Rate Of Lever Research Articles

Effect of context on the instrumental reinforcer devaluation effect produced by taste-aversion learning.

Four experiments manipulated the context in which taste-aversion conditioning occurred when the reinforcer was devalued after instrumental learning. In all experiments, rats learned to lever press in an operant conditioning chamber and then had an aversion to the food-pellet reinforcer conditioned by pairing it with lithium chloride (LiCl) in either that context or a different context. Lever pressing was then tested in extinction to assess its status as a goal-directed action. In Experiment 1, aversion conditioning in the operant conditioning chamber suppressed lever-pressing during the test, but aversion conditioning in the home cage did not. Exposure to the averted pellet in the operant conditioning chamber after conditioning in the home cage did not change this effect (Experiment 2). The same pattern was observed when the different context was a second operant-style chamber (counterbalanced), exposure to the contexts was controlled, and pellets were presented in them in the same manner (Experiment 3). The greater effect of aversion conditioning in the instrumental context was not merely due to potentiated contextual conditioning (Experiment 4). Importantly, consumption tests revealed that the aversion conditioned in the different context had transferred to the test context. Thus, when reinforcer devaluation occurred in a different context, the rats lever pressed in extinction for a reinforcer they would otherwise reject. The results suggest that animals encode contextual information about the reinforcer during instrumental learning and suggest caution in making inferences about action versus habit learning when the reinforcer is devalued in a different context. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The GABAB receptor positive allosteric modulator ASP8062 reduces operant alcohol self-administration in male and female Sprague Dawley rats.

Pre-clinical evidence implicates the GABAergic system in mediating the reinforcing effects of alcohol and offers a therapeutic target for alcohol use disorder (AUD). The orthosteric GABAB receptor agonist baclofen decreases alcohol self-administration in animals and alcohol use in humans; however side effects limit its utility. Pre-clinical evidence shows positive allosteric GABAB receptor modulators also decrease alcohol self-administration without untoward side effects. We assessed the impact of the novel GABAB-positive allosteric modulator ASP8062 and baclofen on operant alcohol self-administration and their potential non-specific effects. The effects of ASP8062 (1 - 10mg/kg, PO) and baclofen (0.3 - 3mg/kg, IP) were evaluated in male and female rats lever pressing for alcohol (10%, w/v) under a fixed ratio 2 schedule of reinforcement. On the fourth consecutive day of vehicle, ASP8062 or baclofen administration, active and inactive lever presses, reinforcers earned, head entries, and estimated alcohol consumed were analyzed. Locomotor activity was assessed in separate groups of rats following dosing. Both ASP8062 and baclofen decreased alcohol self-administration and amount consumed (g/kg) in male and female rats. ASP8062 decreased operant alcohol self-administration to a greater extent in male rats, whereas baclofen was more efficacious in female rats. ASP8062 did not alter locomotor activity in either sex, whereas baclofen (3.0mg/kg) decreased activity in male rats yet (1.0mg/kg) increased activity in female rats. ASP8062 decreases alcohol reinforcement like baclofen but without non-specific effects which are influenced by sex. Results support further development of ASP8062 as a potential treatment for AUD in humans.

COMPARING COORDINATED RESPONDING IN PAIRS OF RATS WHEN BOTH OPERANTS AND AGGREGATE PRODUCTS ARE SELECTED BY INTERMITTENT TEMPORAL CONSEQUENCES

Three pairs of rats worked in two adjacent operant chambers separated by a Plexiglas wall. In some experimental conditions, lever-presses were independent operants maintained by either a fixed-interval (FI) or variable interval (VI) schedule. In other conditions, each rat lever- press was part of two interlocked behavior contingencies as part of a metacontingency: its aggregate product, a brief flash of light, was maintained either by a FI or a VI schedule of mutual water presentation. The results clearly show that the interlocking of behavioral contingencies in the design of an experimental metacontingency established a pattern of cooperation between the rats.

Impact of order of fixed-ratio presentation on demand for self-administered remifentanil in male rats.

The behavioral economics framework has been used extensively to study factors that control operant behavior, including quantification of reinforcing effectiveness of drugs of abuse. Generally, consumption of a commodity decreases with increasing price, and the rate of decrease reflects demand elasticity, which is inversely related to reinforcing effectiveness. Drugs with low elasticity have greater effectiveness than those with greater elasticity. Price is often manipulated by varying the number of responses required to obtain an infusion (e.g. fixed ratio schedule); however, many studies present the fixed ratio in only one order (usually ascending), which could introduce sequence effects that influence estimates of demand. This study examined the impact of the order of fixed ratio presentation on demand for the mu opioid receptor agonist remifentanil (0.0032 mg/kg/infusion) using an ascending and a mixed order of fixed ratio presentation. Seven male rats lever pressed for intravenous infusions. The fixed ratio varied across 3-session blocks, yielding a demand curve. During the first and third phases, the fixed ratio increased, and, during the second phase, fixed ratio values were presented in a mixed order. On average, rats obtained more than 60 infusions per session under baseline (fixed ratio 1) during the each of the three phases, with the number of infusions received decreasing progressively with increasing fixed ratio values. Estimates of elasticity across the three phases were not statistically different indicating that the order of fixed ratio presentation did not markedly alter estimates of demand and further demonstrating the robustness of price as a source of control over operant behavior, including behavior maintained by drug reinforcers.

Effects of environmental enrichment on self-administration of the short-acting opioid remifentanil in male rats.

Opioid abuse is a major problem around the world. Identifying environmental factors that contribute to opioid abuse and addiction is necessary for decreasing this epidemic. In rodents, environmental enrichment protects against the development of low dose stimulant self-administration, but studies examining the effect of enrichment and isolation (compared to standard housing) on the development of intravenous opioid self-administration have not been conducted. The present study investigated the role of environmental enrichment on self-administration of the short-acting μ-opioid remifentanil. Rats were raised in an enriched condition (Enr), standard condition (Std), or isolated condition (Iso) beginning at 21days of age and were trained to lever press for 1 or 3μg/kg/infusion remifentanil in young adulthood. Acquisition of self-administration and responding during increasing fixed ratio requirements were assessed, and a dose-response curve was generated. In all phases, Enr rats lever pressed significantly less than Std and Iso rats, with Enr rats pressing between 9 and 40% the amount of Iso rats. Enr rats did not acquire remifentanil self-administration when trained with 1μg/kg/infusion, did not increase responding over increasing FR when trained at either dose, and their dose-response curves were flattened compared to Std and Iso rats. When expressed as economic demand curves, Enr rats displayed a decrease in both essential value (higher α) and reinforcer intensity (Q 0) compared to Std and Iso rats at the 1μg/kg/infusion training dose. Environmental enrichment reduced remifentanil intake, suggesting that social and environmental novelty may protect against opioid abuse.

Infralimbic GluN2A-Containing NMDA Receptors Modulate Reconsolidation of Cocaine Self-Administration Memory.

Addiction is characterized by high relapse susceptibility, and relapse can be triggered by drug-associated cues. Cue presentation induces retrieval of the drug-cue memory, which becomes labile and must be reconsolidated into long-term storage. Repeated unpaired cue presentation, however, promotes extinction. Cue-reactivity can be reduced by blocking reconsolidation or facilitating extinction, which are mediated by NMDA receptors (NMDArs). However, the role of NMDArs in either process following self-administration is unclear. Thus, to determine their role in extinction, rats learned to self-administer cocaine before receiving injections of the NMDAr antagonist CPP immediately after four 45-min extinction sessions. During a subsequent 90-min extinction retention test, CPP-treated rats lever pressed less than saline-treated rats indicating that NMDAr blockade facilitated extinction or disrupted drug-cue memory reconsolidation. In addition, infusing CPP into the infralimbic medial prefrontal cortex (IL-mPFC), a structure implicated in extinction, before four 45-min or immediately after four 30min extinction sessions, had similar results during the extinction retention tests. Next, the GluN2A-selective antagonist NVP or GluN2B-selective antagonist Ro25 was infused into IL-mPFC or nucleus accumbens (NAc) shell, another structure implicated in extinction, after four 45-min extinction sessions. Blocking GluN2A-, but not GluN2B-, containing NMDArs, in IL-mPFC or NAc shell reduced lever pressing during the extinction retention tests. Finally, to dissociate reconsolidation from extinction, NVP was infused into IL-mPFC after four 10-min reactivation sessions, which resulted in reduced lever pressing during the retention test. These results indicate that IL-mPFC GluN2A-containing NMDArs modulate reconsolidation, and suggest a novel treatment strategy, as reducing cue reactivity could limit relapse susceptibility.

Systemic injection of the DAD1 antagonist SCH 23390 reduces saccharin seeking in rats

Conditioned cues can elicit drug- and sucrose-seeking behaviors that have been shown to depend on dopamine (DA) D1 receptors. If DAD1 receptors are also involved in seeking behavior in general, blocking these receptors should reduce seeking behavior for a non-caloric, non-drug of abuse reinforcer such as saccharin. Forty-six male Long-Evans rats lever pressed for 0.3% saccharin solution 1 h/day for 10 days. A lever response also activated a tone plus a white stimulus light. This compound stimulus lasted for 5 s. After 1 day of forced abstinence, rats received systemic (0, 1, or 10 μg/kg IP; n = 15–16 per group) injections of SCH 23390 15 min prior to extinction testing. Systemic SCH 23390 reduced saccharin seeking evidenced by a significant reduction in active lever responding and a significant reduction in the number of active lever-contingent deliveries of the tone + light cue following pretreatment with 10 μg/kg SCH 23390. The slope of responding across the Test session in this group was also significantly steeper, indicating that SCH 23390 may have reduced the persistence of saccharin seeking. The results indicate that DAD1 receptors are involved in saccharin seeking and generalize the previously demonstrated anti-seeking effects of DAD1 antagonism to a non-caloric, non-drug of abuse reinforcer.

Wheel-running reinforcement in free-feeding and food-deprived rats

Rats experiencing sessions of 30min free access to wheel running were assigned to ad-lib and food-deprived groups, and given additional sessions of free wheel activity. Subsequently, both ad-lib and deprived rats lever pressed for 60s of wheel running on fixed ratio (FR) 1, variable ratio (VR) 3, VR 5, and VR 10 schedules, and on a response-initiated variable interval (VI) 30s schedule. Finally, the ad-lib rats were switched to food deprivation and the food-deprived rats were switched to free food, as rats continued responding on the response-initiated VI 30-s schedule. Wheel running functioned as reinforcement for both ad-lib and food-deprived rats. Food-deprived rats, however, ran faster and had higher overall lever-pressing rates than free-feeding rats. On the VR schedules, wheel-running rates positively correlated with local and overall lever pressing rates for deprived, but not ad-lib rats. On the response-initiated VI 30s schedule, wheel-running rates and lever-pressing rates changed for ad-lib rats switched to food deprivation, but not for food-deprived rats switched to free-feeding. The overall pattern of results suggested different sources of control for wheel running: intrinsic motivation, contingencies of automatic reinforcement, and food-restricted wheel running. An implication is that generalizations about operant responding for wheel running in food-deprived rats may not extend to wheel running and operant responding of free-feeding animals.

Temporal distributions of schedule-induced licks, magazine entries, and lever presses on fixed- and variable-time schedules.

In this article, schedule-induced drinking (SID) refers to increased drinking by hungry rats exposed to intermittent delivery of food pellets. Two major accounts of SID differ in their explanation of why such drinking tends be concentrated soon after pellet delivery. Temporal discrimination theories propose that drinking is a form of displacement activity that occurs when a pellet is least likely. Adventitious reinforcement theories propose that drinking is displaced to early in an interpellet interval (IPI) by magazine-directed behavior that occurs toward the end of an IPI. The main aim of this study was to examine the latter response-competition account by recording distributions of both licking and magazine entries as SID developed when pellets were delivered to different groups either on a fixed-time (FT 30 s) or on a variable-time schedule (VT 30 s), as in Experiment 1. Although VT 30-s schedules produced essentially flat distributions of magazine entries, licking still tended to be concentrated early in an IPI. Furthermore, there was no indication (Experiments 1 and 2) that magazine entry distributions developed ahead of licking distributions. Experiment 3 examined distributions of lever presses instead of licks: Initially high rates of lever pressing declined both with response-independent schedules (FT and VT) and when a minimal response-dependency was introduced (recycling conjunctive schedule), yet this response also tended to be most frequent soon after pellet delivery. Overall, the data were generally consistent with temporal conditioning theories.

Differential effects of clozapine, metoclopramide, haloperidol and risperidone on acquisition and performance of operant responding in rats.

Prior research has not systematically investigated the effects of systemic antipsychotic drugs on operant response acquisition, specifically their behavioural microstructure, reinforcement blunting and relative potency in acquisition compared to performance once operant responding has stabilized. This study aims to systematically investigate the effects of systemically administered clozapine, metoclopramide, haloperidol and risperidone during free operant response acquisition and performance. Following magazine training, food-restricted male Wistar rats lever pressed for food reward in 15 min daily operant conditioning sessions. All drugs suppressed operant response acquisition and performance. Risperidone and metoclopramide, but not clozapine or haloperidol, suppressed operant responding more potently during acquisition than performance. The dopamine D2-like receptor antagonists haloperidol and metoclopramide that affect the ventral and dorsal striatum blunted reinforcement and decreased inactive lever presses in acquisition. In contrast, the atypical antipsychotics clozapine and risperidone that affect the ventral striatum and prefrontal cortex failed to decrease inactive lever presses during acquisition, suggesting a possible decision-making deficit. Haloperidol decreased active lever pressing over performance days. The drugs did not appear to affect rats' sensitivity to active lever press outcome, even though they suppressed active lever pressing. Results suggest that reinforcement impact during operant acquisition is dependent on dopamine D2 receptors while drugs affecting, among other areas, the prefrontal cortex produce a deficit in ability to suppress inactive lever press responses.

Incubation of saccharin craving and within-session changes in responding for a cue previously associated with saccharin

Time-dependent increases in cue-induced sucrose seeking after forced abstinence have been described in rats with a history of sucrose self-administration, suggesting sucrose craving “incubates”. In the present study, we examined whether the incubation of craving generalizes to the artificial sweetener, saccharin. Thirty-one male Long-Evans rats lever pressed for 0.3% saccharin solution 1h/day for 10days. On either Day 1 or 30 of forced abstinence, rats responded for 1h for presentation of a tone+light cue previously presented with every saccharin delivery during self-administration training. Rats responded more during this cue-reactivity test session following 30 vs. 1day of forced abstinence (“incubation of craving”). This result is the first demonstration of the “incubation of saccharin craving” and suggests that a post-ingestive caloric consequence of self-administration is not a necessary condition for the development of incubation of sucrose craving. We also examined the time course (within-session decreases) of active-lever responding during the 1-h cue-reactivity test session. Rats in the Day 30 group responded more than rats in the Day 1 group from the beginning of the test session. In addition, within-session decreases in responding were shallower in slope in the Day 30 than the Day 1 group. These results indicate that “incubation of saccharin craving” enhances the persistence of seeking behavior.

The mGlu5 positive allosteric modulator LSN2463359 differentially modulates motor, instrumental and cognitive effects of NMDA receptor antagonists in the rat

Metabotropic glutamate 5 (mGlu5) receptors are known to functionally interact with N-methyl-d-aspartate (NMDA) receptors at both neuronal and behavioural levels, in a manner that may be of relevance to the treatment of schizophrenia. We have previously described a novel mGlu5 positive allosteric modulator (PAM), LSN2463359 and provided evidence of its ability to attenuate aspects of the behavioural response to administration of the competitive NMDA receptor antagonist, SDZ 220,581. In addition, LSN2463359 was found to selectively attenuate reversal learning deficits observed in the neurodevelopmental MAM E17 model but not in the acute phencyclidine (PCP) model. In the present study, the interactions between this mGlu5 PAM and the NMDA receptor were explored further by assessing the effects of LSN2463359 against some of the motor, instrumental and cognitive effects induced by the non-competitive NMDA receptor antagonists PCP and MK-801, the competitive NMDA receptor antagonist SDZ 220,581 and the GluN2B selective NMDA receptor antagonist, Ro 63-1908. LSN2463359 had either no or minor impact on locomotor hyperactivity induced by either PCP or SDZ 220,581. However, in rats lever pressing for food rewards under a variable interval 30s schedule of instrumental responding, the drug clearly attenuated not only the suppression of response rate induced by SDZ 220,581 but also the stimulation of response rate induced by Ro 63-1908. In contrast, LSN2463359 failed to alter both of the instrumental effects induced by the open channel blockers PCP and MK-801. In addition, although PCP and SDZ 220,581 induced similar deficits in a discrimination and reversal learning task, LSN2463359 was again only able to reverse the deficit induced by SDZ 220,581. The results indicate that the interactions between mGlu5 and NMDA receptors are dependent on both the mechanism of the blockade of the receptor and the behavioural domain under investigation. Our work has implications for the preclinical use of NMDA receptor antagonists in the prediction of potential therapeutic efficacy in the search for novel treatments for schizophrenia. Positive allosteric modulators of the mGlu5 receptor certainly question the predictive validity of such approaches.This article is part of a Special Issue entitled ‘Cognitive Enhancers’.

Responding during signaled availability and nonavailability of iv cocaine and food in rats: age and sex differences

Research suggests that age and sex are vulnerability factors for drug abuse. However, few studies have systematically examined their interaction. The purpose of the present study was to examine male and female, adult and adolescent rats under a procedure that measures responding during periods of signaled availability and nonavailability of iv cocaine and food reinforcers. Adolescent and adult rats lever pressed for iv infusions of cocaine or food pellets under a procedure with three components of signaled availability of the reinforcer alternating with two components of signaled nonavailability. Adolescent rats were removed and then later retested under the same conditions as adults, and a group of adult rats was also removed and retested after a similar number of days. A subset of rats earning cocaine infusions under the initial test was later retested with food pellets under the same behavioral task to assess the influence of prior cocaine exposure on subsequent responding for a nondrug reinforcer. Adolescents (vs. adults) made more responses during periods of signaled iv cocaine availability and nonavailabiltiy, and adult females responded more than adult males during these periods. Responding during periods of signaled nonavailability of iv cocaine and food did not differ between the initial and subsequent retest conditions in adult rats. Further, adult males and females exposed to cocaine during adolescence responded more during periods of food availability compared to cocaine-naïve adults. These results indicate that sex and age are vulnerability factors in cocaine abuse, and cocaine exposure during critical developmental stages can have long-lasting effects.

Differential Effects of Serotonin 5-HT1A Receptor Agonists on the Discriminative Stimulus Effects of the 5-HT2A Receptor Agonist 1-(2,5-Dimethoxy-4-methylphenyl)-2-aminopropane in Rats and Rhesus Monkeys

Although many drugs act by indirectly stimulating multiple receptors (e.g., reuptake inhibitors), relatively little is known about interactions between agonism at different receptors. This study compared the effect of serotonin (5-HT)(1A) receptor agonists with the discriminative stimulus effects of the 5-HT(2A) receptor agonist 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) in rats and rhesus monkeys. Eight rats discriminated 0.56 mg/kg i.p. DOM and responded under a fixed ratio (FR) 10 schedule of food presentation, whereas three rhesus monkeys discriminated 0.32 mg/kg s.c. DOM and responded under an FR 5 schedule of stimulus shock termination. DOM and the 5-HT(2A) receptor agonists 2,5-dimethoxy-4-n-propylthiophenethylamine (2C-T-7) and dipropyltryptamine (DPT), but not the 5-HT(1A) receptor agonists 8-hydroxy-2-(di-n-propylamino) tetralin hydrochloride (8-OH-DPAT) and 3-chloro-4-fluorophenyl-(4-fluoro-4-([(5-methyl-6-methylaminopyridin-2-ylmethyl) amino) methyl] piperidin-1-yl) methanone (F13714), occasioned responding on the DOM-associated lever in rats and monkeys. Both 8-OH-DPAT and F13714 attenuated the discriminative stimulus effects of DOM in monkeys but not in rats; these effects of 8-OH-DPAT and F13714 were prevented by the 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide (WAY 100635). DPT and 2C-T-7 enhanced the discriminative stimulus effects of DOM in rats and monkeys in an additive manner. Taken together, the results suggest that the DOM discriminative stimulus is pharmacologically similar and mediated by 5-HT(2A) receptors in rats and monkeys; however, the ability of 5-HT(1A) receptor agonists to modify the effects of DOM is markedly different between these species. These results indicate possible differences in the neurobiology of 5-HT systems that could be important for studying drugs that have multiple mechanisms of action (e.g., reuptake inhibitors that indirectly stimulate multiple receptors).

Discriminative Stimulus Effects of 1-(2,5-Dimethoxy-4-methylphenyl)-2-aminopropane (DOM), Ketanserin, and (R)-(+)-α-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-pipidinemethanol (MDL100907) in Rats

Very little is known about constitutive activity in vivo. This study examined whether constitutive activity and inverse agonism contribute to discriminative stimulus effects of drugs acting at serotonin (5-HT)(2A) receptors. Rats were trained to discriminate between saline and either 0.56 mg/kg 5-HT(2) receptor agonist 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM), 1.0 mg/kg 5-HT(2A) receptor antagonist ketanserin, or 0.1 mg/kg purported 5-HT(2A) receptor inverse agonist (R)-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-pipidinemethanol (MDL100907). Discriminative control was established with each drug after 33 to 35 sessions. MDL100907 and ketanserin did not occasion DOM lever responding but attenuated the discriminative stimulus effects of DOM. DOM did not occasion responding on the drug-associated lever in rats discriminating MDL100907 or ketanserin, but attenuated the discriminative stimulus effects of both drugs. Ketanserin and ritanserin occasioned MDL100907-lever responding, whereas rats discriminating ketanserin responded only partially on the drug-associated lever after receiving MDL100907, ritanserin, or the alpha(1)-adrenergic antagonist prazosin. Combining prazosin with MDL100907 or ritanserin resulted in near-complete ketanserin-lever responding, indicating that the ketanserin stimulus involves both 5-HT(2A) and alpha(1)-adrenergic receptors. Administration of p-chlorophenylalanine methyl ester, then fenfluramine, significantly decreased cortical 5-HT, enhanced sensitivity to the discriminative stimulus effects of DOM, and occasioned partial MDL100907-lever responding. Collectively, these results show that DOM and MDL100907 discriminative stimulus effects are mediated by 5-HT(2A) receptors and that ketanserin discriminative stimulus effects involve both 5-HT(2A) and alpha(1)-adrenergic receptors. Results in 5-HT-depleted rats further suggest that the discriminative stimulus effects of MDL100907 might involve antagonism of endogenous 5-HT and/or inverse agonism at 5-HT(2A) receptors.

Context blocking in rat autoshaping: Sign-tracking versus goal-tracking

Prior experience of unsignaled food can interfere with subsequent acquisition by birds of autoshaped key-pecking at a signal light. This has been understood to indicate that unsignaled food results in context conditioning, which blocks subsequent learning about the keylight–food relationship. In the present experiment with rats lever insertion as the conditioned stimulus (CS) preceded sucrose delivery as the unconditioned stimulus (US). Half the rats initially received unsignaled USs in the conditioning context, while the remainder did not. Both lever-presses (sign-tracking) and magazine-entries (goal-tracking) were recorded. Under immediate reinforcement conditions, prior unsignaled US interfered with sign-tracking, but had no effect on goal-tracking. In two further groups, a trace condition prevented development of sign-tracking. In this case, prior context conditioning interfered with goal-tracking. These results suggest that interference with sign-tracking may reflect response competition, while interference with goal-tracking under trace conditions may reflect failure to acquire a CS–US association.

Effect of naltrexone during extinction of alcohol-reinforced responding and during repeated cue-conditioned reinstatement sessions in a cue exposure style treatment

The ability of alcohol-related cues to promote craving can be attenuated independently by giving the opioid antagonist naltrexone (NTX) or by subjecting alcohol-dependent patients to a cue exposure treatment. The effects of cue exposure treatment may be enhanced if conducted in the presence of NTX. The purpose of these experiments was to determine if NTX given during extinction of responding for alcohol in rats would alter cue-conditioned reinstatement of responding and to determine if NTX, paired with repeated cue-conditioned reinstatement, would reduce subsequent cue-conditioned reinstatement or reacquisition of self-administration in the absence of NTX. Rats lever pressed for alcohol in the presence of an olfactory cue. Visual and auditory stimuli were presented during alcohol delivery. In the first experiment, rats were injected with saline or 3 mg/kg NTX prior to extinction sessions followed by cue-conditioned reinstatement tests. In the second experiment, extinction was followed by cue-conditioned reinstatement sessions presented twice per week. The rats received saline or NTX (3 and 10 mg/kg) prior to several sessions. All rats received reinstatement tests with and without a pretreatment of NTX followed by reacquisition of alcohol self-administration. NTX had no effect on responding during extinction or on subsequent cue-conditioned reinstatement. Only 10 mg/kg NTX reduced responding during the twice weekly reinstatement sessions. The twice weekly NTX treatment had no effect on subsequent cue-conditioned reinstatement in the absence of NTX. Reacquisition of responding for alcohol was reduced in the group receiving saline during repeated reinstatement sessions, whereas this effect was blocked in the NTX group. These findings support the notion that NTX given during a brief abstinence period (i.e., extinction) has minimal effects on future sensitivity to alcohol cues and alcohol consumption. NTX given during the repeated alcohol cue exposure does not alter the subsequent incentive value of alcohol cues in the absence of NTX or enhance the beneficial effects of cue exposure treatment.

Cold Turkey and MAP Kinase

Glial cell line-derived neurotrophic factor (GDNF) acts in the ventral tegmental area (VTA) of the brain, a brain region associated with drug-seeking behavior, to decrease self-administration of ethanol in mice. Its receptor is a complex that includes a glycosyl-phosphatidylinositol-linked GDNF family receptor and the receptor tyrosine kinase Ret. Carnicella et al . further explored the signaling mechanisms of GDNF and its effects on ethanol-drinking behavior. Administration of GDNF into the VTA, but not other nearby brain areas, reduced the frequency with which mice activated a lever that administered a dose of ethanol. After treatment of animals with GDNF or saline solution, initial rates of lever pressing for an ethanol reward were similar, but GDNF-treated animals repeated the ethanol-seeking behavior less often and terminated sessions of drinking earlier than did control animals. These effects were evident within 10 minutes after administration of GDNF and were associated with increased activity of the mitogen-activated protein kinases (MAPKs) ERK1 and 2 (ERK1/2). Pharmacological inhibition of the MAPK pathway prevented the effects of GDNF. Administration of GDNF also was effective in a mouse model of relapse of drinking behavior after a period of extinction of the behavior. The authors conclude that GDNF appears to reduce the incentive value of alcohol and the strength of behavioral reinforcement associated with alcohol consumption. Interestingly, GDNF did not alter self-administration of a "natural" reward such as sucrose. The effect in the relapse model suggests that GDNF’s effects extend to modification of ethanol-seeking behavior, as well as limiting ethanol consumption. Thus, the authors propose that GDNF signaling in the VTA might be a useful target for therapeutic intervention in alcoholism in humans. S. Carnicella, V. Kharazia, J. Jeanblanc, P. H. Janak, D. Ron, GDNF is a fast-acting potent inhibitor of alcohol consumption and relapse. Proc. Natl. Acad. Sci. U.S.A. 105 , 8114-8119 (2008). [Abstract] [Full Text]

AVOIDANCE OF TIMEOUT FROM RESPONSE‐INDEPENDENT FOOD: EFFECTS OF DELIVERY RATE AND QUALITY

In three experiments, a rat's lever presses could postpone timeouts from food pellets delivered on response-independent schedules. In Experiment 1, the pellets were delivered at variable-time (VT) rates ranging from VT 0.5 to VT 8 min. Experiment 2 replicated the VT 1 min and VT 8 min conditions of Experiment 1 with new subjects. Finally, subjects in Experiment 3 could postpone timeouts from delivery of pellets that differed in quality rather than quantity (unsweetened versus sweetened pellets). In general, response rates and success in avoiding increased as a function of the rate and quality of the pellets. Also, performance efficiency increased as the experiments progressed, that is, the avoidance response occurred later and later in the response-timeout interval. The results support the conclusion that timeout from reinforcement has functional properties similar to those of more commonly studied aversive stimuli (e.g., shock).

Heightened drug-seeking motivation following extended daily access to self-administered cocaine

Rats allowed extended daily access (6 h) to cocaine, consume high doses of the drug and escalate their cocaine intake over days, resembling the pattern of cocaine use seen in human addicts. The current study was designed to test whether such animals would also demonstrate the heightened motivation to seek cocaine seen in human addicts. Rats were trained to lever press for i.v. cocaine (0.25 mg/infusion) over a 5-day period of 1 h sessions. Subjects were then assigned to either a brief-access (1 h/day) or an extended-access condition for an additional 10 days. Control rats lever pressed for i.v. saline. Following the final self-administration session animals were tested for their motivation to receive cocaine in an operant runway apparatus. Extended-access animals exhibited significantly higher motivation for cocaine in the runway (where they received 1.0 mg/kg cocaine i.v. upon goal-box entry) as was evident by faster run times and less ambivalence about entering the goal box (i.e. retreat behavior) than either brief-access or control subjects. Brief and extended-access animals, tested in the Elevated Plus Maze, exhibited comparable and significant increases in anxiety following a single 1.0 mg/kg i.v. injection of cocaine, as compared to saline control animals that were challenged with i.v. saline infusion. Together, these data suggest that extended access to cocaine results in an especially high motivation for the drug that is not accounted for by reductions in the anxiogenic properties of cocaine.