Selective attention to elements of a morphine stimulus: Idiosyncratic stimulus additivity of incidental cues.

Twelve male Sprague-Dawley rats (Rattus norvegicus) were trained to discriminate between the presence and absence of 5.6 mg/kg morphine sulfate in a lever-press operant task under a fixed-ratio 10 schedule of food delivery. Stimulus cross-generalization profiles were determined for a number of over-the counter (OTC) medications that were hypothesized to engender elements of a compound morphine cue including sedation and lethargy: dextromethorphan, doxylamine, diphenhydramine, pyrilamine, loperamide, and the B vitamins, pyridoxine, thiamine, and cyanocobalamin. On the basis of the individual rat's cross-generalization profile, each rat was retested for stimulus element additivity following the administration of various OTC binary and ternary combinations. For each rat, a test combination was formulated that engendered > 90% morphine-appropriate responding. These test combinations were idiosyncratic, exhibited high test-retest reliability, and followed rules predicted by simple effect additivity. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Conditioning following repeated exposure to MDMA in rats: Role in the maintenance of MDMA self-administration.

There has been some controversy in the literature concerning the ability of ±3,4 methylenedioxymethamphetamine (MDMA) to reinforce operant responding in rats. In the present study, operant responding maintained by intravenous MDMA infusions increased when the fixed ratio schedule was increased from 1 to 5, decreased when saline was substituted for MDMA, and increased again when MDMA was reintroduced. During self-administration training, each infusion of MDMA was paired with the illumination of a light stimulus. The role of the continued presentation of this drug-associated stimulus in operant responding was measured in groups of rats that had received comparable exposure (average 19 daily test sessions) to MDMA during training. When either the light stimulus or the drug infusion was omitted, operant responding decreased gradually over the 15-day test period following training. When both the light stimulus and the MDMA infusion were omitted, there was a dramatic decrease in operant responding that persisted for the entire 15-day test period. These findings suggest that cues associated with MDMA develop conditioned properties that might contribute to drug taking. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Stimulus compounding enhances conditioned suppression produced by cocaine-paired stimuli.

When 2 stimuli that occasion cocaine self-administration are presented in compound, their ability to increase cocaine-reinforced operant responding is substantially enhanced. The goal of the present experiment was to determine whether stimulus compounding could produce analogous enhancements of a classically conditioned drug effect. Food-maintained responding in rats was suppressed by a tone and a light that were individually paired with response independent cocaine (3 mg/kg iv). This conditioned suppression was significantly enhanced when the stimuli were presented together in a stimulus-compounding test. The magnitude of this enhancement was similar to that in previous studies in which responding was suppressed by shock-paired stimuli. These results demonstrate that multiple drug-related cues interact in a predictable manner to influence both operant and classically conditioned behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Overshadowing effects in the stimulus control of morphine analgesic tolerance.

Attempted to replicate previous demonstrations of classical conditioning of morphine analgesic tolerance and to determine whether stimulus overshadowing effects might explain previous conflicting findings. In Exp I, 8 groups of male Sprague-Dawley rats received a series of 10 morphine (5 mg/kg) and/or saline injections, differing only with respect to the contingency between a compound visual-auditory CS and the substance injected. When tested for analgesic responding to morphine in the presence of the compound CS, only those groups for which the CS and morphine injections were paired during the acquisition sequence evidenced tolerance. In Exp II, tolerant Ss were tested in the presence of 1 component of the compound CS. When a loud tone (85 db) was used in the compound, less analgesic tolerance was elicited later by the weaker visual stimulus alone. This differential stimulus control of the analgesic response suggests that overshadowing may contribute to failures to replicate conditioned morphine tolerance. It is possible that internal morphine-produced stimuli may overshadow external cues. (18 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Serotonin 1A receptor involvement in the discriminative stimulus effect of benzodiazepines in rats.

The purpose of this study was to examine the role of serotonin 1A (5-HT1A) receptors in the discriminative stimulus effects of benzodiazepines (BZs). Rats (Rattus norvegicus) were trained to discriminate either 7 mg/kg of chlordiazepoxide (CDP) or bretazenil from water. During substitution tests, CDP, bretazenil, and a novel β-carboline anxiolytic, abecarnil, produced > 95% responding on the drug-appropriate lever in both groups. In contrast, the selective 5-HT1A agonist (+)8-hydroxy-(di-N-dipropyl-2-amino)tetralin (8-OH-DPAT) did not substitute for either training drug but it potentiated the discriminative stimulus effects of a low dose of bretazenil or CDP, which suggests that serotonin may be involved in the discriminative stimulus effects of these compounds. Interestingly, 8-OH-DPAT did not potentiate the effects of a low dose of abecarnil in either group, nor did it potentiate the effects of a low dose of bretazenil in CDP-trained rats or a low dose of CDP in bretazenil-trained rats. The lack of reciprocity with abecarnil, CDP, and bretazenil may be due to the fact that only a single dose of each of these drugs was tested in combination with 8-OH-DPAT. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Hazardous materials and work safety in veterinary practice. 1: Hazardous material definition and characterization, practice documentation and general rules for handling

The role of the nicotinic acetylcholine receptor (nAChR) in the discriminative and aversive stimulus effects of ethanol was studied in rats. In the operant drug discrimination procedure the rats were trained to discriminate between 1.0 g/kg ethanol and saline under the FR10 schedule of sweetened milk reinforcement. Neither the nAChR agonist, nicotine (0.1-0.6 mg/kg) nor the nAChR antagonist, mecamylamine (3.0-6.0 mg/kg) substituted for the ethanol stimulus. Moreover, mecamylamine (0.5-6.0 mg/kg) did not antagonise the ethanol stimulus. The cross-familiarisation conditioned taste aversion procedure was used as an alternative method to study stimulus resemblance between ethanol and nicotine. Six daily injections of nicotine (0.6 mg/kg) significantly decreased a subsequent ethanol-induced taste aversion conditioning. The aversive stimulus effects of ethanol were investigated with the conditioned taste aversion (CTA) paradigm. Mecamylamine (1.0-3.0 mg/kg) did not attenuate an ethanol-induced CTA. These results suggest that: (1) nAChRs are not primarily involved in the discriminative stimulus effects of ethanol when studied with the operant drug discrimination test; (2) nAChRs are not critically involved in the ethanol-induced CTA.     

A selective attention deficit in the rat following induced dopamine receptor supersensitivity.

In the blocking paradigm, prior training to 1 conditioned stimulus (CSA) blocks the ability to attend to a 2nd conditioned stimulus (CSB) when the 2 form a compound (CSAB) in subsequent training. Blocking is an associative process by which animals learn to ignore CSB because it contains no new information regarding the reinforcing event. In Exp I, dopamine (DA) receptor supersensitivity was induced in 20 male Sprague-Dawley rats by prolonged pretreatment (21 days) with haloperidol (0.5 mg/kg). 20 control Ss received saline injections for 21 days. Results show that Ss with DA receptor supersensitivity failed to show blocking by responding equivalently to both elements of the CSAB compound (tone and light). This effect was replicated in Exp II, which also tested for an arousal interpretation of disrupted blocking by introducing a novel stimulus following training. 10 male Sprague-Dawley rats were randomly assigned to either saline or haloperidol pretreatment groups, and following 21 days of treatment and a 7-day drug free period, Ss were run in the 3-stage blocking procedure used in Exp I over 2 days. Findings indicate that supersensitive Ss were no more responsive to the novel stimulus than were controls, which supports a selective attention deficit interpretation of disrupted blocking with DA receptor supersensitivity. It is suggested that this attentional deficit resembles behavioral perseverations induced by DA agonists. (24 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The reinforcing effects of ethanol are altered by the endogenous neurosteroid, allopregnanolone

We examined the effect of systemic administration of the endogenously occurring progesterone metabolite, allopregnanolone, on oral self-administration of ethanol by male rats. Rats were trained to perform an operant response for presentation of 0.1 ml of a solution of 10% ethanol in water using the sucrose fading technique. After acquisition of stable lever-press responding on a fixed-ratio 4 schedule, subjects received subcutaneous injections of 1, 3, or 10 mg/kg of allopregnanolone, or vehicle, 20 min prior to the self-administration session. Pretreatment with 3 mg/kg, but not 1 or 10 mg/kg, increased the mean total number of lever press responses made to obtain ethanol, and therefore increased the mean total number of ethanol presentations. The number of responses and response rate were examined as a function of the number of "runs" within the 30-min session; a "run" was defined as a series of consecutive responses with an interresponse interval of <1 min. The increase in total responses after 3 mg/kg was due in part to an increased number of responses for the first run of the session, with no effect on response rates. However, the higher dose of 10 mg/kg decreased response rates within the first run. Thus, allopregnanolone alters ethanol-reinforced responding at concentrations lower than those that depress rates of responding. The effects of administration of the benzodiazepene, diazepam, were determined for comparison with those of the neurosteroid. The subcutaneous injection of 0.3, 1.0, or 3.0 mg/kg of diazepam did not produce any clear dose-dependent changes in measures of ethanol-reinforced operant responding, supporting the suggestion of differences in the contribution of the benzodiazepene and neurosteroid binding sites to GABA(A) receptor function. The results indicate that exogenous administration of allopregnanolone dose-dependently alters ethanol-reinforced operant responding, and suggest that this endogenously occurring neurosteroid could mediate some of the reinforcing effects of ethanol.     

Simple and configural association learning in rats with bilateral quisqualic acid lesions of the nucleus basalis magnocellularis

We hypothesized that bilateral quisqualic acid lesions of the nucleus basalis magnocellularis (NBM) in rats would impair configural but not simple association learning. In experiment 1, rats were tested in a negative patterning operant discrimination where they were food-reinforced for responding to a light or a tone (L+, T+) but not for responding to the configural stimulus consisting of the light and tone presented simultaneously (LT-). Consistent with our hypothesis, NBM-lesioned rats showed a transient but significant impairment, responding normally to L+ and T+ but responding more often to LT-, in addition to responding more often during the inter-trial interval (ITI) than controls. In experiment 2, rats were tested in a simple operant discrimination where rats were food-reinforced for responding to a light (L+) but not for responding to a tone (T-). Although NBM-lesioned rats again responded normally to L+ as predicted, NBM-lesioned rats were transiently impaired, making more T- responses and more ITI responses than controls. Together, these results suggest that the NBM is involved in both configural and simple association learning but that this involvement is limited to learning to withhold responding to non-reinforced contextual or discrete stimuli. Finally, rats from experiment 2 underwent extinction trials, where results showed no difference between NBM-lesioned and control groups, suggesting that the NBM is not involved in the extinction of conditioned responding to previously reinforced stimuli.     

Multiple interruptions of responding maintained by a fixed-interval schedule of electric-shock presentation in squirrel monkeys.

Recent experiments have demonstrated that the characteristic pattern of responding engendered by a fixed-interval (FI) schedule of food reinforcement can also be established and maintained by response-contingent electric shocks. Under an FI schedule of food presentation, the characteristic pattern of responding survives repeated interruption by stimulus conditons absent at the time of reinforcement. The present experiment, with 3 male squirrel monkeys, demonstrates a similar phenomenon under circumstances in which the sole consequence of FI responding was the delivery of response-contingent shocks. Several possible interpretations of FI performance maintained by electric-shock presentation are discussed. (15 ref.) (French summary) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Interaction of an aversive Pavlovian conditional stimulus with aversively and appetitively motivated operants in rats.

Reports results of 5 experiments with a total of 168 male albino Sprague-Dawley rats. Presentation of an aversive CS produced an acceleration of free-operant Sidman shock-avoidance responding only if the CS had been paried with a relatively weak-shock UCS. Stimuli paired with a relatively strong UCS produced suppression of avoidance responding. With appropriate shock intensities, both suppression and acceleration were obtained. Responses of controls showed that this effect was not due to interactions between the operant response and UCS. In a within-S experiment, the same aversive CS produced suppression of an appetitive response (CER) and acceleration of avoidance. However, a CS which had produced avoidance acceleration did not suppress an appetitive operant. (23 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Stimulus compounding in interval timing: The modality–duration relationship of the anchor durations results in qualitatively different response patterns to the compound cue.

We have previously demonstrated that rats trained on a two-duration peak procedure in which two modal signals (i.e., tone and houselight) predicted probabilistic reinforcement availability at two times (10 s and 20 s) would respond in a scalar manner at a time between the trained durations in response to the simultaneous compound cue (tone + houselight). In these experiments, we evaluated whether this scalar response pattern would remain with greater relative separation between the anchor durations. Results revealed an effect of the modality–duration relationship, such that scalar responding was seen on compound trials in rats trained that the auditory stimulus signaled the shorter duration, whereas the visual stimulus signaled the longer duration, but not in the reverse condition. In rats showing scalar responding on compound trials, post hoc analyses demonstrated that the peak time of compound responding was most accurately predicted by the reinforcement probability weighted average of anchor peak times. In contrast, rats trained that the visual stimulus signaled the shorter duration, whereas the auditory stimulus signaled the longer duration, responded in a highly rightward skewed manner. In these rats, initiation of responding to the compound stimulus appeared to be controlled by the visual stimulus only, whereas response terminations reflected control by both modal stimuli. These latter data provide evidence of separate determinants of response initiation and termination. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Response preconditioning effects.

Two experiments investigated the effects on instrumental responding of a sequence of training stages similar to that followed in demonstrations of sensory preconditioning. In Exp I, 62 male hooded rats that experienced response-correlated presentations of a neutral stimulus, followed by pairings of the neutral stimulus with food, showed an enhanced tendency to emit the response during a test in which responding had no programmed consequences. In Exp II, in which the 2nd stage of training involved pairings of the neutral stimulus with shock, responding by the 24 Ss during the test was suppressed. Two interpretations of the results are discussed: (a) Enhancement and suppression of the operant response were mediated by Pavlovian processes (viz., sensory preconditioning); (b) the critical association formed was between the response and the neutral stimulus, and the observed variations in instrumental responding reflected response preconditioning. (19 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Acute effects of eltoprazine on aggressive and point-maintained responding of normal male participants: Phase I study.

Aggressive and point-maintained operant responding of normal male participants were measured during 7 25-min sessions conducted over 8-hr experimental days. Aggressive responding ostensibly subtracted points exchangeable for money from another participant. Aggressive responding was engendered by subtracting points from the participants and maintained by initiation of intervals free of point subtractions. Point subtractions presents to the participants were attributed to other persons. Participants earned points exchangeable for money on a 2nd response option. Placebo and 5, 10, or 20 mg of eltoprazine were administered orally, and peak effects of eltoprazine on operant response measures occurred at 3 hr. Aggressive and point-maintained responding was decreased following the 10- and 20-mg eltoprazine doses. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effect of dehydration on stimulation of ADH release by heterologous renin infusions in conscious dogs

The effect of acute administration of morphine on cerebral excitability was investigated in rats with two convulsant drugs: flurothyl (hexafluorodiethyl ether) and pentylenetetrazol (PTZ). In the flurothyl study, adult male Sprague-Dawley (S-D) rats were injected subcutaneously with morphine sulfate in doses ranging from 0.5 to 256 mg/kg. At 15, 30, 60 and 120 minutes after morphine injection, flurothyl was administered by inhalation and the seizure thresholds were determined. In the PTZ study, 64 mg/kg of morphine sulfate were injected subcutaneously into both S-D and CFN (Wistar-derived) rats. Thresholds to PTZ seizures were measured after administering the convulsant either by the intraperitoneal or intravenous route. The data revealed an anticonvulsant action of morphine on both flurothyl and PTZ. Peak time for this effect on flurothyl seizures was 30 minutes after subcutaneous administration of the opiate, with the maximal anticonvulsant activity appearing at the 64-mg/kg dose. The increase in seizure threshold in S-D rats at this dose was 36% with flurothyl, 94% with intravenous PTZ and 352% with i.p. PTZ. Morphine had a less dramatic influence on raising the latter seizure threshold in the CFN than in the S-D strain. The graded dose-related anticonvulsant action is independent of the respiratory depression associated with morphine administration and appears to be a reflection of an altered central nervous system excitability produced by the narcotic in rats.     

Long-term potentiation facilitates behavioral responding to single-pulse stimulation of the perforant path.

Three experiments, with 32 male hooded Sprague-Dawley rats, examined whether long-term potentiation (LTP) could enhance the stimulus properties of electrical brain stimulation. In Exp I, a paradigm was developed in which single-pulse stimulation of the perforant path (PP) could acquire control over operant responses. Evoked potentials were recorded from the dentate gyrus (DG) to measure the postsynaptic consequences of the stimulus and to monitor synaptic efficacy in the PP–DG synapses. Exp II confirmed the relation between the amount of evoked activity and acquisition rate and also showed that transecting the PP impaired performance. In Exp III, high-frequency stimulation of the PP produced LTP and accelerated subsequent acquisition of behavioral responding to PP stimulation. Results document a link between increases in synaptic efficacy and changes in behavior and thereby demonstrate the ability of LTP to serve as at least 1 component of the neural bases of learning and memory. (24 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Clonidine blocks acquisition but not expression of conditioned opiate withdrawal in rats

Previous studies in rodents have reported that clonidine, an alpha 2-adrenergic receptor agonist, attenuated conditioned aversions to naloxone-precipitated opiate withdrawal when administered prior to each withdrawal conditioning episode. The current study was designed to determine whether clonidine could modify the expression of previously established conditioned place aversions and conditioned suppression of operant responding. Dose- and time-dependent effects of clonidine on activity and suppression of operant responding for food identified appropriate treatment parameters for subsequent studies in which rats rendered dependent on opiates through implantation of morphine pellets were tested for: (1) conditioned place aversion; and (2) conditioned suppression of operant responding for food (fixed ratio-15 schedule), in a paradigm wherein rats received four pairings of naloxone with a distinct tone and odor stimulus. Clonidine dose-dependently blocked the acquisition of both conditioned behaviors when administered prior to naloxone on each conditioning trial, but was ineffective in blocking the expression of these conditioned withdrawal signs when administered prior to the test session.     

(R)-methanandamide, but not anadamide, substitutes for Δ–9-THC in a drug-discrimination procedure.

Fourteen male rats were trained to discriminate between injections of 2 mg/kg delta-9 tetrahydrocannabinol (Δ–9-THC) and vehicle in a 2-lever operant drug-discrimination paradigm. Following training, substitution tests using a cumulative dosing procedure revealed that anandamide (0.5-16 mg/kg ip), the putative endogenous cannabinoid receptor ligand, failed to generalize to the discriminative stimulus properties of the training dose of Δ–9-THC. However, dose-dependent generalization to the Δ–9-THC cue was observed following administration of both CP-55,940 (0.05-0.8 mg/kg ip), a synthetic cannabinoid, and (R)-methanandamide (0.5-8 mg/kg ip), a metabolically stable analog of anandamide. Collectively, these results demonstrate a cannabinoid-specific in vivo effect of an anandamide compound and suggest that the naturally occurring form of anandamide may be metabolized too rapidly to produce a cannabimimetic interoceptive state when administered peripherally. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Behavioral evaluation of modafinil and the abuse-related effects of cocaine in rhesus monkeys.

Modafinil is a central nervous system stimulant used to promote wakefulness, and it is being evaluated clinically as an agonist medication for treating stimulant abuse. This is the first report of the effects of modafinil on the abuse-related effects of cocaine in nonhuman primates. The behavioral effects of modafinil were examined in three studies. First, the discriminative stimulus effects of modafinil (3.2–32 mg/kg) were evaluated in rhesus monkeys (Macaca mulatta) trained to discriminate either low (0.18 mg/kg, IM) or high (0.4 mg/kg, IM) doses of cocaine from saline. Modafinil dose-dependently substituted for cocaine in 6 of 7 monkeys. In the second study, the effects of chronically administered modafinil (32–56 mg/kg/day, IV) on food- and cocaine-maintained (0.001–0.1 mg/kg/inj) operant responding were examined. Modafinil was administered 3 times/hr for 23 hr/day to ensure stable drug levels. Chronic treatment with 32 mg/kg/day modafinil selectively reduced responding maintained by intermediate and peak reinforcing doses of cocaine, but responding maintained by higher doses of cocaine was unaffected. Food-maintained behavior did not change during chronic modafinil treatment. In a third study, modafinil (32 and 56 mg/kg/day, IV) was examined in a reinstatement model. Modafinil transiently increased responding during extinction. These findings indicate that modafinil shares discriminative stimulus effects with cocaine and selectively reduces responding maintained by reinforcing doses of cocaine. In addition, modafinil reinstated cocaine-seeking behavior, which may reflect its cocaine-like discriminative stimulus effects. These data support clinical findings and indicate that these preclinical models may be useful for predicting the effectiveness of agonist medications for drug abuse treatment. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A case of asymptomatic central pontine myelinolysis

This study investigates the influence of possible stress due to housing in Bolman cages on antinociception and on respiratory depression following opioid administration. To evaluate the functional role of this stressor and to modulate it, rats were subcutaneously pretreated with the anxiolytic chlordiazepoxide (CDP; 10 mg/kg) or saline (SAL) before the immobilization in the Bolman cages and before the intravenous administration of small doses of morphine (MOR), sufentanil (SUF), or vehicle (VEH). Antinociception, respiratory impairment and stress were evaluated by means of the tail-flick latency, blood gas analysis, and serum corticosterone (CS), adrenocorticotropic hormone (ACTH), and prolactin (PRL) determinations. The results demonstrated that 10 mg/kg CDP did not alter the antinociceptive effects of low doses of morphine and sufentanil. CDP pretreatment differentially affected the various blood gas parameters. Compared to vehicle pretreatment, there was a larger decrease in PaO2 following MOR and SUF in the CDP-pretreated rats. The effects were most pronounced at the lowest doses of both opioids. A CDP potentiation was also observed for the short-lasting raises in PaCO2 with the lowest concentrations of the opioids. At higher concentrations of the opioids, CDP was without any effect. With regard to the stress hormones, immobilization and an intravenous injection resulted in increases in CS and PRL in both CDP- and VEH-pretreated rats. ACTH did not change in these controls. SUF prevented the CS raises independent of a CDP pretreatment, while ACTH only increased in the SUF plus CDP groups, pointing to a stress-reducing effect of SUF. Also, MOR without CDP prevented the increases in CS, but the opioid intrinsically increased ACTH. These results indicate that restraint in Bolman cages in the present setup, with animals recovering for several hours in these cages after being equipped with an arterial catheter, is stressful but without any significant effect on the opioid-induced antinociception. Pretreatment with an anxiolytic benzodiazepine only minimally affected the outcome of the opioids on respiratory depression and pointed to a stress-reducing effect of low doses of the opioids, especially sufentanil.