Feeding induced by ventricular bromocriptine and amphetamine: A possible excitatory role for dopamine in eating behavior.

The effects of intracerebroventricular (ICV) administration of the dopamine (DA) agonists, bromocriptine and d-amphetamine, on feeding and feeding-associated behaviors were examined. Male Wistar rats were injected ICV with 80-μg bromocriptine or its vehicle or with 10-μg d-amphetamine or saline. For 2 hrs, the activity, duration of individual grooming, eating, and drinking bouts, and the amount of food and water consumed were recorded. Bromocriptine and amphetamine significantly increased the amount the animals ate and meal duration, but did not significantly affect the other observed behaviors (grooming, drinking, activity, or number of meals). The findings are interpreted as being consistent with the anhedonia hypothesis (Wise, 1982), in which DA is involved with the reinforcing components of external stimuli (i.e., food). (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)     

The role of interference produced by conflicting associations in contextual control.

In 2 experiments, participants completed a computer task in which they judged the probability of outcomes occurring (e.g., flowers growing, a bug infestation) given cues (e.g., treatment of soil with a fictitious garden product). In each 2-phase experiment, cue X was associated with 1 outcome in Phase 1 and with a 2nd outcome in Phase 2. When the outcome in Phase 1 (e.g., X led to a bug infestation) was replaced in Phase 2 (e.g., X led to flowers growing), contextual control was observed (Experiments 1 and 2). Information learned in each phase was less likely to be retrieved when the cue was tested in a context different from the 1 where training occurred. When the 2nd outcome did not conflict with information acquired in the 1st phase (e.g., X led to flowers and bugs), no contextual control was observed (Experiment 2). Acquiring a 2nd association to X resulted in contextual control only when it conflicted with an association learned earlier. The authors discuss the role of interference produced when conflicting information is acquired in establishing contextual control. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effects of limbic lesions on locomotion and stereotypy elicited by dopamine agonists in the rat

The purpose of this experiment was to investigate the functional contributions of various limbic structures to locomotion and stereotypy induced by dopaminergic drugs. Female rats were randomly assigned to one of 5 groups (n = 10-14 rats/group) that received either a lesion of the hippocampus (colchicine + kainic acid), basolateral amygdala (quinolinic acid), frontal cortex (aspiration), nucleus accumbens (ibotenic acid), or served as unoperated controls. Beginning at least 2 weeks following surgery locomotion (measured as photocell beam breaks) elicited by D-amphetamine (0.0, 0.32, 1.0 and 3.2 mg/kg), SKF 82958 (0.0, 0.04, 0.08 and 0.16 mg/kg) or quinpirole (0.0, 0.25, 0.1 and 0.5 mg/kg) was determined. In agreement with previous results rats with hippocampal lesions were hyperactive in response to amphetamine. In comparison to these changes in drug-induced locomotion, lesions of the basolateral amygdala, and frontal cortex had only minor effects on drug-induced locomotion. Lesions of the nucleus accumbens produced consistent hyperactivity that was suppressed by doses of amphetamine or quinpirole that elicited behavioral stereotypy. These results provide evidence suggesting that, in comparison to other limbic structures that have substantial inputs to the nucleus accumbens, the hippocampus play a relatively prominent role in the modulation of drug-induced locomotion.     

Chronic morphine induces visible changes in the morphology of mesolimbic dopamine neurons

The mesolimbic dopamine system, which arises in the ventral tegmental area (VTA), is an important neural substrate for opiate reinforcement and addiction. Chronic exposure to opiates is known to produce biochemical adaptations in this brain region. We now show that these adaptations are associated with structural changes in VTA dopamine neurons. Individual VTA neurons in paraformaldehyde-fixed brain sections from control or morphine-treated rats were injected with the fluorescent dye Lucifer yellow. The identity of the injected cells as dopaminergic or nondopaminergic was determined by immunohistochemical labeling of the sections for tyrosine hydroxylase. Chronic morphine treatment resulted in a mean approximately 25% reduction in the area and perimeter of VTA dopamine neurons. This reduction in cell size was prevented by concomitant treatment of rats with naltrexone, an opioid receptor antagonist, as well as by intra-VTA infusion of brain-derived neurotrophic factor. In contrast, chronic morphine treatment did not alter the size of nondopaminergic neurons in the VTA, nor did it affect the total number of dopaminergic neurons in this brain region. The results of these studies provide direct evidence for structural alterations in VTA dopamine neurons as a consequence of chronic opiate exposure, which could contribute to changes in mesolimbic dopamine function associated with addiction.     

Behavioural sensitization of mesolimbic dopamine D2 receptors in chronic fluoxetine-treated rats

A common action of chronic antidepressant treatments is the potentiation of dopaminergic transmission in the limbic system. We now report that chronic, but not acute, treatment with fluoxetine (2.5 mg/kg by intragastric gavage once a day for 21 days) potentiates the locomotor stimulant effect of quinpirole, a selective dopamine D2/D3 receptor agonist. However, neither quinpirole-induced stereotypies nor the sedative effects elicited by low doses of this dopamine receptor agonist are influenced by chronic fluoxetine. These results suggest that fluoxetine, as well as classical antidepressants, sensitize postsynaptic dopamine D2/D3 receptors in the mesolimbic system.     

The role of hydrodynamic interaction in the locomotion of microorganisms

A general Boundary Element Method is presented and benchmarked with existing Slender Body Theory results and reflection solutions for the motion of spheres and slender bodies near plane boundaries. This method is used to model the swimming of a microorganism with a spherical cell body, propelled by a single rotating flagellum. The swimming of such an organism near a plane boundary, midway between two plane boundaries or in the vicinity of another similar organism, is investigated. It is found that only a small increase (less than 10%) results in the mean swimming speed of an organism swimming near and parallel to another identical organism. Similarly, only a minor propulsive advantage (again, less than 10% increase in mean swimming speed) is predicted when an organism swims very close and parallel to plane boundaries (such as a microscopic plate and (or) a coverslip, for example). This is explained in terms of the flagellar propulsive advantage derived from an increase in the ratio of the normal to tangential resistance coefficients of a slender body being offset by the apparently equally significant increase in the cell body drag. For an organism swimming normal to and toward a plane boundary, however, it is predicted that (assuming it is rotating its flagellum, relative to its cell body, with a constant angular frequency) the resulting swimming speed decreases asymptotically as the organism approaches the boundary.     

The role of GABA and anxiety in the reconsolidation of conditioned fear.

The current study examined the effects of systemic administration of a GABA agonist [midazolam (MDZ)] and a GABA antagonist (bicuculline) on fear responding after brief CS exposure, a procedure thought to involve memory reconsolidation. Using a contextual fear-conditioning paradigm, rats were initially given two context-shock training trials, followed 24 hrs later by a 90-s context exposure (reactivation), and 24 hrs later by a 3-min context test. In Experiment 1, MDZ (2 mg/kg, i.p.), whereas in Experiment 2, bicuculline (1 mg/kg, i.p.), was administered immediately after reactivation. MDZ reduced conditioned freezing, whereas bicuculline only marginally potentiated conditioned freezing. The MDZ fear disruption effect did not occur in the absence of reactivation, and was evident 10 days after the initial test. Experiment 3 induced high levels of baseline anxiety using the single prolonged stress paradigm, and replicated the essential procedure of Experiment 1. Results indicated that MDZ fear disruption did not differ between high and low anxiety rats. The data suggest the involvement of GABA receptors in reconsolidation processes, and the possible clinical use of MDZ in fear reduction with brief reexposure. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A role for affect in context-dependent sensitization to amphetamine.

Repeated exposure to stimulant drugs, such as amphetamine, induces sensitization to their behavioral activating effects. It is commonly assumed that behavioral sensitization is expressed in the environment explicitly paired with the drug but not in a different environment explicitly unpaired with the drug. The experiments reported here show that this assumption is incorrect. It was found that sensitization was expressed in an environment explicitly unpaired with amphetamine, but imbued with positive affective valence by its association with a natural reward, oral sucrose. These results suggest that the affective valence of the environment in which the drug is administered plays a decisive role in the expression of drug effects, regardless of any previous association of that environment with the drug. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The interaction between locomotion, striatal dopamine and paramedian reticular nucleus in rats

Either intact rats, sham-operated rats, or rats with lesions of the paramedian reticular nucleus (PRN) were exposed to cold (2 degrees C) or heat (36 degrees C) stress and their locomotor activity responses and striatal dopamine (DA) release were compared. At room temperature (22 degrees C), results analyzed revealed significant effects in the PRN-lesioned rats: increases in locomotion (including both horizontal and vertical motion), direction of turnings (including both clockwise and anticlockwise) or striatal DA release. In both the intact rats and the sham-operated rats, either cold or heat stress increased the locomotion, the direction of turnings and the striatal DA release. The increases in both vertical motion and striatal DA release following cold or heat stress were attenuated by PRN lesions. The data suggest that a PRN-striatal DA link existing in rat's brain which affects both the spontaneous and the thermal stress induced locomotor activities.     

Conditioned increases in behavioral activity and accumbens dopamine levels produced by intravenous cocaine.

In vivo microdialysis, behavioral activity assessments, and a conditioned place preference (CPP) test were used to investigate dopaminergic correlates of cocaine-conditioned behaviors. Over 12 days, rats were given either intravenous cocaine (4.2 mg/kg) or saline (6 cocaine and 6 saline infusions) daily in distinctively different environments. The following day, rats were tested in the cocaine- and saline-paired environments; 48 hr later, CPP was determined. The cocaine-associated environment elicited greater nucleus accumbens dopamine (NAcc DA) levels, hyperactivity, and place preference, though the emergence of DA increases was not in synchrony with peak behavioral activation. Although conditioned behavioral effects after repeated cocaine are well documented, direct evidence of increased NAcc DA in response to a cocaine-paired environment has not been previously reported. Discrepancies with previous work are attributed to a number of methodological differences. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Dissociation of conditioned locomotion and Fos induction in response to stimuli formerly paired with cocaine.

A discrete stimulus (flashing light) was paired with cocaine (20 mg/kg) to induce conditioned locomotion. To identify brain regions activated during this response, Fos was measured with immunohistochemistry. Although paired subjects displayed robust conditioned locomotion, Fos was not increased in any limbic brain regions analyzed. In contrast, pairing of cocaine with generalized contextual cues (whole room) produced conditioned locomotion and Fos activation in the prelimbic portion of prefrontal cortex and the nucleus accumbens core. These results suggest that the pattern of neuronal activation during cocaine-conditioned activity differs depending on whether a discrete or contextual stimulus is used as a conditioned stimulus. The possibility that expectancy and frustrative nonreward contribute to Fos expression in rats conditioned to contextual cues is discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Exposure to elevated levels of dietary fat attenuates psychostimulant reward and mesolimbic dopamine turnover in the rat.

Recent studies indicate that decreased central dopamine is associated with diet-induced obesity in humans and in animal models. In the current study, the authors assessed the hypothesis that diet-induced obesity reduces mesolimbic dopamine function. Specifically, the authors compared dopamine turnover in this region between rats fed a high-fat diet and those consuming a standard low-fat diet. The authors also assessed behavioral consequences of diet-induced obesity by testing the response of these animals in a conditioned place paradigm using amphetamine as a reinforcer and in an operant conditioning paradigm using sucrose reinforcement. Results demonstrate that animals consuming a high-fat diet, independent of the development of obesity, exhibit decreased dopamine turnover in the mesolimbic system, reduced preference for an amphetamine cue, and attenuated operant responding for sucrose. The authors also observed that diet-induced obesity with a high-fat diet attenuated mesolimbic dopamine turnover in the nucleus accumbens. These data are consistent with recent hypotheses that the hormonal signals derived from adipose tissue regulate the activity of central nervous system structures involved in reward and motivation, which may have implications for the treatment of obesity and/or addiction. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

When pentobarbital is the conditioned stimulus and amphetamine is the unconditioned stimulus, conditioning depends on the type of conditioned response.

Injections of drugs into rats were used as conditioned stimuli (CSs) and as unconditioned stimuli (UCSs). With heart rate (HR) conditioning, the pentobarbital CS produces a higher HR than under control conditions. With avfail (aversion failure) conditioning, the pentobarbital CS loses much of its capacity to induce a conditioned taste aversion. HR conditioning was obtained with forward delays of up to 30 min and backward delays of up to 270 min, where the delays are defined by the interinjection interval. Avfail was obtained with forward delays of up to 270 min but not with backward delays. Neither HR conditioning nor avfail were context specific but could be demonstrated in a test apparatus after pairings that occurred in the home cage. This indicated that the external environment was not an important part of the effective stimulus complex. When HR conditioning was obtained, its latency and duration was not related to the delay between the CS and UCS injections or whether they were forward or backward. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Mechanisms of amphetamine action revealed in mice lacking the dopamine transporter

Amphetamine (AMPH) inhibits uptake and causes release of dopamine (DA) from presynaptic terminals. AMPH can act on both vesicular storage of DA and directly on the dopamine transporter (DAT). To assess the relative importance of these two processes, we have examined the releasing actions of AMPH in mice with a genetic deletion of the DAT. The sequence of actions of AMPH has been determined by following the real time changes of DA in the extracellular fluid of intact tissue with fast scan cyclic voltammetry. In striatal slices from wild-type mice, AMPH causes a gradual (approximately 30 min) increase in extracellular DA, with a concomitant disappearance of the pool of DA available for depolarization-evoked release. Conversely, in slices from mice lacking the DAT, although a similar disappearance of electrically stimulated DA release occurs, extracellular DA does not increase. Similarly, microdialysis measurements of DA after AMPH in freely moving animals show no change in mice lacking the DAT, whereas it increases 10-fold in wild-type mice. In contrast, redistribution of DA from vesicles to the cytoplasm by the use of a reserpine-like compound, Ro4-1284, does not increase extracellular DA in slices from wild-type animals; however, subsequent addition of AMPH induces rapid (<5 min) release of DA. Thus, the DAT is required for the releasing action, but not the vesicle-depleting action, of AMPH on DA neurons, and the latter represents the rate-limiting step in the effects of AMPH. Furthermore, these findings suggest that in the absence of pharmacological manipulation, such as the use of amphetamine, endogenous cytoplasmic DA normally does not reach sufficient concentrations to reverse the DAT.     

Dissociation of morphine-induced potentiation of turning and striatal dopamine release by amphetamine in the nigrally-lesioned rat

Morphine has been reported to increase extracellular levels of dopamine in the brain of intact rats and to potentiate turning induced by amphetamine in nigrally-lesioned rats. The present study tested the hypothesis that there is a causal relationship between these two effects of morphine. We tested morphine alone, amphetamine alone, and the combination in separate groups of nigrally-lesioned rats for effects on turning and, by microdialysis, on extracellular dopamine levels. Morphine (3.0 or 10 mg/kg) did not produce significant turning but amphetamine (1.0 mg/kg) did. The lower dose, but not the higher dose, of morphine potentiated amphetamine-induced turning. Amphetamine, but not morphine, produced increases in extracellular dopamine levels. In contrast to what occurred with turning, 10 mg/kg but not 3.0 mg/kg morphine potentiated amphetamine-induced increases in extracellular dopamine levels. These results show that the potentiation of amphetamine-induced turning by morphine in nigrally-lesioned rats is not due to the potentiation of dopamine release in the intact striatum.     

The recalibration of rotational locomotion.

Rotational locomotion (i.e., turning in place) can be recalibrated by arranging a situation in which one steps around at 1 speed but turns through the world at a different speed. After exposure to such a situation, people will show predictable changes if asked to look at a target, close their eyes, and turn to face it. In 5 experiments, this recalibration was shown to be attributable to 2 different mechanisms, one a sensory adaptation-like component from simply turning in place for several minutes and the other a perceptual-learning-like component related to the discrepancy created by the rearrangement of optical flow and action. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of postnatal stress on dopamine mesolimbic system responses to aversive experiences in adult life

The effects of postnatal stress on mesolimbic dopamine (DA) functioning in 90-day-old mice were investigated. Postnatal stress consisted of 15 min daily exposure to clean bedding (CB) in the absence of the mother for the first two weeks of life. Controls were daily exposed to home cage bedding (HCB) in the absence of the mother. A single brief (5-10 min) exposure to restraint produced a clear-cut increase in DA metabolites (3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 3-methoxytyramine (3-MT)) in the nucleus accumbens septi (NAS) of adult HCB but not CB mice. Moreover, when tested in an elevated plus maze, CB mice showed more exploration and reduced fearfulness in comparison with HCB mice. Taken together, these results indicate reduced emotional reactivity in adult mice repeatedly stressed during postnatal development. Moreover, HCB mice but not CB mice showed altered behavioral responsiveness to apomorphine following repeated restraint stress (10 daily 120 min) in adult life, although no difference in the behavioral response to either a low or a high dose of apomorphine was observed in adult unstressed mice of the CB and HCB groups. These results indicate that the effects of early experiences on brain DA functioning may not be evident in basal conditions and be revealed only under environmental pressure.(ABSTRACT TRUNCATED AT 250 WORDS)     

The role of temporal relationships in the transfer of conditioned inhibition

We have cloned and molecularly and functionally characterized the first human member of the family of Ca2+-activated Cl- channels, human (h) CLCA1. The 31,902-bp gene is located on chromosome 1p22-31 and is preceded by a canonic promoter region that contains an L1 transposable element. In contrast to all previously known homologs in other species, hCLCA1 is exclusively expressed in intestinal basal crypt epithelia and goblet cells, suggesting that it does not represent the human counterpart of any of them. Expression of the 914-amino-acid hCLCA1 protein in HEK 293 cells yielded a 125-kDa precursor that was processed to yield two cell-surface-associated subunits, a 90-kDa protein and a group of 37- to 41-kDa proteins. Four transmembrane domains were established within the 90-kDa subunit. HEK 293 cells transfected with CLCA1 exhibited an increase in whole-cell Ca2+-sensitive Cl- currents that were outwardly rectified and inhibited by 4,4'-diisothiocyanatostilbene-2, 2'-disulfonic acid, dithiothreitol, and niflumic acid. Cell-attached patch recordings of transfected cells revealed single channels with a slope conductance of 13.4 pS. These findings suggest that human CLCA1 mediates a Ca2+-activated Cl- conductance in the human intestine and make it an interesting candidate as a modulating factor in the pathogenesis of cystic fibrosis.