A possible social relative reward effect: Influences of outcome inequity between rats during operant responding.

Social interactions/situations have dramatic influences on motivation. Creating animal models examining these influences promotes a better understanding of the psychological and biological underpinnings of social motivation. Rodents are sensitive to social history/experience during associative conditioning and food-sharing tasks. Would reward-oriented operant behavior be sensitive to social influences by showing a negative contrast-like effect when another organism obtains a greater value outcome? We used a side-by-side arrangement of operant response chambers wherein one animal obtained consistently high reward signaled by a discrete cue. The neighboring, experimental rat experienced different combinations of high and low reward trial sequences. Control conditions included distraction from a conspecific in the neighboring chamber (rat distractor) or cue/food dispenser operating without a conspecific (program distractor) in addition to testing subjects alone. Results support an influence of the other animal actively performing the task on the experimental subject's behavior. Primarily, responding was significantly slower for the low reward trials while the neighboring rat was receiving the higher magnitude reward. The lever-press and not food-cup retrieval latency was significantly slower during exposure to a conspecific neighbor performing the operant task. The effect was not obtained in all session sequences and was more pronounced using longer series of consecutive low reward trials. The slowing effect was also obtained with the program-distractor experience in a different trial sequence. These findings suggest a social-induced negative incentive contrast effect in rats possibly mediated by an outcome inequity process that could have key similarities to complex situational-affective effects on motivation involving frustration or jealously.

Relative reward effects on operant behavior: Incentive contrast, induction and variety effects.

Comparing different rewards automatically produces dynamic relative outcome effects on behavior. Each new outcome exposure is to an updated version evaluated relative to alternatives. Relative reward effects include incentive contrast, positive induction and variety effects. The present study utilized a novel behavioral design to examine relative reward effects on a chain of operant behavior using auditory cues. Incentive contrast is the most often examined effect and focuses on increases or decreases in behavioral performance after value upshifts (positive) or downshifts (negative) relative to another outcome. We examined the impact of comparing two reward outcomes in a repeated measures design with three sessions: a single outcome and a mixed outcome and a final single outcome session. Relative reward effects should be apparent when comparing trials for the identical outcome between the single and mixed session types. An auditory cue triggered a series of operant responses (nosepoke-leverpress-food retrieval), and we measured possible contrast effects for different reward magnitude combinations. We found positive contrast for trials with the greatest magnitude differential but positive induction or variety effects in other combinations. This behavioral task could be useful for analyzing environmental or neurobiological factors involved in reward comparisons, decision-making and choice during instrumental, goal-directed action.

Emotion and relative reward processing: an investigation on instrumental successive negative contrast and ultrasonic vocalizations in the rat.

Incentive contrast effects include changes in behavioral responses after a reward upshift (positive contrast) or downshift (negative contrast). Proposed influences on these behavioral changes are emotional state reactions after experiencing or anticipating a change in reward outcome. Rat ultrasonic vocalizations have been shown to be indicators of emotional state during behavior and anticipatory periods. The objective of the present study was to monitor rodent ultrasounds during incentive contrast using a classical runway procedure called instrumental successive negative contrast. The procedure is one that has been used often to examine incentive relativity because of its reliability in measuring negative contrast effects. Rats were trained to run in the alleyway to receive a high (12 pellets) or low magnitude (1 pellet) outcome. The high magnitude was then shifted to the low and running speeds in the alleyway for the reward and USV emission were compared. Replicating previous work, a negative contrast effect was observed with postshift running speeds significantly slower in the shifted group compared to the unshifted group. USVs did not follow the same pattern with an apparent lack of significant differences between the groups following the reward downshift. We also tested another group of animals using a visual predictive cue in the same runway test. When visual cues predicted high or low magnitude outcome, no incentive contrast was found for the running speeds following an outcome downshift, but a weak contrast effect was observed for the USV emission. These results demonstrate a separation between USVs and behavioral indicators of incentive contrast suggesting that concomitant shifts in negative affect may not be necessary for anticipatory relative reward processes.

Selective breeding for 50 kHz ultrasonic vocalization emission produces alterations in the ontogeny and regulation of rough-and-tumble play.

Ultrasonic vocalizations (USVs) are emitted by rodents and can signal either negative or positive affective states in social and nonsocial contexts. Our recent work has utilized selective breeding based upon the emission of 50 kHz USVs in response to standard cross species hand play-namely experimenters 'tickling' rats. Previous work has shown that high-tickle responsive animals (i.e., rats emitting abundant 50 kHz USVs) are gregarious and express enhanced positive emotional behaviors relative to animals exhibiting low 50 kHz USVs. The present study extends this work by examining the developmental profile of play behavior and the suppression of play behavior by predator (cat) odor in juvenile high-line and low-line animals. Results support dissociations in key play measures between these groups, with high-line animals emitting more dorsal contacts during play and low-line animals emitting more pinning behavior. For cat-odor induced play suppression, we found that high-line animals exhibit elevated suppression of play for a prolonged period compared to low-line rats. In contrast, low-line animals returned to normal levels of play just 1 day post-predator odor experience. These findings support the idea that emotional arousal may differ between these selectively bred groups, and extends previous work by demonstrating a possible influence of altered emotional learning and conditioning in these phenotypically different animals. One possibility is that high-line animals exhibit enhanced associative learning abilities leading to stronger negative contextual conditioning. These findings suggest that selection for positive or negative social-emotional phenotypes may also segregate genes that control emotional learning abilities in unanticipated ways.

Wistar-Kyoto rats as an animal model of anxiety vulnerability: support for a hypervigilance hypothesis.

Inbred Wistar-Kyoto (WKY) rats have been proposed as a model of anxiety vulnerability as they display behavioral inhibition and a constellation of learning and reactivity abnormalities relative to outbred Sprague-Dawley (SD) rats. Together, the behaviors of the WKY rat suggest a hypervigilant state that may contribute to its anxiety vulnerability. To test this hypothesis, open-field behavior, acoustic startle, pre-pulse inhibition and timing behavior were assessed in WKY and Sprague-Dawley (SD) rats. Timing behavior was evaluated using a modified version of the peak-interval timing procedure. Training and testing of timing first occurred without audio-visual (AV) interference. Following this initial test, AV interference was included on some trials. Overall, WKY rats took much longer to leave the center of the arena, made fewer line crossings, and reared less, than did SD rats. WKY rats showed much greater startle responses to acoustic stimuli and significantly greater pre-pulse inhibition than did the SD rats. During timing conditions without AV interference, timing accuracy for both strains was similar; peak times for WKY and SD rats were not different. During interference conditions, however, the timing behavior of the two strains was very different. Whereas peak times for SD rats were similar between non-interference and interference conditions, peak times for WKY rats were shorter and response rates higher in interference conditions than in non-interference conditions. The enhanced acoustic startle response, greater prepulse inhibition and altered timing behavior with audio-visual interference supports a characterization of WKY strain as hypervigilant and provides further evidence for the use of the WKY strain as a model of anxiety vulnerability.

Rats selectively bred for low levels of 50 kHz ultrasonic vocalizations exhibit alterations in early social motivation.

In rats, the rates of 50 kHz ultrasonic vocalizations (USVs) can be used as a selective breeding phenotype and variations in this phenotype can be an indicator of affective states. The 50 kHz USV is elicited by rewarding stimuli (e.g., food, sexual behavior) and therefore can express a positive affective state. Conversely, the 22 kHz USV is elicited by aversive stimuli (e.g., presence of a predator, social defeat) indicating a negative affective state. In the present study, we tested the effect of selectively breeding for 50 kHz USVs on a variety of maternal social/emotional behaviors in young rat pups (PND 10-12). These measures consisted of an assessment of isolation calls and conditioned odor preference paradigm. Results indicate that animals selected for low levels of 50 kHz USVs show the greatest alterations in social behaviors compared to the control animals. The low line animals had an increase in isolation calls tested during place preference conditioning and a decrease in 50 kHz ultrasonic calls in all conditions. These same low line animals failed to show a typical preference for a maternally-associated odor during the place preference test. The different social behaviors of the high line animals did not consistently vary from those of the control group. These results have important implications for the study of genetic and epigenetic mechanisms underlying emotional states, and possibly contribute to the research underlying the emotional changes in developmental disorders such as autistic spectrum disorder by providing a novel animal model that displays communication deficits that are interdependent with significant social behavioral impairments.

Effects of restraint and haloperidol on sensory gating in the midbrain of awake rats.

Deficits in sensory processing have been reported to be associated with an array of neuropsychiatric disorders including schizophrenia. Auditory sensory gating paradigms have been routinely used to test the integrity of inhibitory circuits hypothesized to filter sensory information. Abnormal dopaminergic neurotransmission has been implicated in the expression of schizophrenic symptoms. The aim of this study was to determine if inhibitory gating in response to paired auditory stimuli would occur in putative dopaminergic and non-dopaminergic midbrain neurons. A further goal of this study was to determine if restraint, a classic model of stress known to increase extracellular dopamine levels, and systemic haloperidol injections affected inhibitory mechanisms involved in sensory gating. Neural activity in the rat midbrain was recorded across paired auditory stimuli (first auditory stimulus (S1) and second auditory stimulus (S2)) under resting conditions, during restraint and after systemic haloperidol injections. Under resting conditions, a subset of putative GABA neurons showed fast, gated, short latency responses while putative dopamine neurons showed long, slow responses that were inhibitory and ungated. During restraint, gated responses in putative GABAergic neurons were decreased (increased S2/S1 or ratio of test to conditioning (T/C)) by reducing the response amplitude to S1. Systemic haloperidol decreased the T/C ratio by preferentially increasing response amplitude to S1. The results from this study suggest that individual neurons encode discrete components of the auditory sensory gating paradigm, that phasic midbrain GABAergic responses to S1 may trigger subsequent inhibitory filtering processes, and that these GABAergic responses are sensitive to restraint and systemic haloperidol.

Single unit and population responses during inhibitory gating of striatal activity in freely moving rats.

The striatum is thought to be an essential region for integrating diverse information in the brain. Rapid inhibitory gating (IG) of sensory input is most likely an early factor necessary for appropriate integration to be completed. Gating is currently evaluated in clinical settings and is dramatically altered in a variety of psychiatric illnesses. Basic neuroscience research using animals has revealed specific neural sites involved in IG including the hippocampus, thalamus, brainstem, amygdala and medial prefrontal cortex. The present study investigated local IG in the basal ganglia structure of the striatum using chronic recording microwires. We obtained both single unit activations and local field potentials (LFPs) in awake behaving rats from each wire during the standard two-tone paradigm. Single units responded with different types of activations including a phasic and sustained excitation, an inhibitory response and a combination response that contained both excitatory and inhibitory components. IG was observed in all the response types; however, non-gating was observed in a large proportion of responses as well. Positive wave field potentials at 50-60 ms post-stimulus (P60) showed consistent gating across the wire arrays. No significant correlations were found between single unit and LFP measures of gating during the initial baseline session. Gating was strengthened (Tamp/Camp ratios approaching 0) following acute stress (saline injection) at both the single unit and LFP level due to the reduction in the response to the second tone. Alterations in sensory responding reflected by changes in the neural response to the initial tone were primarily observed following long-term internal state deviation (food deprivation) and during general locomotion. Overall, our results support local IG by single neurons in striatum but also suggest that rapid inhibition is not the dominant activation profile observed in other brain regions.

Auditory inhibitory gating in medial prefrontal cortex: Single unit and local field potential analysis.

Medial prefrontal cortex is a crucial region involved in inhibitory processes. Damage to the medial prefrontal cortex can lead to loss of normal inhibitory control over motor, sensory, emotional and cognitive functions. The goal of the present study was to examine the basic properties of inhibitory gating in this brain region in rats. Inhibitory gating has recently been proposed as a neurophysiological assay for sensory filters in higher brain regions that potentially enable or disable information throughput. This perspective has important clinical relevance due to the findings that gating is dramatically impaired in individuals with emotional and cognitive impairments (i.e. schizophrenia). We used the standard inhibitory gating two-tone paradigm with a 500 ms interval between tones and a 10 s interval between tone pairs. We recorded both single unit and local field potentials from chronic microwire arrays implanted in the medial prefrontal cortex. We investigated short-term (within session) and long-term (between session) variability of auditory gating and additionally examined how altering the interval between the tones influenced the potency of the inhibition. The local field potentials displayed greater variability with a reduction in the amplitudes of the tone responses over both the short and long-term time windows. The decrease across sessions was most intense for the second tone response (test tone) leading to a more robust gating (lower T/C ratio). Surprisingly, single unit responses of different varieties retained similar levels of auditory responsiveness and inhibition in both the short and long-term analysis. Neural inhibition decreased monotonically related to the increase in intertone interval. This change in gating was most consistent in the local field potentials. Subsets of single unit responses did not show the lack of inhibition even for the longer intertone intervals tested (4 s interval). These findings support the idea that the medial prefrontal cortex is an important site where early inhibitory functions reside and potentially mediate psychological processes.

Behavioral reactions reflecting differential reward expectations in monkeys.

Learning theory emphasizes the importance of expectations in the control of instrumental action. This study investigated the variation of behavioral reactions toward different rewards as an expression of differential expectations of outcomes in primates. We employed several versions of two basic behavioral paradigms, the spatial delayed response task and the delayed reaction task. These tasks are commonly used in neurobiological studies of working memory, movement preparation, and event expectation involving the frontal cortex and basal ganglia. An initial visual instruction stimulus indicated to the animal which one of several food or liquid rewards would be delivered after each correct behavioral response, or whether or not a reward could be obtained. We measured the reaction times of the operantly conditioned arm movement necessary for obtaining the reward, and the durations of anticipatory licking prior to liquid reward delivery as a Pavlovian conditioned response. The results showed that both measures varied depending on the reward predicted by the initial instruction. Arm movements were performed with significantly shorter reaction times for foods or liquids that were more preferred by the animal than for less preferred ones. Still larger differences were observed between rewarded and unrewarded trials. An interesting effect was found in unrewarded trials, in which reaction times were significantly shorter when a highly preferred reward was delivered in the alternative rewarded trials of the same trial block as compared to a less preferred reward. Anticipatory licks preceding the reward were significantly longer when highly preferred rather than less preferred rewards, or no rewards, were predicted. These results demonstrate that behavioral reactions preceding rewards may vary depending on the predicted future reward and suggest that monkeys differentially expect particular outcomes in the presently investigated tasks.

Influence of expectation of different rewards on behavior-related neuronal activity in the striatum.

This study investigated how different expected rewards influence behavior-related neuronal activity in the anterior striatum. In a spatial delayed-response task, monkeys reached for a left or right target and obtained a small quantity of one of two juices (apple, grenadine, orange, lemon, black currant, or raspberry). In each trial, an initial instruction picture indicated the behavioral target and predicted the reward. Nonmovement trials served as controls for movement relationships. Consistent preferences in special reward choice trials and differences in anticipatory licks, performance errors, and reaction times indicated that animals differentially expected the rewards predicted by the instructions. About 600 of >2,500 neurons in anterior parts of caudate nucleus, putamen, and ventral striatum showed five forms of task-related activations, comprising responses to instructions, spatial or nonspatial activations during the preparation or execution of the movement, and activations preceding or following the rewards. About one-third of the neurons showed different levels of task-related activity depending on which liquid reward was predicted at trial end. Activations were either higher or lower for rewards that were preferred by the animals as compared with nonpreferred rewards. These data suggest that the expectation of an upcoming liquid reward may influence a fraction of task-related neurons in the anterior striatum. Apparently the information about the expected reward is incorporated into the neuronal activity related to the behavioral reaction leading to the reward. The results of this study are in general agreement with an account of goal-directed behavior according to which the outcome should be represented already at the time at which the behavior toward the outcome is performed.

Effect of the noncompetitive NMDA antagonists MK-801 and ketamine on the spastic Han-Wistar mutant: a rat model of excitotoxicity.

The neuroprotective effects of the NMDA antagonists MK-801 and ketamine were analyzed in a mutant strain of Han-Wistar rats which develop neurodegeneration in the hippocampus and cerebellum. Previous experiments have shown that the progressive neuronal degeneration observed in this mutant may be the result of a dysfunctional glutamatergic system. For MK-801 studies, mutants were injected in a chronic paradigm with (+)MK-801 or its weaker acting isomer (-)MK-801 at a dose of 1 mg/kg. Ketamine studies consisted of both acute (50 mg/kg once) and chronic (10 mg/kg multiple times) injection paradigms. MK-801-treated mutants exhibited longer life spans (8-23%) compared to saline-injected mutants. Ketamine-injected mutants in both paradigms also lived slightly longer (6-9%) than the saline mutants. Motor skill deterioration was monitored in an open-field test, and after 50 days of age the MK-801 and ketamine mutants displayed over 20% greater motor skill activity than the saline mutants. In the cerebellum, mutants treated with ketamine and both forms of MK-801 had 10-20% more Purkinje cells surviving at 55 days than the saline mutants. Further, the density of CA3c pyramidal hippocampal neurons in ketamine and MK-801-treated mutants as compared to saline mutants appeared to be greater upon qualitative analysis. This study shows that these mutants derive some protective effects from the NMDA antagonists MK-801 and ketamine, confirming glutamate-induced excitotoxicity as a possible cause of neuronal degeneration in this mutant strain of rat.

Electrophysiological and morphological analyses of cortical neurons obtained from children with catastrophic epilepsy: dopamine receptor modulation of glutamatergic responses.

The present study examined the electrophysiological effects produced by activation of specific dopamine (DA) receptors and the distribution of DA receptor subtypes and glutamate receptor subunits [N-methyl-D-aspartate (NMDAR1) and GluR1] in cortical tissue samples obtained from children (ages 3 months to 16 years) undergoing epilepsy surgery. DA receptor activation produced differential effects depending on the receptor subtype that was activated. D1 receptor family agonists generally enhanced cortical excitability and favored the emergence of epileptogenic activity. In contrast, D2 receptor family agonists had more variable effects on cortical excitability and the expression of epileptiform discharges. Activation of D1 or D2 receptors decreased the amplitude of non-NMDA-mediated excitatory postsynaptic potentials. In contrast, DA and D1 agonists increased the amplitude of NMDA-mediated potentials. Immunohistochemical analysis showed that the DA receptor subtypes and glutamate receptor subunits examined were present in all cortical layers and areas throughout development. Whole-cell voltage clamp recordings of pyramidal neurons visualized with differential interference contrast optics and infrared videomicroscopy indicated that these neurons displayed a persistent Na(+) current, followed by an outward current. DA reduced the outward current but had little effect on the persistent Na(+) current. These results suggest a dual role for DA's actions in the human cerebral cortex. Activation of D2 receptors or antagonism of D1 receptors may help control seizures in children.

Cortical damage enhances pemoline-induced self-injurious behavior in prepubertal rats.

Self-injurious behavior (SIB) is a devastating characteristic of several developmental disorders including a number of mental retardation syndromes. The functional neuroanatomy and neuropharmacology of SIB is not well understood. Self-biting behavior (SBB) can be induced in rats by a high dose, systemic injection of pemoline (250 mg/kg, SC). This animal model allows for the investigation of anatomical and pharmacological aspects of SIB. Cortical pathology is a common occurrence in human disorders with SIB, and may be a fundamental pathological factor in producing the behavior. The present experiment was designed to investigate the effects of cortical damage on pemoline-induced SBB in prepubertal rats. Bilateral cortical aspirations were performed in 3-5-week-old rats. One week postsurgery, a pemoline challenge was administered. Behavioral comparisons were completed between the lesion group and an anesthetized-only control group. Results indicated that cortical damage significantly enhanced pemoline-induced SBB, along with some of the other pemoline-induced stereotypical behaviors. These results support the hypothesis that cortical damage influences the expression of stimulant-induced self-injury, and potential mechanisms for this influence are suggested.

Acetylcholine receptor activation enhances NMDA-mediated responses in the rat neostriatum.

The influence of acetylcholine (ACh) upon N-methyl-D-aspartate (NMDA) receptor activation of neostriatal neurons is unknown. In the present study, we used both in vitro intracellular and in vivo electroencephalographic recordings in rats to examine this question. In vitro, iontophoretic application of carbachol, a cholinergic receptor agonist, significantly increased the NMDA-mediated response of neostriatal projection neurons. Carbachol alone had mild excitatory effects. In vivo, intrastriatal NMDA produced focal epileptiform activity restricted to the neostriatum. NMDA applied in conjunction with carbachol produced significantly greater epileptiform activity which propagated to the neocortex. These results suggest that ACh and NMDA receptor co-activation leads to potentiation of the neuronal responses both at the site of the interaction and at the endpoint of the cortico-striato-cortical circuit.

Action sequencing is impaired in D1A-deficient mutant mice.

The role of dopamine in the production of behaviour is multifarious in that it can influence different aspects of movement (e.g. movement initiation, sensorimotor integration, and movement sequencing). A characteristic of the dopamine system which seems to be critical for the expression of this diverse influence is its varied receptor population. Previous studies have shown that specific receptor subtype activation leads to specific behavioural responses or alterations of selective aspects of movement. It is known that one of the important influences of dopamine includes sequential co-ordination of 'syntactic' patterns of grooming movements because moderate loss of the dopaminergic nigrostriatal projections specifically disrupts these patterns without affecting grooming actions in a general fashion (Berridge, K.C. Psychobiology, 15, 336, 1989). The specific receptors of the dopamine family which play a key part in this co-ordination of movement sequences is not known. In the present study, we examined the serial order of particular syntactic sequences or chains of grooming actions in mice lacking D1A receptors to explore the relationship between this receptor subtype and movement sequencing. Mutant mice had shorter grooming bouts and a disruption of the organization of sequential patterns compared with wild-type littermate controls. Sequential disruption was reflected in the failure of D1A mutants to follow the syntactic pattern of grooming to completion. This sequential disruption deficit appeared to be specific, as mutant mice initiated more syntactic chains than wild-type controls even though they were less likely to complete them. These results support the hypothesis that D1A receptor activation plays a part in the sequencing of natural action. This conclusion has important implications for the understanding of the functional heterogeneity of dopamine receptor subtypes and of the aetiology of symptoms observed in patients with basal ganglia disease.

Dopaminergic and glutamatergic interactions in the expression of self-injurious behavior.

Self-injurious behavior occurring in persons with severe mental retardation is a clinically significant and poorly understood problem. Multiple neurotransmitter systems have been implicated in the pathogenesis of this behavior, particularly dopaminergic, opioidergic, and serotonergic systems. Pemoline, a central stimulant, administered systemically at high doses reliably produces self-biting behavior in the rat. The systemic bolus of pemoline produces sustained neostriatal levels of pemoline for over 24 h in a continuous infusion paradigm. Studies of the effect of cortical lesions on pemoline-mediated behaviors reveal that cortical damage, as is common in profound mental retardation, lowers the threshold for pemoline-induced self-biting behavior. Data from the corticostriatal slice suggests that sustained exposure to pemoline produces a shift in N-methyl-D-aspartate receptor-mediated responses rendering them more susceptible to dopaminergic enhancement. Thus, dopaminergic and glutamatergic interactions appear to play an important role in the development and expression of self-biting in the pemoline model.

Haloperidol decreases hyperkinetic paw treading induced by globus pallidus lesions in the rat.

Systemic haloperidol injections decrease the severity of several hyperkinetic syndromes caused by damage to the basal ganglia in humans. A model of hyperkinesia in the rat, exaggerated paw treading triggered by oral sensory stimulation, has been reported previously to result from lesions of the globus pallidus or ventral pallidum/substantia innominata. This hyperkinesia appears as forepaw and forelimb extension and retraction, which can be emitted vigorously and repeatedly for up to minutes at a time. The present study aimed to discover whether this experimental hyperkinesia is pharmacologically similar to human hyperkinetic syndromes: can it be suppressed by neuroleptic administration? Systemic injections of haloperidol (2 mg/kg), diazepam (5 mg/kg, as a sedative comparison), or vehicle were given to rats that expressed the paw treading syndrome after pallidal lesions. Effects on hyperkinetic treading and on tests of sensorimotor function were compared. Results indicated that haloperidol was effective in ameliorating the hyperkinesia in rats with bilateral globus pallidus lesions but not in rats with ventral pallidum/substantia innominata lesions. By contrast, diazepam, which produced sedation and sensorimotor impairment, did not decrease the hyperkinesia induced by either lesion. Although only haloperidol decreased hyperkinetic treading after globus pallidus lesions, haloperidol produced less of a sensorimotor impairment than diazepam on climbing, hanging, and righting reflex tests. These results implicate a specific role for dopamine neurotransmission in the expression of triggered hyperkinetic treading induced by globus pallidus lesions.

Pemoline alters dopamine modulation of synaptic responses of neostriatal neurons in vitro.

Pemoline, a central stimulant, administered systemically at high doses (300 mg/kg) reliably produces self-biting behavior in rats. Pemoline-induced self-biting shares many similarities with self-injury seen in certain human disorders. Recent evidence has shown that alterations in neostriatal neurochemistry accompany the self-biting behavior seen in the rat. The present study used intracellular electrophysiological techniques to reveal changes in neostriatal cellular physiology in slices from rats which had displayed self-injury. Depolarizing postsynaptic potentials (DPSPs) were examined in neostriatal slices from rats that received pemoline and had been engaging in self-injurious behavior and from two control populations: rats that received the same concentration of pemoline and did not engage in self-biting, and rats that received vehicle alone (peanut oil). Data were acquired in standard artificial cerebral spinal fluid. DPSPs were evoked by cortical electrical stimulation in the slice. In neurons from rats that received the vehicle or that had received pemoline but had not engaged in self-injury, dopamine (DA, 20 microM) application produced a significant decrease in the size of the cortically evoked neostriatal DPSP. In contrast, DA application produced an increase in DPSP size in neurons from rats which had received pemoline and had engaged in self-injury. Bath application of a combination of D1 and D2 receptor agonists best replicated the enhancing effect of DA. Furthermore, the enhancement could be blocked by pretreatment with the competitive N-methyl-d-aspartate receptor antagonist, 2-amino-5-phosphonopentanoic acid. The results indicate that alterations in neostriatal DA-glutamate interactions accompany pemoline injections which produce self-injurious behavior.

Neocortical damage alters synaptic responses of neostriatal neurons in vitro.

The present experiments were designed to investigate the physiological impact of a partial decortication upon neostriatal synaptic responses using intracellular recording techniques in the in vitro brain slice preparation. In the intact rat, the locally evoked neostriatal synaptic response is primarily mediated by excitatory amino acid receptor activation. Following neocortex damage, the contributions of both N-methyl-D-aspartate and non-N-methyl-D-aspartate receptor activation were significantly diminished, although responses remained robust in amplitude and duration. Components of the locally evoked synaptic response mediated by activation of GABAA receptors were relatively unchanged, while presynaptic inhibition mediated by activation of GABAB receptors was markedly reduced. Furthermore, the normally minimal acetylcholine contribution to the synaptic response was significantly increased after neocortical damage. This enhanced cholinergic role in the generation of the synaptic response appeared to be mediated primarily by activation of nicotinic receptors. Thus, neocortical damage leads to novel physiological relationships between intrinsic neostriatal cholinergic interneurons and the GABAergic projection neurons. One possibility is that cholinergic interneurons have the potential for substituting for the loss of excitation created by the absence of neocortical glutamatergic input.