Discriminative stimulus effects of morphine in squirrel monkeys: stimulants, opioids, and stimulant-opioid combinations.
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Morphine and other mu opioids mimic and/or modulate the discriminative stimulus (DS) effects of cocaine, possibly reflecting mutual stimulation of mesolimbic dopamine activity. Less is known about the capacity of cocaine and related stimulants to modulate the DS effects of morphine. The present study investigated the effects of cocaine, amphetamine, and reference drugs, administered alone and with morphine, in squirrel monkeys trained to discriminate morphine from vehicle. Additional studies determined the ability of opioid and dopamine receptor antagonists to attenuate the DS effects of morphine and the morphine-like effects of other drugs. The DS effects of morphine were mimicked by the mu-opioid agonist fentanyl but not the delta-opioid agonists SNC 80 and BW 373U86 or the kappa-opioid agonist U50,488H, and were antagonized by the opioid antagonist naltrexone but not the dopamine antagonist flupenthixol. In three of five monkeys, the DS effects of morphine also were mimicked by cocaine, amphetamine, and the dopamine transport inhibitor GBR 12909 but not the norepinephrine transport inhibitor talsupram or the serotonin transport inhibitor fluoxetine, and were antagonized by flupenthixol but not naltrexone. In this subgroup, pretreatment with cocaine or amphetamine enhanced the DS effects of morphine, whereas in the other two monkeys pretreatment with either stimulant attenuated the DS effects of morphine. The results demonstrated individual differences in morphine-like DS effects of stimulants that are mirrored by individual differences in their interactions with morphine. Furthermore, different mechanisms appear to mediate the DS effects of morphine and the morphine-like DS effects of cocaine and amphetamine. (+info)
Discriminative stimulus effects of the nonpeptidic delta-opioid agonist SNC80 in rhesus monkeys.
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Five rhesus monkeys were trained to discriminate the nonpeptidic, delta-opioid agonist SNC80 (0.32 mg/kg i.m.) from saline by using a food-reinforced drug-discrimination procedure. Cumulative doses of SNC80 produced a dose-dependent increase in SNC80-appropriate responding and a dose-dependent decrease in response rate. In time-course studies, peak effects of the training dose of SNC80 were observed after 15 min, and these effects diminished over 240 min. In substitution studies, other piperazinyl benzamide delta agonists (SNC86, SNC162, and SNC243A) substituted for SNC80 with relative potencies similar those of SNC80. However, SNC67, the (-)-enantiomer of SNC80, did not occasion SNC80-appropriate responding up to a dose (32.0 mg/kg) that produced convulsions in one monkey. The mu agonists morphine and fentanyl and the kappa agonists U-50,488 and enadoline failed to substitute for SNC80 up to doses that eliminated responding. Two nonopioids (the N-methyl-D-aspartate antagonist ketamine and the monoamine reuptake inhibitor cocaine) also produced primarily saline-appropriate responding. Both the discriminative stimulus and rate-decreasing effects of SNC80 were antagonized by the delta-selective antagonist naltrindole (0.01-1.0 mg/kg) but not by doses of the opioid antagonist quadazocine (0.1-1.0 mg/kg) that block the effects of mu and kappa agonists. These data suggest that the discriminative stimulus effects of SNC80 are mediated by delta-opioid receptors and that the discriminative stimulus effects of delta opioids in primates can be differentiated from the effects of other opioid and nonopioid compounds. (+info)
Impaired capacity of cerebellar patients to perceive and learn two-dimensional shapes based on kinesthetic cues.
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This study addresses the issue of the role of the cerebellum in the processing of sensory information by determining the capability of cerebellar patients to acquire and use kinesthetic cues received via the active or passive tracing of an irregular shape while blindfolded. Patients with cerebellar lesions and age-matched healthy controls were tested on four tasks: (1) learning to discriminate a reference shape from three others through the repeated tracing of the reference template; (2) reproducing the reference shape from memory by drawing blindfolded; (3) performing the same task with vision; and (4) visually recognizing the reference shape. The cues used to acquire and then to recognize the reference shape were generated under four conditions: (1) "active kinesthesia," in which cues were acquired by the blindfolded subject while actively tracing a reference template; (2) "passive kinesthesia," in which the tracing was performed while the hand was guided passively through the template; (3) "sequential vision," in which the shape was visualized by the serial exposure of small segments of its outline; and (4) "full vision," in which the entire shape was visualized. The sequential vision condition was employed to emulate the sequential way in which kinesthetic information is acquired while tracing the reference shape. The results demonstrate a substantial impairment of cerebellar patients in their capability to perceive two-dimensional irregular shapes based only on kinesthetic cues. There also is evidence that this deficit in part relates to a reduced capacity to integrate temporal sequences of sensory cues into a complete image useful for shape discrimination tasks or for reproducing the shape through drawing. Consequently, the cerebellum has an important role in this type of sensory information processing even when it is not directly associated with the execution of movements. (+info)
Differential patterns of c-fos mRNA expression in amygdala during successive stages of odor discrimination learning.
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Expression of the activity-dependent gene c-fos was used to assess relative levels of neuronal activation in the amygdala and related structures of rats at different stages of odor discrimination learning. In situ hybridization was used to evaluate c-fos mRNA content within the amygdalar subdivisions, the bed nucleus of the stria terminalis, and the hippocampus. After initial exploration of the test apparatus, c-fos mRNA levels were increased in the medial and, to lesser extent, basolateral subdivisions and remained low in the central division. The balance of amygdala to hippocampal labeling favored hippocampus. Rats engaged in familiar nose-poke responses had comparably elevated labeling in the medial and basolateral divisions and low labeling densities in the central division. The ratio of hippocampal to amygdala labeling was at control levels. Rats required to switch from ad libitum responding to cued responding to odors had high basolateral to medial labeling ratios. This was in marked contrast to the medial dominance found in control and exploration rats. Hybridization was substantially more dense in basolateral amygdala than in hippocampal CA1; this imbalance was unique to the group required to form first associations between odors and rewards. Rats performing an overtrained odor discrimination had the least differentiation between amygdalar subdivisions of any behavioral group. The hippocampus-to-amygdala labeling ratio favored hippocampus and was nearly identical to the ratio in exploration rats. These results demonstrate that the balance of activity within the between limbic structures shifts according to behavioral demands. It is suggested that the balances reflect the availability of pertinent afferent cues, interactions between hippocampus and the extended amygdala, and relative levels of activity in the diffuse projections to the limbic system. (+info)
Preserved performance by cerebellar patients on tests of word generation, discrimination learning, and attention.
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Recent theories suggest that the human cerebellum may contribute to the performance of cognitive tasks. We tested a group of adult patients with cerebellar damage attributable to stroke, tumor, or atrophy on four experiments involving verbal learning or attention shifting. In experiment 1, a verb generation task, participants produced semantically related verbs when presented with a list of nouns. With successive blocks of practice responding to the same set of stimuli, both groups, including a subset of cerebellar patients with unilateral right hemisphere lesions, improved their response times. In experiment 2, a verbal discrimination task, participants learned by trial and error to pick the target words from a set of word pairs. When age was taken into account, there were no performance differences between cerebellar patients and control subjects. In experiment 3, measures of spatial attention shifting were obtained under both exogenous and endogenous cueing conditions. Cerebellar patients and control subjects showed similar costs and benefits in both cueing conditions and at all SOAs. In experiment 4, intra- and interdimensional shifts of nonspatial attention were elicited by presenting word cues before the appearance of a target. Performance was substantially similar for cerebellar patients and control subjects. These results are presented as a cautionary note. The experiments failed to provide support for current hypotheses regarding the role of the cerebellum in verbal learning or attention. Alternative interpretations of previous results are discussed. (+info)
Sex dimorphisms in the rate of age-related decline in spatial memory: relevance to alterations in the estrous cycle.
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The present experiments demonstrate the existence of sex differences in the rate of development and the magnitude of age-dependent impairments in cognitive and sensorimotor abilities. Although no sex differences were found in spatial reference memory at a young age, the mnemonic ability of female rats deteriorated more rapidly than that of male rats. A major drop in reference memory of the females occurred at the age of 12 months, whereas in the males the onset of impairments occurred later, at the age of 18 months. In spatial working memory, on the other hand, the magnitude of decline was greater in females than in males, although the onset of these impairments occurred at the age of 24 months in both sexes. A sexual dimorphism-aging interaction also was observed in sensorimotor performance. Up to the age of 18 months the females outperformed the males. Subsequently, by the age of 24 months, the performance of the females declined to a level similar to that of the males. The deficits observed in reference and working memory seem to be cognitive in origin and not attributable to alterations in sensory and motor abilities. In addition, the earlier onset of reference memory impairments in females generally coincides with the onset of alterations in the estrous cycle, suggesting that a decline in the estrogenic milieu of the females could be a factor in accelerating the rate of age-related cognitive impairments in the female rat. (+info)
Olfactory discrimination ability and odor structure-activity relationships in honeybees.
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Using the training procedure introduced by von Frisch in 1919, we tested the ability of free-flying honeybees to discriminate a conditioning odor from an array of 44 simultaneously presented substances. The stimuli included homologous series of aliphatic alcohols, aldehydes and ketones, isomeric forms of some of these substances, as well as several terpenes and odor mixtures, and thus comprised stimuli of varying degrees of structural similarity to any conditioning odor. We found (i) that the honeybees significantly distinguished between 97.0% of the 1848 odor pairs tested, thus showing an excellent discrimination performance when tested in a free-flying situation with an array of structurally related substances; (ii) a significant negative correlation between discrimination performance and structural similarity of odorants in terms of differences in carbon chain length with all aliphatic substance classes tested; (iii) that both the position and type of a functional group also affected discriminability of odorants in a substance class-specific manner; and (iv) striking similarities in odor structure-activity relationships between honeybees and human and nonhuman primates tested previously on a subset of substances employed here. Our findings demonstrate that the similarities found in the structural organization of the olfactory systems of insects and vertebrates are paralleled by striking similarities in relative discrimination abilities. This strongly suggests that similar mechanisms of odor coding and discrimination may underlie olfaction in vertebrates and insects. (+info)
Effects of the long-acting monoamine reuptake inhibitor indatraline on cocaine self-administration in rhesus monkeys.
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Cocaine is a nonselective monoamine reuptake inhibitor that is widely abused. Useful pharmacotherapies for cocaine dependence may include substitution medications that produce cocaine-like effects but have a slower onset and longer duration of action. Accordingly, the present study examined the effects of the long-acting, nonselective monoamine reuptake inhibitor indatraline in assays of cocaine discrimination and cocaine self-administration that have been used to evaluate other candidate treatment medications. In rhesus monkeys trained to discriminate cocaine (0.4 mg/kg) from saline, indatraline (0.1-1.0 mg/kg) produced a dose- and time-dependent substitution for cocaine. The effects of 1.0 mg/kg indatraline peaked after 30 min and lasted up to 24 h. In monkeys trained to self-administer 0.032 mg/kg/injection cocaine and food pellets during alternating daily sessions of cocaine and food availability, indatraline (0.0032-0.032 mg/kg/injection) maintained lower rates of responding than cocaine. Repeated treatments with indatraline (0.1-0.56 mg/kg/day) for 7 days produced dose-dependent and sustained decreases in cocaine self-administration across a broad range of cocaine doses (0.0032-0.1 mg/kg/injection), and the highest dose of indatraline (0.56 mg/kg/day) nearly eliminated cocaine-maintained responding. However, doses of indatraline that decreased cocaine self-administration also usually decreased rates of food-maintained responding and produced behavioral stereotypies and trends toward weight loss and mild anemia. These findings suggest that although indatraline may decrease cocaine-taking behavior in rhesus monkeys, it also produces undesirable side effects that may limit its clinical utility in the treatment of cocaine dependence. (+info)