporter-2 (VMAT2). A novel derivative of nor-lobelane, cis-2,5-di-(2-phenethyl)-pyrrolidine hydrochloride (UKCP-110), and its trans-isomers, (2R,5R)-trans-di-(2-phenethyl)-pyrrolidine hydrochloride (UKCP-111) and (2S,5S)-trans-di-(2-phenethyl)-pyrrolidine hydrochloride (UKCP-112), were evaluated for inhibition of [(3)H]dihydrotetrabenazine binding and [(3)H]dopamine uptake by using a rat synaptic vesicle preparation to assess VMAT2 interaction. Compounds were evaluated for inhibition of [(3)H]nicotine and [(3)H]methyllycaconitine binding to assess interaction with the major nicotinic receptor subtypes. In addition, compounds were evaluated for inhibition of methamphetamine-evoked endogenous dopamine release by using striatal slices. The most promising compound, UKCP-110, was evaluated for its ability to decrease methamphetamine self-administration and methamphetamine discriminative stimulus cues and for its effect on food-maintained operant responding. UKCP-110, UKCP-111, and UKCP-112 inhibited [(3)H]dihydrotetrabenazine binding (K(i) = 2.66 ± 0.37, 1.05 ± 0.10, and 3.80 ± 0.31 µM, respectively) and had high potency inhibiting [(3)H]dopamine uptake (K(i) = 0.028 ± 0.001, 0.046 ± 0.008, 0.043 ± 0.004 µM, respectively), but lacked affinity at nicotinic receptors. Although the trans-isomers did not alter methamphetamine-evoked dopamine release, UKCP-110 inhibited (IC(50) = 1.8 ± 0.2 µM; I(max) = 67.18 ± 6.11 µM) methamphetamine-evoked dopamine release. At high concentrations, UKCP-110 also increased extracellular dihydroxyphenylacetic acid. It is noteworthy that UKCP-110 decreased the number of methamphetamine self-infusions, while having no effect on food-reinforced behavior or the methamphetamine stimulus cue. Thus, UKCP-110 represents a new lead in the development of novel pharmacotherapies for the treatment of methamphetamine abuse.

Nicotine reduction does not alter essential value of nicotine or reduce cue-induced reinstatement of nicotine seeking.

Reduction of nicotine content in tobacco products is a regulatory control strategy intended to decrease smoking dependence, and is hypothesized to produce gradual reductions of nicotine intake. Rats were initially trained to self-administer 0.06 mg/kg/infusion nicotine (Phase 1), which was followed by a threshold procedure to determine nicotine demand via a behavioral economics (BE) paradigm (Phase 2). Rats then either self-administered the training dose (high dose group), or were switched to a low dose of nicotine (0.001 mg/kg/infusion; low dose group) in Phase 3. Both groups then underwent a second threshold procedure and demand curves were re-determined (Phase 4). In Phase 5, responding for nicotine was extinguished over the course of 21 sessions. Cue-induced reinstatement was then evaluated (Phase 6). Rats in the low dose group maintained a steady amount of infusions, and thus, did not compensate for nicotine reduction. Rats in the low dose group also showed similar demand elasticity and nicotine seeking (Phase 6) compared to the high dose group, indicating that nicotine reduction did not decrease nicotine demand or seeking. Further, both groups displayed resistance to extinction, indicating that nicotine reduction did not facilitate extinction learning. These results suggest that although compensation of intake does not occur, decreasing the dose of nicotine does not alter nicotine reinforcement value or relapse vulnerability. Further, these results indicate persistence of nicotine-motivated behavior after self-administration of a low nicotine dose. Translationally, these results suggest that alternative strategies may be needed to achieve positive smoking cessation outcomes.