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At least 955 records · Page 53Linked to original sources
PubMed1987

Effects of single or multiple choice trials per session on drug discrimination performance.

Drug discrimination procedures typically provide for multiple choice opportunities per training session. This practice allows non-drug cues (presence or absence of reinforcement) to mediate choice behavior during that portion of the session following the initial choice. In this experiment, rats were trained to discriminate 1.0 mg/kg cyclazocine from saline using a novel procedure that employed a single-choice trial per training session. Drug discrimination acquisition and generalization were compared to those of rats given discrimination training with 30 choice trials per session. The one-trial procedure yielded stable and reliable acquisition but more slowly than did the multiple trials procedure. The one-trial procedure produced longer first trial choice latencies and enhanced the tendency for subjects to respond on both choice levers during the first trial. The cyclazocine generalization functions were comparable, but the one-trial subjects more often responded on both choice levers, particularly when administered intermediate test doses of cyclazocine. Control of choice behavior by the reinforcer cue was evaluated on a mid-session cue reversal test. Multiple-trial subjects persisted in responding on the saline level following a mid-session injection of cyclazocine, whereas one-trial subjects shifted to the cyclazocine-appropriate lever.

Animals↗
PubMed1978

Further evidence of impaired tactile learning after removals of the second somatic sensory projection cortex (SII) in the monkey.

Four rhesus monkeys with bilateral removals of SII and five unoperated monkeys were trained on tests of tactile equivalence, weight discrimination and generalization, tactile discrimination learning (including concurrent learning and serial reversal) and inter-manual transfer of tactile learning. Lesioned animals were impaired on almost all tactile learning tasks and on inter-manual transfer but not on the test of tactile equivalence nor on the propioceptive tasks. The results are considered in the context of previous studies of somatosensory and parietal cortex.

Animals↗
PubMed1976

Delta 9-Tetrahydrocannabinol, ethanol, and amphetamine as discriminative stimuli-generalization tests with other drugs.

Three groups of rats (A, B, C) were trained in a T-maze discriminate between drug-and control solution-induced internal discriminative stimuli. The drugs used to induce discriminative stimuli were: delta 9-THC, 5.0 mg/kg (Group A); ethanol, 1.2 g/kg (Group B), and amphetamine, 1.0 mg/kg(Group C). After discrimination acquisition several drugs were tested for generalization in each group. Group A was tested with delta 8-THC, CBD, CBN, ethanol, pentobarbital,chlorpromazine, amphetamine, and apomorphine; only delta8-THC and CBN induced delta9-THC-like responses. Group B was tested with delta 9-THC, delta 8-THC, CBD, CBN, pentobarbital, and amphetamine; pentobarbital induced ethanol-like response. Group C was tested with delta 9-THC, apomorphine, and ethanol; delta 9-THC and apomorphine elicited amphetamine-like responses.

Animals↗
PubMed1978

Changes of sensitivity to the cuing properties of narcotic drugs as evidenced by generalization and cross-generalization experiments.

With a discrete-trial, food-reward, two-lever procedure, rats were trained to discriminate 0.04 mg/kg fentanyl from saline. Individual threshold doses for generalization of fentanyl and for cross-generalization of morphine were determined repeatedly during a 17-week posttraining period. Threshold doses of both drugs almost continuously shifted in both the up- and downward direction. Shifts of fentanyl threshold doses covaried with those of morphine threshold doses. These shifts can best be described by a sustained oscillation, the mean amplitude of which amounts to a factor 3.65 of the dose-range for fentanyl, and to a factor 1.85 for morphine. The upper and lower limits of oscillation were symmetrical with respect to baseline. The oscillation can be described by a function expressing that the more distant a point along the function is from the baseline, the more it is susceptible to (positive/negative) acceleration along the intensity (i.e., dose) axis.

Animals↗
PubMed1978

Morphine as a discriminative cue in gerbils: drug generalization and antagonism.

Gerbils were trained in an electrified, T-shaped maze to discriminate between one of the three training doses of morphine (8, 16, or 32 mg/kg) and the nondrug condition. The rate of acquisition of the morphine discriminations was a function of dose, the high dose being the most rapidly discriminable condition. Dose generalization tests with morphine showed that the higher the training dose, the higher the ED50 value in producing 50% morphine-appropriate responding. Antagonism of the discriminable effects of morphine by naltrexone (dose range tested: 0.025-0.40 mg/kg) also was related to the training dose of morphine; i.e., the higher the training dose of morphine, the higher the corresponding ED50 value for blockade by naltrexone. A stereoisomeric requirement for morphine discrimination was evident since levorphanol, but not the analgesically inactive dextrophan, yielded morphine-appropriate responses when tested by substitution.

Animals↗
PubMed1980

Ability of 3-carboxysalsolinol to produce ethanol-like discrimination in rats.

The purpose of the present study was to investigate the possible generalization to 3-carboxysalsolinol (3C-SAL) in a group of rats trained to discriminate a low dose of ethanol (200 mg/kg IP) from the nondrug condition and in antoher group trained to discriminate 0.16 mg/kg IP apomorphine (AP) from the nondrug condition using a drug discrimination paradigm. In test sessions, ED50 for ethanol was 52.0 mg/kg and ED50 for AP was 0.01 mg/kg. In the ethanol-trained rats, 1.8 mg/kg 3C-SAL produced drug responses. In the AP-trained rats, 200 mg/kg ethanol produced drug responses whereas 1.8 mg/kg 3C-SAL produced only a partial drug response. The results are in harmony with the hypothesis that salsolinol in the central nervous system of the rat may be responsible for the discriminability of ethanol. The possible involvement of dopaminergic systems is discussed.

Animals↗
PubMed1985

Behavioral effects of a novel kappa opioid analgesic, U-50488, in rats and rhesus monkeys.

U-50488 [trans-3,4-dichloro-N-(2-(1-pyrrolidinyl) cyclohexyl)-benzeneacetamide] is a structurally novel analgesic reported to have specific kappa opioid receptor agonist properties. Potent antinociceptive activity was demonstrated in rhesus monkeys and the effect was reversed by naloxone. The overt behavioral effects of U-50488 at supra-analgesic doses more closely resembled those of ethylketocyclazocine (EKC) than morphine. In monkeys trained to discriminate a 10-micrograms/kg dose of EKC from saline, the stimulus effects generalized completely to U-50488 and other kappa agonists (e.g., bremazocine, cyclazocine), but not to the pure mu agonists. Like the other kappa agonists, U-50488 produced diuresis in monkeys by a naloxone-sensitive mechanism. In drug-naive rats offered continuous opportunity to self-administer drugs IV, most rats self-administered morphine or EKC, but none of the rats self-administered U-50488 at a rate above that of a group offered saline. Rats with continuous IV infusion of U-50488 for 3 weeks exhibited few abstinence signs and no weight loss when challenged with an injection of naloxone or after abrupt cessation of drug infusion. These experimental results support the previous reports in mice that U-50488 is a very selective kappa opioid agonist in rats and rhesus monkeys.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1985

Characterization of the bupropion cue in the rat: lack of evidence for a dopaminergic mechanism.

Using a two-lever operant task rats were trained to discriminate 40 mg/kg IP of bupropion from saline. Despite bupropion's established dopaminergic activity in vitro and in vivo, it was found that the bupropion cue was neither mimicked by the dopaminergic drugs L-DOPA and bromocriptine nor blocked by a variety of neuroleptics (haloperidol, thioridazine, and thiothixene). In addition, bupropion was active in attenuating the behavior-suppressing effects of haloperidol, unlike amphetamine and the atypical antidepressants, nomifensine and viloxazine. The bupropion cue was not mimicked or disrupted by adrenergic or serotonergic drugs, but it did generalize to some stimulants (amphetamine, cocaine and caffeine) as well as to nomifensine and viloxazine. The generalizations were blocked by neuroleptics. These data indicate that bupropion's cue properties may not be based on its ability to modulate dopaminergic receptor activity. The possible involvement of phenylethylamine in the bupropion cue is also discussed.

Animals↗
PubMed1985

Generalization tests with intraventricularly applied pro-enkephalin B-derived peptides in rats trained to discriminate the opioid kappa receptor agonist ethylketocyclazocine.

Rats were trained in a two-lever food-reinforced procedure to discriminate between the effects of saline and the opioid kappa receptor agonist ethylketocyclazocine. After acquisition of this discrimination, generalization tests with opioid peptides such as beta-endorphin, alpha-neoendorphin, dynorphin A and some dynorphin-derived peptides were conducted. The rats dose-dependently generalized the effects of intracerebroventricularly injected ethylketocyclazocine but not beta-endorphin, alpha-neoendorphin, dynorphin A1-8, dynorphin A1-13, D-Cys2-L-Cys5-dynorphin A1-13 or dynorphin A. D-Cys2-L-Cys5-dynorphin A1-13, in contrast to dynorphin A itself, dose-dependently caused analgesia and catatonia that was reversible with naloxone. Studies into the receptor preference of this derivative, using the technique of "selective tolerance", revealed that this dynorphin derivative is almost devoid of kappa-receptor activity.

Animals↗
PubMed1980

Intraductal proliferation in the pancreas and its relationship to human and experimental carcinogenesis.

In 21 patients who had undergone total pancreatectomy for pancreatic head carcinoma, the uninvolved pancreas was examined with regard to the type, incidence and regional distribution of duct epithelial proliferation. The results were compared with those in 37 operative specimens from patients with chronic pancreatitis, in 46 normal pancreases from autopsies and with findings in experimental pancreatic carcinogenesis. While the incidence of squamous metaplasia and non-papillary epithelial hypertrophy varied little in the different groups, papillary epithelial hyperplasia was found three times more often in cases of carcinoma, with associated mild duct obstruction. Atypical epithelial proliferation was only detected in the vicinity of carcinomas. Unequivocal transition from papillary hyperplasia to atypical proliferation was not observed. In hamsters treated with dihydroxy-di-n-propylnitrosamine (DHPN) for induction of pancreatic duct carcinomas, the early duct lesions closely resembled atypical epithelial proliferation of human pancreas. It is concluded that (1) papillary epithelial hyperplasia is probably only indicative of early duct obstruction and/or a general neoplastic stimulus, (2) intraductal epithelial proliferation with atypia is a true precursor of duct carcinoma, and (3) chronic pancreatitis lacks atypical duct lesions.

Adult↗
PubMed1980

delta 9-THC as a discriminative stimulus in rats and pigeons: generalization to THC metabolites and SP-111.

In a drug discrimination paradigm pigeons and rats were trained with an operant procedure to discriminate between the presence and absence of the effects of delta 9-THC (1.0 and 3.0 mg/kg, injected IM 90 min and I.P. 30 min before the start of the session). Once trained, various THC metabolites as well as a water-soluble derivative of THC (SP-111), were substituted for delta 9-THC to test for generalization to the training drug. Generalization to delta 9-THC occurred with the 11-hydroxy metabolites and the potency order was 11-OH-delta 9-THC > 11-OH-delta 8-THC greater than or equal to delta 9-THC. Among the other metabolites tested (8 alpha-OH-delta 9-THC, 8 alpha, 11-di-OH-delta 9-THC, 8 beta-OH-delta 9-THC, 8 beta, 11-di-OH-delta 9-THC), it was only 11-di-OH-delta 9-THC that completely substituted for delta 9-THC in pigeons, albeit at very high dose levels (rats were not tested with these metabolites). SP-111 generalized to delta 9-THC in both species. However, the onset of action of SP-111 was slower than that for delta 9-THC, especially in pigeons. These studies show the importance of obtaining complete dose-effect determinations over time when assessing structure-activity relationships with drug-discrimination procedures.

Animals↗
PubMed1989

Differential effects of cholinergic drugs on discriminative cues and self-stimulation produced by electrical stimulation of the ventral tegmental area.

Cholinergic receptors have been shown to modulate a subset of discriminative cues produced by electrical stimulation of the ventral tegmental area (VTA) in rats. The present study identified the specific cholinergic receptor type modulating these electrical brain-stimulation (EBS) cues, and assessed whether these receptors also mediated the rewarding effects of VTA EBS. The EBS cues were enhanced by the acetylcholinesterase inhibitor physostigmine and the muscarinic receptor agonists pilocarpine and RS-86, whereas the nicotinic receptor agonist nicotine had no effect. The enhancing effects of pilocarpine or RS-86 were attenuated by the muscarinic antagonist scopolamine. The EBS cues were not affected when scopolamine was injected alone, although high doses disrupted discriminated responses. Intracranial self-stimulation (ICSS) rates were depressed by physostigmine and pilocarpine and increased by nicotine and scopolamine. These results indicated a facilitatory influence of muscarinic receptors on the EBS cues, and an inhibitory role in VTA ICSS. Nicotinic receptor activation did not affect the EBS cues, but facilitated ICSS. These differential effects of cholinergic receptor activation point to a dissociation of the specific EBS cues measured in this study from the rewarding effects of VTA stimulation.

Animals↗
PubMed1980

Potentiation of gastrin and histamine stimulated acid secretion in Heidenhain pouches by distention--an atropine-resistant mechanism.

1. Distention of the vagally denervated fundic gland area, although by itself a generally ineffective stimulus to acid secretion in this study, will markedly increase the acid secretory response to stimulation by endogenous gastrin, pentagastrin and histamine. Even maximal responses to histamine can be increased, thus demonstrating true potentiation between distention and humoral stimuli. 2. The magnitude of the distention potentiation does not appear to be influenced by the nature of the background stimulus or the background level of secretion. 3. The distention potentiation of the response to histamine is reduced but not abolished by intravenous atropine and hexamethonium. Thus, there appear to be two components to the local distention mechanism. One is cholinergic, the other, atropine-resistant component is possibly non-cholinergic. At least one of these components, possibly the cholinergic, involves a nicotinic synapse in its pathway.

Animals↗
PubMed1989

Desensitization of the nicotinic acetylcholine receptor: molecular mechanisms and effect of modulators.

1. Loss of response after prolonged or repeated application of stimulus is generally termed desensitization. A wide variety of phenomena occurring in living organisms falls under this general definition of desensitization. There are two main types of desensitization processes: specific and non-specific. 2. Desensitization of the nicotinic acetylcholine receptor is triggered by prolonged or repeated exposure to agonists and results in inactivation of its ion channel. It is a case of specific desensitization and is an intrinsic molecular property of the receptor. 3. Desensitization of the nicotinic acetylcholine receptor at the neuromuscular junction was first reported by Katz and Thesleff in 1957. Desensitization of the receptor has been demonstrated by rapid kinetic techniques and also by the characteristic "burst kinetics" obtained from single-channel recordings of receptor activity in native as well as in reconstituted membranes. In spite of a number of studies, the detailed molecular mechanism of the nicotinic acetylcholine receptor desensitization is not known with certainty. The progress of desensitization is accompanied by an increase in affinity of the receptor for its agonist. This change in affinity is attributed to a conformational change of the receptor, as detected by spectroscopic and kinetic studies. A four-state general model is consistent with the major experimental observations. 4. Desensitization of the nicotinic acetylcholine receptor can be potentially modulated by exogenous and endogenous substances and by covalent modifications of the receptor structure. Modulators include the noncompetitive blockers, calcium, the thymic hormone peptides (thymopoietin and thymopentin), substance P, the calcitonin gene-related peptide, and receptor phosphorylation. Phosphorylation is an important posttranslational covalent modification that is correlated with the regulation and desensitization of the receptor through various protein kinases. 5. Although the physiological significance of desensitization of the nicotinic receptor is not yet fully understood, desensitization of receptors probably plays a significant role in the operation of the neuronal networks associated in memory and learning processes. Desensitization of the nicotinic receptor could also possibly be related to the neuromuscular disease, myasthenia gravis.

Animals↗
PubMed1976

The effects of pre-exposure to scopolamine on subsequent drug state discrimination.

This experiment was done to test the prediction that preexposure to a drug state would increase the discriminability of that drug state when used as a cue in a discrimination task. Eight rats were pre-exposed to scopolamine for 20 days and 8 rats were given saline injections. The drug pre-exposed animals acquired a drug state discrimination more quickly than the controls. A difference was also found between the generalization gradients for each group with the pre-exposed group showing a steeper generalization gradient.

Animals↗