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PubMed1997

Serum anticholinergic activity and behavior following atropine sulfate administration in the rat.

Anticholinergic agents such as atropine and scopolamine have long been suggested to produce delirium-like states in humans and experimental animals. Evidence for an anticholinergic mechanism in the pathogenesis of human delirium has accumulated, leading to studies of the behavioral effects of the anticholinergic drug atropine in animals. The current study addresses the adequacy of animal models of delirium in terms of sensitivity, specificity and pharmacological relevance. A multiple fixed-ratio fixed-interval reinforcement schedule was used to test the effects of relatively low doses of atropine on behavior in rats. Additionally, total serum anticholinergic activity (SAA) was measured under dose and time course conditions identical to those used in the behavioral study. Atropine reduced high and low rates of responding in a dose-dependent manner, and SAA increased in a dose dependent manner. SAA at atropine doses of 0.1 mg/kg to 1.0 mg/kg was similar to that found in delirious humans. These behavioral and serum level data suggest that relatively low doses of atropine, substantially below those used in previous attempts to model delirium using rats, may be more pharmacologically relevant to delirium and may minimize non-specific peripheral effects of this drug.

Animals↗
PubMedDate not supplied

Success of autonomic operant conditioning of heart rate without involving contractions of somatic skeletal muscles.

In conscious Wistar rats neuromuscularly paralysed by gallamine, operantly conditioned reduction of heart rate was achieved under both negative and positive reinforcement schedules using the tail shock avoidance or the rewarding brain-stimulations in 20-min test sessions. The primary aim was to assess whether it would be possible to achieve operant conditioning of the heart rate, evoked not as a secondary reflex response of any voluntary skeletal muscular contractions of trunk but as a conditioned voluntary function of the central autonomic regulation of a visceral organ, since this entire subject was peculiarly left in confusion by Miller (5, 8) who wanted that others should independently study it. This study revealed interestingly that not every subject might be able to achieve the visceral learning in a given set of conditions, and suggested that this type of a special learning might be dependent on individual predisposition in the central nervous system. In the present study, 15 showed the learning, out of the 58 subjects assessed. It was also observed that there was a variation in the magnitude of the learning response among different learners, and, also, in the same subject in different sessions conducted on different days. This is considered as an indication that this type of conditioned autonomic function is probably not easily recruited into the long-term memory mechanisms. The overall average of the operant lowering of the heart rate progressively achieved by the end part of the learning session was about 10.5% from the basal average rate, and the score of reinforcement (per cent of painful tail shocks avoided, or of increase in number of brain shocks achieved) was over 80%. The extinction test confirmed the learning. Control experiments revealed that the conditioned heart rate changes were not due to any unconditioned stimulus effects. The learning observed under the brain-stimulation reinforcement was confirmed by losing the learning response after lesioning the site of the rewarding stimulation. The visceral operant learning occurring in state of somatomotor paralysis under both negative and positive types of reinforcement was blocked by haloperidol. Morphine delayed the onset of the pain avoidance operant learning, whereas it speeded up the hedonic brain-stimulation operant learning. The results, considered from all the above angles, dispell the doubt previously expressed about the occurrence of the operant conditioning of heart rate under a visceral learning paradigm.

Animals↗
PubMed1996

Low doses of apomorphine suppress operant motor performance in rats.

The purpose of this study was to examine the effects of low doses of apomorphine on motor performance. Six rats were rewarded with sugar water on a partial reinforcement schedule for pressing force-sensitive beams with a minimum force of 1 g. The kinetics of individual responses and the temporal characteristics of response sequences were measured; open field locomotor activity was also measured in a separate apparatus. Apomorphine (APO), amphetamine (AMP), and haloperidol (HAL) were administered systemically. It was found that low doses of APO (0.03 and 0.1 mg/kg, SC) produced weaker and longer beam presses. These decreases in response peak force resulted from decreases in the rate of rise of force. APO also caused disproportionate lengthening of beam release time. In addition, the low doses of APO increased the time intervals between consecutive components of response sequences. These low doses of APO are known to decrease dopaminergic tone. Hence, the observed pattern of motor dysfunctions produced by APO is similar to the bradykinesia seen in human Parkinson's disease.

Amphetamine↗
PubMed2001

The effects of excitotoxic lesions of the nucleus accumbens core or shell regions on intravenous heroin self-administration in rats.

RATIONALE: It has been suggested that the nucleus accumbens (NAcc) may be involved in heroin reward, and the core and shell regions respond differently following administration of a number of drugs of abuse. OBJECTIVE: The possible role of the NAcc core and shell subregions in the acquisition of heroin self-administration behaviour was investigated. METHODS: Rats were given selective excitotoxic lesions of either the nucleus accumbens core or shell before the acquisition of responding for i.v. heroin (0.04 mg/infusion) under a continuous reinforcement schedule in daily 3 h sessions. After sham-lesioned rats reached a stable baseline, a between-sessions heroin dose-response function was established. RESULTS: Rats with lesions of the NAcc shell did not differ significantly from sham controls in either the acquisition of heroin self-administration or in their heroin dose-response function. The NAcc core lesion group showed reduced levels of responding during the acquisition of heroin self-administration and a reduction in responding during the heroin dose-response function, although this behaviour was sensitive to changes in the dose of heroin. CONCLUSIONS: The NAcc shell does not appear to be critical for heroin self-administration, whereas the NAcc core, although apparently not essential in mediating the rewarding effect of i.v. heroin, may mediate processes that are of special importance during the acquisition of instrumental behaviour.

Animals↗
PubMed1993

D-amphetamine-like stimulus properties are produced by morphine injections into the ventral tegmental area but not into the nucleus accumbens.

We investigated whether injections of morphine into the ventral tegmental area (VTA) or the nucleus accumbens (NAS) could produce amphetamine-like stimulus properties and locomotor stimulant effects. Rats were trained to discriminate 1.0 mg/kg D-amphetamine from saline using both VI-30 and FR-16 reinforcement schedules and they were then tested following bilateral injections of morphine sulfate (2.5, 5.0 and 10.0 micrograms/side) either into the VTA or the NAS. Intra-VTA injections of morphine produced significant increases in amphetamine-lever responding that were comparable to increases observed following intra-NAS D-amphetamine (2.5, 5.0 and 10.0 micrograms/side). Such increases were not observed, however, following intra-NAS injections of morphine. Tests for the effects of intracerebral morphine and D-amphetamine on locomotor activity produced a similar pattern of results. Locomotor activity was increased following intra-VTA morphine and intra-NAS D-amphetamine injections, but not after intra-NAS morphine injections. Together, these findings indicate that activation of opioid receptors within the VTA, but not the NAS, can produce a behavioral state which mimics to some degree the state produced by systemic and intra-NAS injections of D-amphetamine.

Animals↗
PubMed1993

Low-response-rate conditioning history and fixed-interval responding in rats.

Bar presses by one group of rats were conditioned under a differential-reinforcement-of-low-rate reinforcement schedule immediately prior to conditioning under a fixed-interval schedule. In a second group of rats, bar presses were conditioned first under a differential-reinforcement-of-low-rate schedule and then under a fixed-ratio schedule prior to conditioning under a fixed-interval schedule. Low response rates occurred under the fixed-interval schedule only when it was immediately preceded by low-rate conditioning. Otherwise, fixed-interval responding was similar to responding under the fixed-ratio schedule. This finding suggests that responses of laboratory animals are sensitive to immediate history, and, unlike human responses, are relatively insensitive to a history of low-rate conditioning when it is followed by high-rate conditioning.

Animals↗
PubMed2005

Generalization to atypical antipsychotic drugs depends on training dose in rats trained to discriminate 1.25 mg/kg clozapine versus 5.0 mg/kg clozapine versus vehicle in a three-choice drug discrimination task.

The prototypical atypical antipsychotic drug (APD) clozapine (CLZ) elicits a discriminative cue that appears to be similar to the stimulus properties elicited by atypical, but not typical, antipsychotic drugs in two-choice drug discrimination procedures. However, the ability of CLZ to generalize to atypical APDs depends on the training dose, since several atypical APDs (e.g. sertindole, risperidone) do not substitute for a 5.0 mg/kg CLZ training dose in rats, but do so for a 1.25 mg/kg CLZ training dose. Yet, a 1.25 mg/kg CLZ discriminative stimulus has not generalized to all atypical APDs either (e.g. quetiapine); thus, both 1.25 mg/kg and 5.0 mg/kg CLZ discriminative stimuli may be necessary to provide a better screen for atypical APDs. The present study sought to determine whether a three-choice 1.25 mg/kg CLZ versus 5.0 mg/kg CLZ versus vehicle drug discrimination task in rats might better distinguish atypical from typical APDs. Adult male Sprague-Dawley rats were trained in this three-choice drug discrimination task with a fixed ratio 30 reinforcement schedule for food. Clozapine produced full substitution (>or=80% condition-appropriate responding) for both the 1.25 mg/kg CLZ dose (ED50=0.09 mg/kg) and the 5.0 mg/kg CLZ dose (ED50=2.71 mg/kg). The atypical APD olanzapine produced full substitution for the 5.0 mg/kg CLZ dose, but not for the 1.25 mg/kg CLZ dose (ED50=1.55 mg/kg). In contrast, the atypical APD quetiapine produced full substitution for the 1.25 mg/kg CLZ dose (ED50=0.13 mg/kg), but not for the 5.0 mg/kg CLZ dose. Similarly, the atypical APD sertindole produced full substitution for only the 1.25 mg/kg CLZ dose (ED50=0.94 mg/kg). Risperidone, another atypical APD, produced partial substitution (>or=60% and <or=80% condition-appropriate responding) for the 1.25 mg/kg CLZ dose, and failed to substitute for the 5.0 mg/kg CLZ dose. The atypical APD ziprasidone and the typical APDs haloperidol and chlorpromazine failed to substitute for either CLZ training dose. These results demonstrated that the 1.25 mg/kg CLZ training dose provides partial or full stimulus generalization to more atypical APDs than does the 5.0 mg/kg CLZ training dose. Full substitution by olanzapine for only the 5.0 mg/kg CLZ dose suggests that this higher training dose is also important for screening atypical APDs.

Animals↗
PubMed1995

The effects of nucleus accumbens dopamine depletions on continuously reinforced operant responding: contrasts with the effects of extinction.

Two experiments were undertaken to study the role of nucleus accumbens dopamine (DA) in instrumental lever pressing on a continuous reinforcement schedule (CRF). In the first experiment, the neurotoxic agent 6-hydroxydopamine was infused directly into the nucleus accumbens to investigate the effects of DA depletion on lever pressing performance. DA depletion had only a modest effect on the total number of lever presses, and there was a significant effect on total lever presses only on the first test day (third day postsurgery). Analyses also were performed on responding across the 45-min session by breaking down the session into three 15-min periods. During the test session on day 3 postsurgery, there was a significant group x time interaction, with DA-depleted rats showing a significant reduction in the numbers of responses in the first 15-min period, but no significant effects over the second or third 15-min period within the session. Although control rats showed a within-session decline in responding, the DA-depleted rats did not. In addition, analysis of interresponse times (IRTs) indicated that accumbens DA depletions produced a slowing of the local rate of responding as indicated by a significant decrease in high rate (i.e., short-duration IRT) responses and an increase in low rate (i.e., long-duration IRT) responses. In a second experiment, the effects of extinction on CRF performance were investigated. Unlike the effects of nucleus accumbens DA depletion, extinction produced lower levels of responding throughout the entire test session.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1998

Clinical behavior therapy and the experimental analysis of behavior.

Advances in areas of behavior analysis are discussed to show the relevance of experimental science to behavior therapy. It is concluded that there are many areas of mutual interest between experimental operant psychologists and behavior therapists that may serve to enhance the clinical efficacy and range of behavior problems addressed by behavior therapists. Specific examination is given to areas of experimental behavior analysis such as reinforcement, including schedules of reinforcement; the matching law; advanced issues in stimulus control; the interaction between operant and classical conditioning; behavioral momentum; rule-governed behavior; and stimulus equivalence. The argument that behavior therapists are not knowledgeable about behavior analysis is disputed, and it is concluded that behavior therapists are in a unique position to be the practice professionals best able to utilize the principles of learning and behavior analysis in the service of adaptive behavior change.

Behavior↗
PubMed1985

The effect of peripheral noradrenaline depletion on responding on a schedule of differential reinforcement of low rates of response (DRL).

First, it was confirmed that systemic injection of the neurotoxin 6-hydroxydopamine HBr (30 mg/kg IP) depleted noradrenaline levels in rat heart, but not centrally. Losses averaged 90% of control 1 day after injection, and 50% at 42 days. The same drug and dose was then administered to 50% of a group of rats which had been trained to lever-press for food reward on continuous reinforcement (CRF). After further CRF sessions, the rats were changed to a schedule of Differential Reinforcement of Low Rates of Response with a 20-s criterion (DRL 20). The drugged rats earned fewer reinforcements during DRL than did controls, and made fewer responses. Temporal discrimination (shown by the IRT/Opp distribution) was disrupted. It is concluded that peripheral noradrenergic systems may be involved in the control over responding by temporal cues associated with reward and non-reward.

Analysis of Variance↗
PubMed2005

Complex discriminative stimulus properties of (+)lysergic acid diethylamide (LSD) in C57Bl/6J mice.

RATIONALE: The drug discrimination procedure is the most frequently used in vivo model of hallucinogen activity. Historically, most drug discrimination studies have been conducted in the rat. With the development of genetically modified mice, a powerful new tool has become available for investigating the mechanisms of drug-induced behavior. The current paper is part of an ongoing effort to determine the utility of the drug discrimination technique for evaluating hallucinogenic drugs in mice. OBJECTIVE: To establish the training procedures and characterize the stimulus properties of (+)lysergic acid diethylamide (LSD) in mice. METHODS: Using a two-lever drug discrimination procedure, C57Bl/6J mice were trained to discriminate 0.45 mg/kg LSD vs saline on a VI30 sec schedule of reinforcement, with vanilla-flavored Ensure serving as the reinforcer. RESULTS: As in rats, acquisition was orderly, but the training dose was nearly five-fold higher for mice than rats. LSD lever selection was dose-dependent. Time-course studies revealed a rapid loss of the LSD stimulus effects. The 5-HT(2A/2C) receptor agonist, 2,5-dimethoxy-4-bromoamphetamine [(-)DOB] (1.0 mg/kg), substituted fully for LSD and the 5-HT(1A) receptor agonist, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) (1.6 mg/kg), substituted partially for LSD. Pretreatment with the 5-HT(2A) receptor-selective antagonist, MDL 100907, or the 5-HT(1A)-selective antagonist WAY 100635, showed that each antagonist only partially blocked LSD discrimination. Substitution of 1.0 mg/kg (-)DOB for LSD was fully blocked by pretreatment with MDL 100907 but unaltered by WAY 100635 pretreatment. CONCLUSIONS: These data suggest that in mice the stimulus effects of LSD have both a 5-HT(2A) receptor and a 5-HT(1A) receptor component.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1993

D1 dopamine receptors in the nucleus accumbens modulate cocaine self-administration in the rat.

Previous work using systemic injections of dopamine receptor antagonists has established that dopamine D1 receptors may have a role in cocaine self-administration. The purpose of the present study was to test the hypothesis that these effects were mediated by dopamine D1 receptors in the region of the nucleus accumbens. Animals were trained to perform operant responses to self-administer cocaine via an IV catheter on a fixed-ratio 5 (FR 5) schedule of reinforcement. SCH23390, a selective D1 dopamine antagonist, significantly increased the self-administration of cocaine when injected into the nucleus accumbens. This increase in self-administration is thought to reflect decreases in the magnitude of the reinforcer, similar to the increase observed when the dose of cocaine is reduced. Similar doses of SCH23390 injected into the posterior caudate nucleus failed to alter cocaine self-administration. These data suggest that D1 receptors in the nucleus accumbens are important for the reinforcing properties of cocaine.

Animals↗
PubMed2005

A Turing test of a timing theory.

A quantitative theory of timing or conditioning can be evaluated with a Turing test in which the behavioral results of an experiment can be compared with the predicted results from the theory. An example is described based upon an experiment in which 12 rats were trained on three fixed-interval schedules of reinforcement, and a simulation of the predicted results from a packet theory of timing. An objective classification rule was used to determine whether a sample from the data or a sample from the theory was more similar to another sample from the theory. With an ideal theory, the expected probability of a correct classification would be 0.5. The observed probability of a correct classification was 0.6, which was slightly, but reliably, greater than 0.5. A Turing test provides a graded metric for the evaluation of a quantitative theory.

Animals↗
PubMed2006

Cooperative activation of D1-like and D2-like dopamine receptors in the nucleus accumbens shell is required for the reinstatement of cocaine-seeking behavior in the rat.

Activation of D1-like (D1, D5) or D2-like (D1, D3, D4) dopamine receptors in the nucleus accumbens shell is sufficient to reinstate cocaine-seeking behavior in rats. The goal of these experiments was to assess whether cooperative activation of D1-like and D2-like dopamine receptors in the accumbens shell is required to promote cocaine reinstatement. Rats were initially trained to self-administer cocaine (0.25 mg, i.v.) using a fixed-ratio schedule of reinforcement for approximately 21 days. Animals subsequently underwent an extinction phase during which saline was substituted for cocaine. Once cocaine self-administration behavior was extinguished (defined as <15% of the total responses maintained during self-administration), dopamine receptor agonist-induced reinstatement of cocaine seeking was assessed. Administration of the selective D1/5 agonist R-(+)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF-81297) (1.0 microg) or the D2/3 receptor agonist trans-(-)-(4aR)-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo[3,4-g]quinoline hydrochloride (quinpirole) (3.0 microg) directly into the nucleus accumbens shell promoted reinstatement of cocaine seeking. In order to determine if endogenous dopamine tone in the accumbens shell is required for dopamine receptor agonist-induced reinstatement of cocaine seeking, D1/5 or D2/3 dopamine receptor antagonists were administered into the nucleus accumbens shell prior to a selective dopamine receptor agonist. Microinfusion of the D2/3 dopamine receptor antagonist sulpiride ((S)-5-aminosulfonyl-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2-methoxybenzamide) (1.0 microg) into the nucleus accumbens shell 10 minutes prior to SKF-81297 (1.0 microg) blocked the ability of this D1-like dopamine receptor agonist to reinstate cocaine seeking. Similarly, administration of the selective D1/5 dopamine receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH-23390) (1.0 microg) into the nucleus accumbens shell prior to quinpirole (3.0 microg) blocked reinstatement of drug-seeking behavior elicited by this D2/3 dopamine receptor agonist. Moreover, intra-accumbal shell co-administration of subthreshold doses of quinpirole (1.5 microg) and SKF-81297 (0.1 microg) promoted cocaine-seeking behavior. Collectively, these results indicate that cooperative activation of D1-like and D2-like dopamine receptors in the nucleus accumbens shell is necessary to reinstate cocaine seeking in rats.

Animals↗
PubMed2002

Effects of mu-opioid agonists on cocaine- and food-maintained responding and cocaine discrimination in rhesus monkeys: role of mu-agonist efficacy.

Mu-opioid agonists decrease cocaine self-administration in laboratory studies and cocaine use by many cocaine- and opioid-dependent polydrug abusers. To assess the role of mu-agonist efficacy as a determinant of these effects, this study evaluated cocaine- and food-maintained responding by rhesus monkeys (Macaca mulatta) during chronic treatment with saline or the high-efficacy mu-agonist fentanyl (0.001-0.01 mg/kg/h), the intermediate-efficacy mu-agonist morphine (0.032-0.32 mg/kg/h), or the low-efficacy mu-agonists nalbuphine (0.1-1.0 mg/kg/h) and butorphanol (0.0032-0.032 mg/kg/h). Responding was maintained by cocaine and food under a second order schedule of reinforcement during multiple daily sessions of cocaine and food availability. Saline and each opioid dose were administered continuously for 7 consecutive days during availability of each cocaine dose. All four mu-agonists produced dose-dependent and sustained decreases in cocaine self-administration across a range of cocaine doses (0.0032-0.1 mg/kg/injection). Nalbuphine and butorphanol produced the greatest decreases in cocaine self-administration and the smallest effects on food-maintained responding. Morphine and fentanyl produced smaller decreases in cocaine self-administration, and undesirable effects precluded evaluation of higher fentanyl and morphine doses. Decreases in cocaine self-administration produced by nalbuphine and butorphanol probably did not reflect a general blockade of cocaine's abuse-related effects, because nalbuphine and butorphanol did not block the discriminative stimulus effects of cocaine in monkeys trained to discriminate 0.4 mg/kg cocaine from saline in a food-reinforced drug discrimination procedure. These results suggest that low-efficacy mu-agonists may decrease cocaine self-administration to a greater degree and with fewer undesirable effects than high-efficacy mu-agonists.

Analgesics, Opioid↗
PubMed1960

Control of vocal responding in chickens.

Schedules of reinforcement were shown to control the rate of chirping bychickens in the same way as other motor responses in subhumans. Under a discrimination procedure, chickens responded selectively to the visual stimulus associated with food reinforcement for chirping. Control experiments demonstrated that food influenced the rate of responding because it was presented dependent on the chick's vocalizing and not because it had an innate eliciting or "emotionalizing" power.

Animals↗