Effects of whole-brain radiation therapy on the blood-brain barrier in immunocompetent and immunocompromised mouse models.

BACKGROUND: Approximately 20% of all cancer patients will develop brain metastases in their lifespan. The standard of care for patients with multiple brain metastases is whole-brain radiation therapy, which disrupts the blood-brain barrier. Previous studies have shown inflammatory mediators play a role in the radiation-mediated increase in permeability. Our goal was to determine if differential permeability post-radiation occurs between immunocompetent and immunocompromised mice. METHODS: We utilized a commissioned preclinical irradiator to irradiate brains of C57Bl/6J wild-type and athymic nude mice. Acute (3-24 h) effects on blood-brain barrier integrity were evaluated with our in-situ brain perfusion technique and quantitative fluorescent and phosphorescent microscopy. The presence of inflammatory mediators in the brain and serum was determined with a proinflammatory cytokine panel. RESULTS: Blood-brain barrier integrity and efflux transporter activity were altered in the immunocompetent mice 12 h following irradiation without similar observations in the immunocompromised mice. We observed increased TNF-α concentrations in the serum of wild-type mice immediately post-radiation and nude mice 12 h post-radiation. The brain concentration of CXCL1 was also increased in both mouse strains at the 12-h time point. CONCLUSIONS: The immune response plays a role in the magnitude of blood-brain barrier disruption following irradiation in a time- and size-dependent manner.

An exploratory approach to the serotonergic hypothesis of depression: bridging the synaptic gap.

In this exploratory review, we attempt to integrate pre and post synaptic theories of the biochemical basis of depression--in particular with regard to 5-HT. We will be providing evidence that in major depressive disorder, there is a continuity of dysfunction of neural function, i.e. pre and post synaptic serotonergic symptoms are affected. Furthermore, we will also be providing the implications of this approach for normal treatments for depressive disorder.

Manipulations of the features of standard video lottery terminal (VLT) games: effects in pathological and non-pathological gamblers.

The present study was conducted to identify game parameters that would reduce the risk of abuse of video lottery terminals (VLTs) by pathological gamblers, while exerting minimal effects on the behavior of non-pathological gamblers. Three manipulations of standard VLT game features were explored. Participants were exposed to: a counter which displayed a running total of money spent; a VLT spinning reels game where participants could no longer "stop" the reels by touching the screen; and sensory feature manipulations. In control conditions, participants were exposed to standard settings for either a spinning reels or a video poker game. Dependent variables were self-ratings of reactions to each set of parameters. A set of 2(3) x 2 x 2 (game manipulation [experimental condition(s) vs. control condition] x game [spinning reels vs. video poker] x gambler status [pathological vs. non-pathological]) repeated measures ANOVAs were conducted on all dependent variables. The findings suggest that the sensory manipulations (i.e., fast speed/sound or slow speed/no sound manipulations) produced the most robust reaction differences. Before advocating harm reduction policies such as lowering sensory features of VLT games to reduce potential harm to pathological gamblers, it is important to replicate findings in a more naturalistic setting, such as a real bar.

The relationship between open and closed kinetic chain strength of the lower limb and jumping performance.

Closed kinetic chain (CKC) exercise has become popular in rehabilitation partly due to the belief that it is more closely related to function than open kinetic chain (OKC) resistance. This study's purpose was to investigate the relationship between OKC and CKC strength of the lower limb extensors and functional performance. Twenty uninjured female subjects performed isotonic strength tests for the knee extensors in OKC and for the hip, knee, and ankle extensors in the squat exercise (CKC). Vertical and standing long jump performance was assessed using an optoelectric motion analysis system. Pearson product-moment correlation analysis showed that CKC strength scores were correlated with vertical jump performance (r = 0.722, p = 0.002) and standing long jump performance (r = 0.650, p = 0.005). Open kinetic chain strength demonstrated minimal correlation with vertical jump (r = 0.097) and standing long jump performance (r = 0.070). We conclude that lower limb extensor CKC muscle strength is more highly related to jumping performance than knee extensor OKC strength, but further research is needed to assess possible differences in training effectiveness for these two regimes.

Increased striatal dopamine efflux follows scopolamine administered systemically or to the tegmental pedunculopontine nucleus.

The cholinergic cells of the tegmental pedunculopontine nucleus monosynaptically excite dopaminergic neurons of the substantia nigra. In vivo electrochemical methods were used to monitor dorsal striatal dopamine efflux in awake rats following intraperitoneal scopolamine injections and following the direct application of scopolamine to the tegmental pedunculopontine nucleus. Systemic injections of scopolamine (1.0, 3.0 or 10.0 mg/kg) resulted in dose-related increases in peak striatal dopamine oxidation currents of between 1.1 and 2.0 nA. Increases began within 10-20 min after injection and peaked after 40-90 min. Unilateral microinjections of scopolamine into the tegmental pedunculopontine nucleus (10, 50 or 100 micrograms/0.5 microliter) resulted in dose-related increases in dopamine oxidation currents that peaked 60-90 min postinjection (2.9-5.0 nA). Carbachol (4.0 micrograms/0.5 microliter) injected unilaterally into the tegmental pedunculopontine nucleus 20 min before 100 micrograms tegmental pedunculopontine nucleus scopolamine, or injected bilaterally 20 min before 3.0 mg/kg systemic scopolamine, attenuated the increases produced by scopolamine alone. The carbachol preinjection tests suggest that the effects of both systemic and tegmental pedunculopontine nucleus scopolamine treatments are mediated largely by muscarinic receptors near the tegmental pedunculopontine nucleus. These findings are consistent with the proposal that enhanced activation of substantia nigra dopamine cells results from scopolamine-induced disinhibition of the tegemental pedunculopontine nucleus cholinergic cell group via blockade of their inhibitory autoreceptors.

Ibogaine effects on sweet preference and amphetamine induced locomotion: implications for drug addiction.

The neural basis of ibogaine's effects on drug-related behaviours is unclear. One possibility is that ibogaine interferes with the shared capacity of many addictive agents to stimulate brain dopamine activity, but reports of ibogaine effects on dopamine activity have been inconsistent. Our study suggests such inconsistencies may result from variations in prior drug exposure. If ibogaine blocks dopamine activity, then it should, like dopamine blockers, decrease preference for natural rewards such as sweet solutions. However, 40 mg/kg ibogaine i.p. did not decrease preference for a glucose + saccharin solution when it was administered to male Long Evans rats 24 h prior to test in Experiment 1. Nor did ibogaine attenuate conditioned preference for a neutral flavour previously paired with sweet taste in Experiment 2. In Experiment 3, effects of 40 mg/kg ibogaine on amphetamine-induced locomotion were investigated in drug-naive and drug-experienced (four prior doses of 1.5 mg/kg amphetamine) rats. Locomotion was significantly lower in those ibogaine-treated rats that had previously been exposed to amphetamine than in those that had not. Thus, ibogaine may serve to decrease induced levels of dopamine activity in drug-experienced animals or humans from elevated, sensitized levels back to baseline levels. This could lead to a reduction of sensitized levels of drug craving in addiction.

Amphetamine disrupts negative patterning but does not produce configural association deficits on an alternative task.

Three experiments investigated the effects of d-amphetamine on the performance of rats on tasks that required the discrimination of configural cues (i.e., those in which two stimulus elements, tone and light, have a meaning when presented together that is distinct from the meaning of the same elements presented in isolation from each other). In a negative patterning task (Experiment 1), rats were trained in a GO/NO-GO task in which either stimulus alone signalled reward availability whilst the compound did not. Amphetamine (0.5, 1.0 and 2.0 mg/kg) was found to disrupt performance by increasing responses to the unrewarded compound. Responses were also increased during the ITI. In contrast, in Experiments 2 and 3 amphetamine had little impact on performance on a task in which the rats had to respond to either of the single stimuli with one response (lever-press or chain-pull) and to the compound stimulus with the other response. The results add credence to the suggestion of Davidson et al. (Behav. Neurosci., 1993, 107, 227-234) that hippocampal lesions disrupt negative patterning by increasing responsiveness rather than by disrupting a configural association system and do not support the idea that increased dopamine activity disrupts configural associations. The findings are discussed in the context of hippocampal-dopamine interactions.

A model of Pavlovian conditioning: variations in representations of the unconditional stimulus.

We present a model of Pavlovian excitatory conditioning in which associative strength and malleable central representations of unconditional stimuli determine the strength of conditional responding. Presentation of a conditioned stimulus acts through an experientially determined associative bond to activate a representation of the unconditional stimulus. The activation of the representation produces a conditioned response. A striking feature of the model is its ability to describe changes in conditioned response magnitude in terms of alterations of representations of the unconditional stimulus. Another is its acknowledgement of the capacity of associative bonds to survive behavioral extinction. The model describes much of the data reported from excitatory conditioning experiments and predicts counterintuitive phenomena.

Neuroleptic effects on acquisition and performance of learned behaviors: a reinterpretation.

It is well-established that dopamine facilitates motor responsiveness. However, neuroleptics--drugs that block dopaminergic transmission--do not affect equally motor responses to environmental stimuli: responses to some stimuli seem completely preserved while responses to other stimuli are greatly disturbed. For example, escape responses to a noxious stimulus are typically preserved, even when avoidance to a cue predicting the noxious stimulus is absent. In this paper, we propose a connectionist account of this differential effect. We assume that dopamine determines the "gain" of the function relating the activation of a neural ensemble to its excitatory or inhibitory input. Because such a function is necessarily non-linear, we show that the influence of gain on whether a neural ensemble reaches a "threshold" of activation is critically different for low and high excitatory drives. This analysis makes specific predictions about the effect of neuroleptics on motor responses at different stages of training.

Increased extracellular dopamine in the nucleus accumbens of the rat elicited by a conditional stimulus for food: an electrochemical study.

Stearate-modified graphite paste electrodes were implanted chronically into dopamine terminal regions in the nucleus accumbens or caudate nucleus of the rat. Reverse dialysis was used to demonstrate a selective response of these electrodes to dopamine, but not 3,4-dihydroxyphenylacetic acid or ascorbic acid. In a separate behavioural experiment, a significant increase in the chronoamperometric response was observed during presentation of a conditional stimulus predictive of food, and the electrochemical response remained elevated during and following consumption of the meal. Similar trends were observed from electrodes in the caudate nucleus. These data confirm the activation of mesolimbic dopamine neurons by incentive stimuli predictive of food and possibly by consumption of food. Together with other recent data on sex- and thirst-related increases in dopamine levels in the nucleus accumbens, these findings are consistent with a role for the nucleus accumbens as an interface between motivation and activation of the motor system.

Dopamine functions in appetitive and defensive behaviours.

The data reviewed here are compatible with the hypothesis that telencephalic dopamine activity is elicited by motivationally significant stimuli which in turn creates a neural state in which animals are more prepared to respond to significant stimuli in the environment. This analysis may be viewed as extensions of both the sensorimotor hypothesis, which depicts dopamine as potentiating the ability of stimuli to elicit responses (Clody and Carlton, 1980; Marshall et al., 1974; White, 1986) and of the incentive motivational hypothesis, which emphasizes the importance of dopamine in responding to stimuli that serve as signals of biologically significant events (Blackburn et al., 1989a; Crow, 1973; Mogenson and Phillips, 1976). In addition, we have sought to emphasize that not all responses are equally dependent upon the integrity of forebrain dopamine activity. Some responses, such as ingestion of standard foods by hungry animals, copulation, and escape, are relatively impervious to dopamine disruption. Further, once other behaviours, such as avoidance or appetitive operant responses, have been acquired, they can be maintained at an initially high rate despite perturbation of dopamine systems, although performance deteriorates with repeated testing. This analysis has emerged from the joint consideration of how both appetitive and defensive behaviours are influenced by dopamine antagonists, along with an examination of dopamine release during sequences of behaviour. The data reviewed suggest that dopamine is involved in fundamental psychological processes through which environmental stimuli come to exert control over certain aspects of behaviour. In the future, as knowledge in this field advances, there will have to be an integration of the literature on dopamine and motivation with the literature on dopamine and motor systems. We expect that dopamine release will be seen as a mechanism by which important environmental cues, of innate or learned significance, lead to a general enhancement of motor skeletal responses directed towards distal cues. We conclude with a caveat: Caution must be exercised when attempting to infer a general role of any neurotransmitter in motivated behaviour based on the study of a limited number of motivational systems. Although neurotransmitter pathways may figure prominently in the control of certain behaviours, it is incorrect to think of neurotransmitters as having a single role in behaviour. However, when comparative analyses reveal a common thread among different motivational systems, as is becoming apparent for the general role of mesotelencephalic dopamine pathways in behaviour, then the goal of generating coherent and comprehensive theory concerning a neurotransmitter's function in behaviour will begin to be realised.(ABSTRACT TRUNCATED AT 400 WORDS)

Enhancement of freezing behaviour by metoclopramide: implications for neuroleptic-induced avoidance deficits.

Administration of the neuroleptic drug metoclopramide (5.0 mg/kg) potentiated freezing responses of rats following 1.0 mA footshock, but did not produce any freezing prior to shock onset. To determine if inappropriate freezing responses to shock could contribute to deficits in active avoidance produced by metoclopramide, drugged and undrugged rats received unavoidable footshock prior to each of ten one-way avoidance trials, or in a separate apparatus prior to the avoidance session (Experiment 2). In neither case was the performance of control rats affected adversely, but in each case the performance of metoclopramide-treated rats was significantly disrupted. Experiment 3 demonstrated that the avoidance performance of metoclopramide-treated rats was disrupted by presentation of an additional conditional stimulus previously paired with shock, whereas the performance of saline-treated rats was enhanced by this procedure. It was concluded that the enhancement of freezing by neuroleptic drugs contributes to the deficit in avoidance responding produced by dopamine receptor antagonists.

Dopamine and preparatory behavior: III. Effects of metoclopramide and thioridazine.

The effects of metoclopramide and thioridazine on feeding behaviors of male hooded rats were investigated in 2 experiments. Metoclopramide (2.5-7.5 mg/kg) attenuated conditioned preparatory responses to a conditional stimulus signaling delivery of a meal. However, consummatory responses were affected only by the highest dose. Similar effects had previously been observed following administration of pimozide (Blackburn, Phillips, & Fibiger, 1987). Thioridazine (10-30 mg/kg) had no significant effect on any measure of feeding behavior. The different effects of the 2 drugs may be related to their preferential actions at dopamine terminals in anatomically distinct regions of the forebrain.

Dopamine and preparatory behavior: II. A neurochemical analysis.

Changes in the activity of dopamine-containing systems in relation to preparatory and consummatory feeding responses were investigated. In Experiment 1 rats were conditioned to associate food delivery with the presentation of a conditional stimulus (CS+). When sacrificed after exposure to the CS+ alone on a test trial, the ratio of the dopamine metabolite 3,4-dihydroxyphenylacetic acid to dopamine (DOPAC/DA ratio) was increased significantly in the nucleus accumbens. A similar trend in the ratio of homovanillic acid to dopamine (HVA/DA ratio) was also observed. Similar increases were observed in the striatum, but these were not statistically significant. In contrast, no increases were observed in the DOPAC/DA ratio or the HVA/DA ratio in either brain region when rats were permitted to consume an unsignaled meal for 7 min. These findings suggest that activation of dopamine terminals in the nucleus accumbens occurs during the anticipation of a meal, at which times the rat is engaged in preparatory feeding behaviors, but does not accompany the performance of short bouts of consummatory feeding behavior.

Blockade of acquisition of one-way conditioned avoidance responding by haloperidol and metoclopramide but not by thioridazine or clozapine: implications for screening new antipsychotic drugs.

The classical neuroleptic drugs haloperidol and pimozide have a strong disruptive effect on the acquisition of conditioned avoidance responding (CAR), yet have relatively little impact on the performance of previously acquired responses. Separate experiments compared the effects of haloperidol, two atypical neuroleptics, thioridazine and clozapine, and a substituted benzamide, metoclopramide, on one-way avoidance by rats. Thioridazine (10-50 mg/kg) and clozapine (1.25-10.0 mg/kg) disrupted both acquisition and performance of CAR. In contrast, haloperidol (0.075-0.150 mg/kg) and metoclopramide (5.0-7.5 mg/kg) completely blocked the acquisition of CAR, yet initially produced only a slight disruption in the performance of a previously acquired response. The ineffectiveness of the atypical neuroleptics in producing a complete disruption of acquisition of CAR may be due to the anticholinergic properties of these drugs. Alternatively, the differences between metoclopramide and the atypical neuroleptics may be due to a preferential effect of metoclopramide on striatal or amygdaloid dopamine neurotransmission. These results suggest that caution should be exercised in using CAR as an animal model for assessing the antipsychotic potential of new pharmacological agents.

Incubation of conditional suppression is an associatively-based phenomenon.

Ten rats were deprived of water and trained to lick a tube for saccharin reinforcement. In each of the two sessions that followed, the rats received six contiguous pairings of a 30-second illumination of the houselight and a 0.75 second, 0.10 mA electric shock while licking. No sign of conditioning was observed during the first experimental session, but profound conditioning was observed on the first and subsequent trials of the second conditioning session. No comparable change in the rate of licking was observed in groups of rats that received only presentations of the visual stimulus, only presentations of the electric shock, or random presentation of the visual stimulus and electric shock during the first conditioning session. These data establish that the incubation of conditional suppression is an associative phenomenon.

Dopamine and preparatory behavior: I. Effects of pimozide.

The involvement of dopaminergic systems in appetitive and ingestive feeding behaviors was investigated in two experiments. Conditioned preparatory responses to a conditional stimulus (CS+) signaling delivery of a meal were attenuated in rats by doses of 0.4 and 0.6 mg/kg of the dopamine receptor antagonist pimozide. In contrast, animals responded in a normal fashion following the delivery of food. Similarly, in a separate study, the 20-min free-feeding intake of liquid diet by rats that had been deprived of food for 23 hr was unaffected by doses of pimozide as high as 0.6 mg/kg. These findings are consistent with the involvement of dopamine in the production of preparatory behaviors elicited by incentive stimuli.

Increased dopamine metabolism in the nucleus accumbens and striatum following consumption of a nutritive meal but not a palatable non-nutritive saccharin solution.

This study examined the concentrations of dopamine (DA) and its metabolites homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum and nucleus accumbens of rats that were either 20 hr food deprived or had been given 1 hr of access to food pellets, a liquid diet, or a palatable 0.4% saccharin solution. Significant increases were observed in the HVA/DA ratio in both structures following ingestion of either liquid diet or food pellets. Increases in the DOPAC/DA ratio were observed only after the ingestion of liquid diet. Ingestion of saccharin solution had no effect on any index of DA activity. These results indicate that the type of food ingested can influence dopaminergic responses to feeding, and argue against an exclusive role for motor or reward processes in determining DA activity.