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PubMed2002

Rewarding and psychomotor stimulant effects of endomorphin-1: anteroposterior differences within the ventral tegmental area and lack of effect in nucleus accumbens.

Endomorphin-1 (EM-1) is a recently isolated endogenous peptide having potent analgesic activity and high affinity and selectivity for the mu-opioid receptor. The present study was designed to investigate the rewarding and psychomotor stimulant effects of EM-1 in specific brain regions. We found that rats would learn without priming or response shaping to lever-press for microinjections of EM-1 into the ventral tegmental area (VTA); responding was most vigorous for high-dose injections into the posterior VTA. Rats did not learn to lever-press for microinjections of EM-1 into the nucleus accumbens (NAS) or regions just dorsal to the VTA. Lever-pressing for EM-1 in the VTA was extinguished when vehicle was substituted for the peptide and was reinstated when EM-1 reinforcement was re-established. Conditioned place preference was established by EM-1 injections into the posterior but not the anterior VTA or the NAS. Injection of EM-1 (0.1-1.0 nmol) into the posterior VTA induced robust increases in locomotor activity, whereas injections into the anterior VTA had very weak locomotor-stimulating effects. When injected into the NAS, EM-1 (0.1-10.0 nmol) did not affect locomotor activity. The present findings implicate the posterior VTA as a highly specific and sensitive site for opioid reward and suggest a role for EM-1-containing projections to the posterior VTA in the rewarding effects of other reinforcers.

Animals↗
PubMed1999

The behavioral response to novelty is altered in rats neonatally exposed to cocaine.

It has recently been suggested that the effects of in utero cocaine exposure may result in subtle deficits related to a challenging environment, including exposure to novelty or stress. This study used a neonatal drug-exposure model to examine the behavioral response to a novel environment in rodents. Subjects were artificially reared (AR) from postnatal Days 4-10. There were four treatment groups; AR 40 mg/kg/day cocaine, AR 20 mg/kg/day cocaine, AR control group receiving no drug, and a normally reared control. In Experiment 1, subjects were tested for their preference of maternal home-cage or clean wood-chip odors in a T-maze on postnatal Day 15. Subjects from all treatment groups preferred the maternal odor. In Experiment 2, subjects were habituated to four familiar odors and tested with a novel odor in an open field (postnatal Days 16-21). Neonatal exposure to 20 mg/kg/day cocaine led to an overall increase in exploratory behavior during testing, whereas 40 mg/kg/day did not, supporting the hypothesis that developmental exposure to cocaine at some doses may alter the offspring's response to a changing environment.

Animals↗
PubMed2000

A comparative analysis of teenagers who smoke different cigarette brands.

This study analyzed and compared the survey responses of teenagers who smoke different cigarette brands. It was found that teen Marlboro and Camel smokers perceived themselves as having more stress in their lives as compared with teen Newport smokers. On average, Marlboro smokers were depressed or sad more often than were Camel or Newport smokers. Camel smokers were generally less interested in a peer stop-smoking program than were Newport or Marlboro smokers. Finally, these teen smokers, regardless of cigarette brand, had similar opinions about quitting. Given the differences across brands, more flexible approaches may be needed to address teenage smoking.

Adolescent↗
PubMed2000

Role of the perirhinal cortex in rats' conditioned taste aversion response memorization.

The role of the perirhinal cortex (PC) in conditioned taste aversion (CTA) learning was investigated in Long Evans rats. CTA was induced by the intraperitoneal administration of LiCl 60 min after saccharin-sweetened water drinking. The PC was reversibly inactivated by the stereotaxic administration of tetrodotoxin (TTX) 60 min before saccharin drinking, immediately after saccharin drinking (Experiment 1), 6 or 24 hr after LiCl administration (Experiment 2), and 60 min before CTA retrieval testing (Experiment 3). Only pre-saccharin drinking PC inactivation disrupted CTA. Thus, PC integrity is necessary only during the earliest phases of CTA mnemonic processing, that is, taste information acquisition and early gustatory memory elaboration. The results are discussed in relation to PC connectivity and PC temporal involvement in the memorization process of other aversive responses.

Animals↗
PubMed2000

Basolateral amygdala NMDA receptors are selectively involved in the acquisition of taste-potentiated odor aversion in the rat.

In the taste-potentiated odor aversion (TPOA) paradigm, animals acquire a strong aversion to an odor that is followed by delayed intoxication only if a gustatory stimulus is presented with the odor during conditioning. Although previous work has shown that N-methyl-D-aspartate (NMDA) receptors in the basolateral nucleus of the amygdala (BLA) play a role in the acquisition of TPOA, the present study aimed at describing the process in which NMDA receptors in the BLA are involved during acquisition of TPOA. Male Long-Evans rats received intra-BLA infusions of the competitive NMDA receptor antagonist D,L-2-2-amino-5-phosphonovalerate (D-APV; 0.05 and 0.50 microg) immediately before or after the odor-taste conditioned stimulus (CS) presentation, or immediately before the test. Results showed that D-APV impaired acquisition of TPOA when infused before, but not after, the CS presentation, but did not affect retrieval. These results suggest that NMDA receptors of the BLA are involved in the formation of potentiation--by taste--of the olfactory memory trace, but not in the maintenance of this process.

Amygdala↗
PubMed1975

Application of Premack's generalization of reinforcement to modify occupational behavior in two severely retarded individuals.

Premack's generalization that a more probable response will reinforce a less probable one was applied to modify occupational behavior of two severly retarded individuals. When opportunity to work on a more preferred activity was made contingent upon spending some time on a less preferred activity, an increase in the amount of time spent on less preferred work occurred. As the reinforcement schedule was gradually reduced in terms of time allowed on more preferred work, time spent on the less preferred activity tended to increase. Behavior did not return to baseline levels on extinction, however. Possible reasons for these findings are outlined, together with the practical advantages of utilizing Premack's generalization as a reinforcement technique for motivating retarded individuals in rehabilitation settings.

Adult↗
PubMed2001

Linked target selection for saccadic and smooth pursuit eye movements.

In natural situations, motor activity must often choose a single target when multiple distractors are present. The present paper asks how primate smooth pursuit eye movements choose targets, by analysis of a natural target-selection task. Monkeys tracked two targets that started 1.5 degrees eccentric and moved in different directions (up, right, down, and left) toward the position of fixation. As expected from previous results, the smooth pursuit before the first saccade reflected a vector average of the responses to the two target motions individually. However, post-saccadic smooth eye velocity showed enhancement that was spatially selective for the motion at the endpoint of the saccade. If the saccade endpoint was close to one of the two targets, creating a targeting saccade, then pursuit was selectively enhanced for the visual motion of that target and suppressed for the other target. If the endpoint landed between the two targets, creating an averaging saccade, then post-saccadic smooth eye velocity also reflected a vector average of the two target motions. Saccades with latencies >200 msec were almost always targeting saccades. However, pursuit did not transition from vector-averaging to target-selecting until the occurrence of a saccade, even when saccade latencies were >300 msec. Thus, our data demonstrate that post-saccadic enhancement of pursuit is spatially selective and that noncued target selection for pursuit is time-locked to the occurrence of a saccade. This raises the possibility that the motor commands for saccades play a causal role, not only in enhancing visuomotor transmission for pursuit but also in choosing a target for pursuit.

Animals↗
PubMed2001

The role of the nucleus accumbens in instrumental conditioning: Evidence of a functional dissociation between accumbens core and shell.

In three experiments we examined the effect of bilateral excitotoxic lesions of the nucleus accumbens core or shell subregions on instrumental performance, outcome devaluation, degradation of the instrumental contingency, Pavlovian conditioning, and Pavlovian-instrumental transfer. Rats were food deprived and trained to press two levers, one delivering food pellets and the other a sucrose solution. All animals acquired the lever-press response although the rate of acquisition and overall response rates in core-lesioned animals were depressed relative to that in the shell- or sham-lesioned animals. Furthermore, in shell- and sham-lesioned rats, post-training devaluation of one of the two outcomes using a specific satiety procedure produced a selective reduction in performance on the lever that, in training, delivered the prefed outcome. In contrast, the core-lesioned rats failed to show a selective devaluation effect and reduced responding on both levers. Subsequent tests revealed that these effects of core lesions were not caused by an impairment in their ability to recall the devalued outcome, to discriminate the two outcomes, or to encode the instrumental action-outcome contingencies to which they were exposed. Additionally, the core lesions did not have any marked effect on Pavlovian conditioning or on Pavlovian-instrumental transfer. Importantly, although shell-lesioned rats showed no deficit in any test of instrumental conditioning or in Pavlovian conditioning, they failed to show any positive transfer in the Pavlovian-instrumental transfer test. This double dissociation suggests that nucleus accumbens core and shell differentially mediate the impact of instrumental and Pavlovian incentive processes, respectively, on instrumental performance.

Analysis of Variance↗
PubMed2001

Recognition memory correlates of hippocampal theta cells.

Investigations of hippocampal theta cell activity have typically involved behavioral tasks with modest cognitive demands. Recordings in rats locomoting through space or engaged in simple stimulus discrimination or conditioning have revealed some place specificity and S(+)/S(-) selectivity in addition to the hippocampal EEG theta-related behavioral/motor correlates. However, little data exist regarding theta cell activity during performance of more cognitively demanding, hippocampal-dependent recognition memory tasks. Here, we examined the cognitive firing correlates of theta cells in rats that were performing an olfactory recognition memory task with distinct sample and test phases. Discriminant analysis revealed odor and match/nonmatch memory correlates in theta cell activity comparable in relative magnitude to that of the principal cells. Odor-specific theta cell responses in the sample phase were restricted primarily to CA1 and linked to task performance. In the test recognition phase, match/nonmatch theta cells were found primarily in the CA3 and CA1 fields, most of which exhibited greater activity on correct nonmatch trials in which recognition occurred than on error match trials in which recognition failed. Odor selectivity of the match/nonmatch signaling was greatest in the dentate gyrus (DG) and CA3 and least in CA1. This inverted pattern of stimulus specificity in the sample versus test phase was similar to that observed in principal cells but with a greater contrast between the CA1 and DG/CA3 fields. Together, these findings suggest that theta cells actively participate in hippocampal recognition memory processing and play a specific role in shaping the cognitive firing properties of the hippocampal principal cells.

Action Potentials↗
PubMed2001

Hierarchical processing of horizontal disparity information in the visual forebrain of behaving owls.

According to their restricted receptive fields and input-filter characteristics, disparity-sensitive neurons at early processing levels of the visual system perform rather ambiguous computations; they respond vigorously to disparity in false-matched images and show multiple response peaks in their disparity-tuning profiles. On the other hand, the perception of depth from binocular disparity is reliable, thus raising the question as to where and how in the brain additional processing is accomplished leading toward behaviorally relevant disparity detection. To address this issue, tuning data during stimulation with correlated and anticorrelated random-dot stereograms (a-RDS) were obtained from 52 disparity-sensitive visual Wulst neurons in three behaving owls. From the disparity-tuning curves, several quantitative measures were derived that allowed to determine the response ambiguity of a cell. A systematic decline of response ambiguities with increasing response latencies was observed. An increase in response latencies of neurons was correlated with a decrease of the strength of responses to a-RDS. Declining responses to a-RDS are expected for global detectors, because an owl was not able to discriminate depth in psychophysical tests with a-RDS. In addition, suppression of response side peaks was increased and disparity tuning was enhanced with growing response latencies. These results suggest a functional hierarchy of disparity processing in the owl's forebrain, leading from spatial filters to more global disparity detectors that may be able to solve the correspondence problem. Nonlinear threshold operations and inhibition are proposed as candidate mechanisms to resolve coding ambiguities.

Action Potentials↗
PubMed2001

A code for behavioral inhibition on the basis of color, but not motion, in ventrolateral prefrontal cortex of macaque monkey.

To examine the neural mechanism for behavioral inhibition, we recorded single-cell activity in macaque ventrolateral prefrontal cortex, which is known to receive visual information directly from the inferotemporal cortex. In response to a moving random pattern of colored dots, monkeys had to make a go or no-go response. In the color condition, green indicated go, whereas red indicated no-go, regardless of the motion direction; in the motion condition, upward indicated go, whereas downward indicated no-go, regardless of the color. Approximately one-half of the visual cells were go/no-go differential. A majority of these cells (64/73) showed differential activity only in the color condition; they responded nondifferentially in the motion condition, although the same set of stimuli was used. We classified these cells as "go type" (n = 41) and "no-go type" (n = 23) depending on the color for which they showed a stronger response. Interestingly, in both types of cells, the differential effects were observed only for the no-go-indicating color. Compared with the nondifferential responses in the motion condition, go-type cells in the color condition showed weaker responses to the no-go-indicating color, whereas their responses to the go-indicating color were similar; in contrast, no-go type cells showed stronger responses to the no-go-indicating color, whereas their responses to the go-indicating color were similar. Both types of cells did not show any activity change during the actual execution of the go or no-go response. These results suggest that neurons in ventrolateral prefrontal cortex contribute to stimulus-response association in complex task situations by inhibiting behavioral responses on the basis of visual information from the ventral stream.

Animals↗
PubMed2001

A possible function of the preference for hind nipples in prairie voles (Microtus ochrogaster).

Prairie vole pups (Microtus ochrogaster) in laboratory cages prefer hind nipples. In this research, the author observed 8 litters of prairie voles in a seminatural environment to confirm the preference for hind nipples and to determine if young on hind nipples were groomed more frequently or dislodged less frequently than were young on other nipples. Prairie vole pups in seminatural environments preferred hind nipples; this preference was illustrated by the progressive use of more anterior nipples only as litter size increased and by the reluctance of pups to voluntarily release their hold on hind nipples. Maternal grooming of young did not vary with suckling location. Prairie vole young on hind nipples, however, were dislodged less frequently than were young on other nipples. Less frequent dislodgment from hind nipples during maternal movements may play a role in the preference for hind nipples in prairie voles.

Animals↗
PubMed2002

Area postrema lesions impair flavor-toxin aversion learning but not flavor-nutrient preference learning.

Rats with lesions of the area postrema (APX) or sham lesions were trained to associate flavored solutions with positive or negative postingestive consequences. The APX rats were similar to controls in learning preferences for flavors paired with concurrent intragastric infusions of maltodextrin or corn oil and for a flavor paired with delayed maltodextrin infusions. In contrast, the APX rats displayed impaired aversion learning for flavors paired with toxic drug treatments (lithium chloride infusion or methylscopolamine injection). The aversion learning deficit ranged from mild to total, depending on training procedures. These findings confirm the important role of the area postrema in flavor-toxin learning but provide no evidence for its involvement in flavor-nutrient conditioning.

Animals↗
PubMed2002

Stimulus control by same-versus-different relations among multiple visual stimuli.

The authors devised a go/no-go discrimination learning task that allowed but did not require pigeons to report (a) from which of 2 different sets a collection of visual items was drawn and (b) the relations between or among the items as being the same as or different from one another. The results of 2 experiments using this task disclosed stimulus control by the particular items in the arrays and by the same-different relations exemplified by those items. Relational and item control depended on how many items were in the arrays. Same-different discrimination was evident with 2-item displays, but it was much stronger with 6 or more items. These findings help to define the substrates of advanced conceptual behavior.

Analysis of Variance↗
PubMed2003

A critical role for the cannabinoid CB1 receptors in alcohol dependence and stress-stimulated ethanol drinking.

Although many people drink alcohol regularly, only some become addicted. Several studies have shown that genetic and environmental factors contribute to individual differences in the vulnerability to the effects of alcohol (Nestler, 2000; Kreek, 2001; Crabbe, 2002). Among the environmental factors, stress is perhaps the most important trigger for relapse after a period of abstinence (Koob and Nestler, 1997; Piazza and Le Moal, 1998; Koob and Le Moal, 2001; Weiss et al., 2001). Here we show that ethanol withdrawal symptoms were completely absent in cannabinoid CB1 receptor-deficient mice, although acute effects of ethanol and ethanol tolerance and preference were basically normal. Furthermore, foot-shock stress had no affect on alcohol preference in Cnr1-/- mice, although it induced a dramatic increase in Cnr1+/+ animals. These results reveal a critical role for the CB1 receptor in clinically important aspects of alcohol dependence and provide a rationale for the use of CB1 receptor antagonists in the treatment of alcohol addiction.

Alcohol Drinking↗
PubMed2003

Early odor preference learning in the rat: bidirectional effects of cAMP response element-binding protein (CREB) and mutant CREB support a causal role for phosphorylated CREB.

Early odor preference learning in rats is associated with increases of phosphorylated CREB (pCREB) in mitral cells of the olfactory bulb. In the present study, herpes simplex virus expressing CREB (HSV-CREB) and dominant-negative mutant CREB (HSV-mCREB) have been injected into the bulb to assess a causal role for CREB and pCREB in this model. Odor paired with stroking or with the beta-adrenoceptor agonist isoproterenol produces odor approach 24 hr later. Isoproterenol-induced learning exhibits an inverted U curve dose-dependent learning relationship with both low and high doses failing to produce learning. pCREB increases have only been seen at the learning effective dose. In the present study, injection of an HSV vector expressing mutant CREB into the olfactory bulb prevented learning induced by stroking. Control HSV expressing LacZ was without effect. Expression of mutant CREB shifted the dose-learning curve for isoproterenol to the right such that a higher dose was required to induce learning. Expression of CREB shifted the dose-learning curve for isoproterenol to the left, with a lower dose now producing learning. As expected from this shift, CREB overexpression interfered with learning induced by stroking. When learning occurred, with either CREB or mutant CREB, pCREB was observed to be elevated relative to the nonlearning LacZ control groups. Unexpectedly, with odor plus stroking in the nonlearning CREB group, the level of pCREB was also higher than with odor plus stroking in LacZ controls that did learn. The data demonstrate a causal role for CREB and pCREB in early mammalian odor preference learning, reinforcing CREB as a "universal" memory molecule. They support evidence that CREB overexpression can be deleterious and suggest the hypothesis of an optimal pCREB window for learning.

Adrenergic beta-Agonists↗
PubMed2003

Cyclic estrogen replacement improves cognitive function in aged ovariectomized rhesus monkeys.

Among the identified risks and benefits of hormone-replacement therapy, the effects of treatment on cognitive function in postmenopausal women have proved difficult to define. Here we conducted a controlled, prospective analysis in a nonhuman primate model to test whether surgical menopause and estrogen replacement influence the cognitive outcome of normal aging. Sixteen aged rhesus monkeys were ovariectomized, and throughout the course of subsequent neuropsychological assessment, half received a regimen of low-dose, cyclic estradiol replacement. Hormone treatment substantially reversed the marked age-related impairment vehicle-injected monkeys exhibited on a delayed response test of spatial working memory. Modest improvement was also observed on a delayed nonmatching-to-sample recognition memory task. In contrast, ovariectomy exacerbated age-related deficits in object discrimination learning; the magnitude of this effect was equivalent among vehicle- and estrogen-treated monkeys. Together, these results demonstrate that ovarian hormone status can broadly influence normal cognitive aging in monkeys, affecting capacities mediated by multiple brain regions, including the prefrontal cortex and the medial temporal lobe memory system. The animal model established here should enable progress toward defining the neurobiological mechanisms that mediate the beneficial effects of estrogen on age-related cognitive decline in primates.

Aging↗