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PubMed2004

Individual differences in sensitivity to factors provoking reinstatement of cocaine-seeking behavior.

Among cocaine addicts, there is a strong variation in response to relapse provoking factors like conditioned cues and renewed contact with the drug. Here we show that such large individual differences also exist in rats. Reinstatement of extinguished cocaine-seeking behavior was triggered by contingent presentation of a cocaine-conditioned cue or an amphetamine priming injection. We found no positive correlation between cue- and drug-controlled reinstatement of cocaine seeking. Rather, a slight, but significant negative correlation was observed, which was particularly evident in two subgroups of rats that responded highest following either amphetamine priming or cue presentation. A large middle group responded equally for both relapse provoking factors. Further, cocaine-seeking behavior during the first extinction session correlated positively with cue-induced reinstatement. In conclusion, the present findings indicate that the therapeutic efficacy of relapse prevention strategies may depend on individual sensitivity to distinct relapse provoking stimuli.

Amphetamine↗
PubMed2005

Sequential behavior in the rat: a new model using food-reinforced instrumental behavior.

Sequential behavior, probably reflecting procedural learning, has intensively been investigated in humans. This work has mainly been done using so-called serial reaction time tasks. In such tasks, subjects have to respond rapidly to simple visual stimuli appearing at one of four locations by pressing a corresponding response key. Unknown to the subjects, these stimuli can follow a specific repeating sequence. Learning of such a sequence is typically inferred from faster reaction times to sequence as compared to random blocks of stimuli. In contrast to human subjects, the analysis of sequential behavior has received considerably less attention in rodents, possibly due to the lack of analogous animal models there. In order to establish such a model, a method was developed in rats to investigate serial reactions under conditions of random or sequential stimulus presentation. Operant testing chambers were used which consisted of four nose-poke holes with cue lights. These holes were arranged in a square fashion with a pellet receptacle in the center. The task of the rat was to rapidly respond to an illuminated hole by poking into it in order to obtain food. The stimulus locations varied permanently, and these changes pursued either a random or serial order. In three experiments with differing methodological details, responding under such conditions was analyzed with sequences consisting of 6, 12 or 13 positions. Evidence was obtained that rats can improve their performance under sequence as compared to random conditions, for example, with respect to the percentage of reinforcements obtained, or with respect to reaction times. Furthermore, methodological factors, like response requirements, were addressed which may critically affect experimental outcome. Together, this new kind of instrumental task might be useful to analyze sequential performance in the rat, and the brain mechanisms by which it is mediated.

Analysis of Variance↗
PubMed2005

Behavioral effects of intra-cranial self-stimulation in an animal model of attention-deficit/hyperactivity disorder (ADHD).

Attention deficit/hyperactivity disorder (ADHD), characterized by inappropriate levels of activity, attention, and impulsivity, has been suggested to be caused by changes in reinforcement and extinction processes possibly linked to dysfunctioning dopamine systems. The present study investigated reinforcement processes in spontaneously hypertensive rats (SHR), an animal model of ADHD. Using intra-cranial self-stimulation (ICSS), behavioral effects of varying current intensity, reinforcer density, and reinforcer delay were tested. Current was varied in order to find the weakest current producing the maximal response rate (optimal current) in the SHR and the controls during high (120 reinforcers/min) and low reinforcer densities (1 reinforcer/min). The results showed that optimal current was significantly lower in the SHR than in the controls during high reinforcer density while maximal response rates were not significantly different. During low reinforcer density, optimal current was not significantly different in the two strains, but maximal response rate was significantly higher in the SHR than in the controls. The SHR produced more responses during the testing of reinforcer density, but changes in reinforcer density affected response rates similarly in the two strains. The decrease in response rate as a function of reinforcer delay was more pronounced in the SHR than in the controls. Overall, more responses with short inter-response times (IRT) were found in the SHR compared to the controls during intermittent reinforcement. The results are consistent with a steepened delay-of-reinforcement gradient in SHR.

Analysis of Variance↗
PubMed2005

Slower extinction of responses maintained by intra-cranial self-stimulation (ICSS) in an animal model of attention-deficit/hyperactivity disorder (ADHD).

Children with attention-deficit/hyperactivity disorder (ADHD) show performance deficits and excessive motor activity during extinction and in situations where no reinforcer can be identified, suggesting an extinction deficit in ADHD possibly linked to dopamine dysfunction. The present study examined extinction of responding previously maintained by intra-cranial self-stimulation (ICSS) in spontaneously hypertensive rats (SHR), an animal model of ADHD using three different extinction procedures. Delivery of electrical pulses were terminated altogether or presented independently of responding using two different current intensities. The results showed that more responses were retained in the SHR, especially during the initial transition from ICSS-maintained responding to response-independent delivery of electrical pulses with current reduced relative to that given during reinforcement. Slower extinction of previously reinforced behavior is suggested as an alternative explanation for the frequently observed increased behavioral output that has previously been interpreted as "disinhibition" of behavior in ADHD.

Analysis of Variance↗
PubMed2006

Nucleus accumbens lesions decrease sensitivity to rapid changes in the delay to reinforcement.

Both humans and non-humans discount the value of rewards that are delayed or uncertain, and individuals that discount delayed rewards at a relatively high rate are considered impulsive. To investigate the neural mechanisms that mediate delay discounting, the present study examined the effects of excitotoxic lesions of the nucleus accumbens (NAC) on discounting of reward value by delay and probability. Rats were trained on delay (n=24) or probability discounting (n=24) tasks. Following training, excitotoxic lesions of the NAC were made by intracranial injections of 0.5 microl 0.15 M quinolinic acid (n=12) or vehicle (n=12) aimed at the NAC (AP +1.6, ML +/-1.5, DV -7.1). NAC lesions did not alter performance in animals tested with a constant delay (4s) or probability (0.4) of reinforcement. However, when tested with between session changes in the delay (0, 1, 2, 4, and 8s) of reinforcement, the lesioned rats had flatter discount curves than the sham group, indicating that they were less sensitive to frequent changes in the delay to reward. In contrast, the NAC lesions did not affect discounting of probabilistic rewards. NAC lesions impaired the ability to adapt to frequent between session changes in the delay to reward but did not increase or decrease discounting when the delay was held constant across sessions. NAC lesions may disrupt the ability of the animals to predict the timing of delayed rewards when the delay to reward is changed frequently.

Animals↗
PubMed2004

Amount-dependent temporal discounting?

Amount-dependent temporal discounting has been demonstrated for human choice between outcomes differing in amount and delay. In the only study to date with non-humans, Grace reported no evidence for amount-dependent temporal discounting with pigeons in a concurrent-chains procedure. The present experiments repeated Grace's procedure but with modifications to enhance the discrimination between small and large magnitude outcomes. In Experiment 1, sensitivity of pigeons' initial-link choice to the terminal link delay ratio was greater with large reinforcer durations in the terminal links than with small reinforcer durations. This result is consistent with a greater rate of temporal discounting for larger reinforcers (the reverse of the result for humans), but can also be explained as enhanced discrimination of delay ratios with larger reinforcer durations. The results of a second experiment supported Grace's conclusion that amount-dependent temporal discounting does not characterize pigeons' choice in concurrent chains. Because reinforcer amount was held constant between choice alternatives in the present experiments and that of Grace, but varied in the human studies, our results question whether prior demonstrations of amount-dependent discounting reflect the effects of reinforcer delay or of reinforcer amount. Differences in the procedures used to study discounting in humans (titration procedures) and non-humans (concurrent chains) may contribute to the divergent results across species.

Animals↗
PubMed2004

Interval timing in Siamese fighting fish (Betta splendens).

The present study evaluated the temporal performance of Siamese fighting fish (Betta splendens) given short-term exposure to four fixed interval (FI) schedules of reinforcement, FI 30, 60, 120, and 240 s, during which a reinforcer (mirror image) was given for the first response (swimming through a hoop) after the interval requirement had elapsed. Response levels were generally low early in an interval and increased as the interval elapsed; wait times and break points in an interval increased with increases in the FI requirement. The results were similar to that obtained with other species and different types of responses and reinforcers, and demonstrate that the procedure is a feasible method for studying interval timing in fish.

Animals↗
PubMed2005

Prazosin, an alpha-1 adrenergic antagonist, reduces cocaine-induced reinstatement of drug-seeking.

BACKGROUND: Norepinephrine is implicated in cocaine's behavioral effects. In this study, we tested the effect of prazosin, an alpha1-adrenergic receptor antagonist, on cocaine-induced reinstatement of drug-seeking behavior. METHODS: Rats were trained to self-administer cocaine intravenously under a fixed-ratio 3 schedule of reinforcement. After behavior was established, cocaine was replaced with saline and behavior extinguished. The ability of cocaine (0, 5-20 mg/kg) alone or combined with prazosin (.3 mg/kg) to reinstate lever press responding was tested. The effects of prazosin on lever press responding for food was examined in another set of rats. RESULTS: Cocaine induced a dose-dependent reinstatement of drug-seeking behavior that was significantly attenuated by prazosin. This dose of prazosin did not alter lever press response rates for food. CONCLUSIONS: The attenuation in drug-induced reinstatement is likely not due to prazosin-induced suppression of activity. These results suggest alpha1-adrenergic mechanisms contribute to reinstatement in rats and perhaps, to relapse in addicts.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed2006

Temporal memory in mature and aged rats is sensitive to choline acetyltransferase inhibition.

The effects of a potent inhibitor of choline acetyltransferase (ChAT), BW813U, on timing behavior in mature (6-10 months) and aged (26-30 months) male rats were assessed. Twenty rats were trained on a discrete trial 20-s peak-interval (PI) procedure. During baseline (non-drug) training, the time of the maximum response rate (peak time) for mature rats was approximately at the time of scheduled reinforcement, but peak time for aged rats was reliably later. A single administration of BW813U (100 mg/kg, ip) produced a long-lasting increase in peak time for both mature and aged rats that occurred gradually and was synergistic with age. These horizontal shifts in peak time indicate a change in the content of reference memory for the remembered time of reinforcement that is similar for both aging processes and BW813U administration. When a 5-s gap was imposed in the signal, PI-GAP procedure, control rats of both ages summed the signal durations before and after the gap, whereas rats given BW813U showed no retention of the signal duration prior to the gap. This loss of trial-specific temporal information suggests a drug-induced working memory dysfunction. Taken together, these results demonstrate that both working and reference memory for temporal information are sensitive to choline acetyltransferase inhibition in rats.

Acetylcholine↗
PubMed2004

Using growth models to relate acquisition of nicotine self-administration to break point and nicotinic receptor binding.

Growth modeling can be used to characterize individual and mean acquisition trajectories for drug self-administration. Individual characteristics can also be incorporated into the growth model, providing a powerful tool for investigating the relationship between acquisition and other behavioral and biological measures. We illustrate the utility of this method by examining the relationship between acquisition of nicotine self-administration and (1) break point on a progressive ratio schedule of reinforcement, and (2) the density of brain nicotinic receptors (B(max)). Daily infusion rates from male and female Sprague-Dawley rats were modeled with break point or B(max) as time-invariant covariates. Use of this model led to two novel findings regarding individual differences in acquisition. First, greater rates of change in infusions early in acquisition were related to higher break points; this relationship was mediated by a similar effect of increasing the number of responses required to obtain nicotine. Second, animals displaying more resistance to increases in the response requirement during acquisition, as indicated by a smaller drop in the rate of nicotine self-administration, generally had fewer nicotinic receptors at the end of the experiment. The relationships revealed demonstrate the usefulness of growth models in the quantitative analysis of individual differences in drug self-administration behavior.

Animals↗
PubMed2004

Analyzing the acquisition of drug self-administration using growth curve models.

Current approaches to studying acquisition of drug self-administration have modest power to detect individual differences in the pattern of acquisition or to efficiently and accurately describe trajectories of behavior change. Methodological advances in human research have elucidated approaches to describing repeated measure data that focus on modeling the behavior of individual subjects. In this article, we re-analyzed data published in using growth curve modeling to characterize the acquisition of nicotine-taking in rats. Change over time in the infusion rate was examined, revealing that the acquisition process could be described with a quadratic equation represented by intercept, slope, and acceleration parameters. Unit dose of nicotine, sex and fixed ratio (FR) schedule of reinforcement had significant effects on the acquisition curves. Dose altered the absolute rate of infusions, but not the slope or acceleration, indicating that, when an effective dose was available, the shape of acquisition trajectories was not affected by dose. In addition, dose impacted acquisition by moderating the disruption in infusion rates after an increase in the response requirement. Thus, the role of a higher dose may not be to accelerate the acquisition process but to lead to behavior that is more resistant to change. Trajectories differed between males and females at the smallest dose, but these differences dissipated by the end of acquisition. Growth curve modeling captures the process of acquisition of drug self-administration and facilitates a greater understanding of the individual differences in change in drug-taking behavior over time.

Animals↗
PubMed2005

Suppression of alcohol self-administration and cue-induced reinstatement of alcohol seeking by the mGlu2/3 receptor agonist LY379268 and the mGlu8 receptor agonist (S)-3,4-DCPG.

Glutamatergic neurotransmission has been suggested to modulate cue-induced drug-seeking behavior. Here we examined the effects of metabotropic glutamate receptor agonists on alcohol self-administration and cue-induced reinstatement. Rats were trained to self-administer 10% w/v ethanol under an FR1 schedule of reinforcement during 30-min sessions. In the reinstatement experiments, ethanol and a non-rewarding quinine solution (available on alternating days) were paired with olfactory stimuli (S+/S-) as well as light (CS+) or tone (CS-) stimuli. Following extinction training, reinstatement of responding was induced by the ethanol-associated stimuli (S+/CS+). The mGlu2/3 receptor agonist LY379268 (0, 1, 3 and 5 mg/kg i.p.) and the mGlu8 receptor agonist (S)-3,4-DCPG (0, 5, 10 and 15 mg/kg i.p.) attenuated alcohol self-administration and reinstatement at doses that decreased also spontaneous locomotor activity. The results suggest that metabotropic glutamate receptors may have a role in the modulation of alcohol seeking and self-administration. However, further studies with ligands with fewer motor-suppressant side effects are needed.

Alcohol Drinking↗
PubMed2006

Weighing up the benefits of work: behavioral and neural analyses of effort-related decision making.

How we decide whether a course of action is worth undertaking is largely unknown. Recently, neuroscientists have been turning to ecological approaches to address this issue, examining how animals evaluate the costs and benefits of different options. We present here evidence from rodents and monkeys that demonstrate the degree to which they take into account work and energetic requirements when deciding what responses to make. These calculations appear to be critically mediated by the anterior cingulate cortex (ACC) and mesolimbic dopamine (DA) pathways, with damage to either causing a bias towards options that are easily obtained but yield relatively smaller reward rather than alternatives that require more work but result in greater reward. The evaluation of such decisions appears to be carried out in systems independent of those involved in delay-discounting. We suggest that top-down signals from ACC to nucleus accumbens (NAc) and/or midbrain DA cells may be vital for overcoming effort-related response costs.

Animals↗
PubMed2004

Exposure to cadmium during gestation and lactation decreases cocaine self-administration in rats.

This investigation examined the effects of perinatal cadmium exposure on subsequent self-administration of cocaine during the adult cycle. Female Sprague-Dawley rats were gavaged daily with 0.0 (14% sucrose solution, w/v) or 5.0 mg cadmium chloride (dissolved in 14% sucrose solution, w/v) for 30 days prior to breeding with non-exposed males. Dams continued to experience cadmium exposure through gestation and until pups were weaned at postnatal day (PND) 21. On PND 70, offspring were anesthetized and chronic indwelling jugular catheters were implanted. Following recovery, test subjects were trained in operant chambers to self-administer 0.500 mg/kg infusion (inf) intravenous cocaine on a fixed-ratio (FR) 2 schedule of reinforcement. Following acquisition, self-administration rates were tested for saline, 0.030, 0.060, 0.125, 0.250, and 0.500 mg/kg inf cocaine. Rats exposed developmentally to cadmium self-administered significantly less than controls at saline, 0.030, and 0.060 mg/kg inf cocaine. These data indicate that early-life cadmium exposure, a common exposure vector of which is the use of tobacco products, may affect cocaine sensitivity.

Animals↗
PubMed2006

Environmental enrichment reduces impulsivity during appetitive conditioning.

Although environmental enrichment is presumed to enhance learning, appetitive behavior may also be altered by this experience: anticipatory responding for sucrose is reduced in environmentally enriched (EE) rats [van der Harst, J.E., Baars, A.M. and Spruijt, B.M. Standard housed rats are more sensitive to rewards than enriched housed rats as reflected by their anticipatory behaviour. Behav Brain Res 2003;142:151-156]. To assess the impact of differential environmental experience on learning and appetitive behavior, we trained 17 EE and socially isolated (SI) rats in a three-phase, operant-shaping procedure for sucrose reinforcement. In phase one, a feeder cue was paired with sucrose availability. In phase two, a nose poke to either one of two lit holes on the opposing wall activated the feeder cue. In phase three, the feeder cue was elicited by a poke to a single lit hole. While acquisition rates in phase one and phase two were similar, EE animals reached phase-three criteria [completion of 100 trials in 45 min and 15 or fewer bad pokes] faster than SI animals. These two groups showed similar session completion rates, reinforced and non-reinforced licking responses, and overall behavioral activity during phase three acquisition; however, SI rats performed more bad pokes (responses to the non-lit hole after nose-poke cue onset) and intertrial interval (ITI) pokes during this training period. Because all ITI (and presumably many bad) pokes were initiated before onset of nose-poke cue, this difference indicates greater anticipatory responding in SI animals. This experience-dependent alteration in appetitive behavior may explain, in part, the tendency of SI rats to show attenuated learning rates in appetitive contexts in which complex contingencies exist.

Animals↗
PubMed1997

Investigations into the nature of a 7-OH-DPAT discriminative cue: comparison with D-amphetamine.

In the present study, separate squads of rats were trained to discriminate either the dopamine D3 receptor preferring ligand 7-hydroxy-2-(di-N-propylamino)-tetralin (7-OH-DPAT) (0.03 mg/kg) from saline, or D-amphetamine (0.3 mg/kg) from saline using a standard operant schedule (FR10 schedule reinforcement). Following stable acquisition of responding, tests of generalisation and antagonism were conducted. A number of dopamine agonists having high dopamine D2-like receptor (D2, D3 or D4) affinity generalised to the 7-OH-DPAT, but not amphetamine, cue. The dopamine D2/3 receptor agonist SKF38393 showed no generalisation to either drug cue. Subsequent correlational analysis suggested that this effect was most likely mediated through the dopamine D3 receptor. The dopamine D2/3 receptor antagonist raclopride significantly attenuated both cues. The failure of these drugs to generalise to amphetamine, suggest that there is little involvement of the dopamine D3 receptor subtype in mediating its discriminative stimulus properties.

Animals↗