Biomedical subjects

T W Robbins

Publications and source records attributed to T W Robbins.

At least 217 records · Page 12Linked to original sources

PubMed1994

Amphetamine-induced disruptions of latent inhibition are reinforcer mediated: implications for animal models of schizophrenic attentional dysfunction.

Latent inhibition (LI) is a phenomenon observed when repeated, non-reinforced presentation of a stimulus results in a retardation of subsequent conditioning to that stimulus. Several recent experiments have suggested that LI is abolished in conditioned suppression paradigms following acute, low doses of amphetamine given during pre-exposure and conditioning. Experiment 1 sought to increase the generality of this finding in an appetitive LI paradigm, using a dose of amphetamine previously shown to disrupt the LI effect in an aversive paradigm (Killcross and Robbins 1993). However, no evidence for any disruption of LI was found. Experiment 2 extended this investigation to additional, higher doses of d-amphetamine, and also examined the role of reinforcer magnitude in the effect. A non-significant trend towards an attenuated LI effect was found, which was reversed by decreases in the concentration of the sucrose reinforcer. Experiments 3 and 4 investigated the influence of systemic amphetamine in aversive paradigms, with specific attention to the increased response to the aversive foot-shock reinforcer found in amphetamine-treated animals. These experiments revealed that the influence of amphetamine on the LI effect in conditioned suppression paradigms could be reversed by reducing the intensity of footshock used in conditioning, thereby paralleling the effect found in the appetitive paradigm. Therefore it is unlikely that a simple attentional account of the abolition of the LI effect in previous experiments can be sustained.

Amphetamine↗

PubMed1994

Effects of the neuroleptic alpha-flupenthixol on latent inhibition in aversively- and appetitively-motivated paradigms: evidence for dopamine-reinforcer interactions.

Three experiments examined the influence of the dopamine (DA) D1/D2 receptor antagonist alpha-flupenthixol on the latent inhibition (LI) effect. LI is a phenomenon which is manifest when non-reinforced pre-exposure to a stimulus retards subsequent conditioning to that stimulus, and has been proposed as an animal model of the selective attentional processes that are disrupted in acute schizophrenia. Experiment 1 extended previous findings that neuroleptics enhance the LI effect in conditioned suppression paradigms in rats to alpha-flupenthixol (0.23 mg/kg). Experiment 2 demonstrated that this enhancement of the LI effect was also seen in a parallel appetitively-motivated conditioning paradigm at the same dose. In both Experiment 1 and Experiment 2, the enhancement of the LI effect by alpha-flupenthixol appeared to be accompanied by a decrease in the impact of the reinforcer (be it appetitive or aversive). Experiment 3 investigated the possible role of the reinforcer in the effect of alpha-flupenthixol on the LI effect in the aversive, conditioned suppression paradigm by increasing the intensity of footshock in rats treated with alpha-flupenthixol. Increasing the intensity of the footshock completely abolished the enhancement of LI found following injection of alpha-flupenthixol, a result which could not be attributed to a floor effect. The results provide no support for interpretations of the influence of DA manipulations on the LI effect that draw parallels with deficits in selective attention observed in acute schizophrenia.

Acoustic Stimulation↗

PubMed1994

Mesoaccumbens dopamine-opiate interactions in the control over behaviour by a conditioned reinforcer.

These experiments examined the role of dopamine-opiate interactions in the ventral tegmental area (VTA) and nucleus accumbens in the mediation of reinforcement-related behaviour. It has been shown previously that opiates induce a dopamine-dependent increase in locomotor activity in rats when infused into the VTA, and a dopamine-independent hyperactivity when infused into the nucleus accumbens. The present study investigated the generality and significance of these two findings, by examining dopamine-opiate interactions in the control over behaviour exerted by a conditioned reinforcer (CR), an arbitrary stimulus which gains control by association with primary reinforcement. Rats were trained to associate a light/noise stimulus with sucrose reinforcement, and the efficacy of the CR in controlling behaviour was assessed by measuring its ability to support a new lever pressing response. Responding on one lever (CR lever) produced the CR, responding on the other lever had no programmed consequences. In experiment 1, intra-accumbens infusions of d-amphetamine (10 micrograms), the D1 dopamine receptor agonist SKF-38393 (0.1 microgram), the D2 dopamine receptor agonist LY-171555 (quinpirole; 0.1 microgram) or the opiate receptor agonist [D-Ala2]-methionine enkephalinamide (DALA; 1 microgram) selectively increased responding on the CR lever. Infusion with DALA intra-VTA had no effect. However, pretreatment with DALA intra-VTA (10 x 1 microgram/day) subsequently reduced the selectivity of the response to infusions intra-accumbens with d-amphetamine or SKF-38393, and blocked the response to LY-171555 or DALA. Pretreatment also shifted to the right the dose-response function for DALA intra-accumbens. In experiment 2, intra-accumbens infusions of d-amphetamine, SKF-38393, LY-171555 or DALA again increased responding on the CR lever only. Pretreatment with intra-accumbens d-amphetamine (5 x 1 microgram/day) reduced the selectivity of the response subsequently to d-amphetamine, and blocked the response to SKF-38393, LY-171555 or DALA. In experiment 3, intra-accumbens infusions of the mu-opiate receptor agonist [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (0.003-0.1 microgram), or the delta-opiate receptor agonist [D-Pen2,5]-enkephalin (0.03-1 microgram) enhanced selectively responding on the CR lever. Thus, the dopamine-dependent locomotor-stimulant properties of intra-VTA infusions of opiates are associated with impaired conditioned reinforcer efficacy. Finally, repeated stimulation of the mesoaccumbens dopamine pathway may compromise the dopamine-independence of the opiate system within the nucleus accumbens.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1994

Isolation rearing enhances the locomotor response to cocaine and a novel environment, but impairs the intravenous self-administration of cocaine.

Male Lister hooded rats were raised from weaning either alone (isolation reared) or in groups of five (socially reared controls). At 5 months of age, experiments began. Experiment 1 examined the effect of isolation rearing upon the locomotor response to a novel environment, and the locomotor stimulant effect of an injection of cocaine (10 mg/kg). Isolation reared animals were more active in a novel environment, and were more responsive to the locomotor stimulant action of cocaine. In succeeding experiments, the effects of isolation rearing on the reinforcing efficacy of intravenous cocaine were assessed. Animals were never "primed" with noncontingent infusions of cocaine at any time during these experiments. In experiment 2, the effect of isolation rearing upon the acquisition of the intravenous self-administration of cocaine was examined. Two levers were present in the operant chambers. Depression of one lever resulted in the intravenous delivery of a 1.5 mg/kg infusion of cocaine, responses on the second, control lever were recorded but had no programmed consequences. Isolation reared animals acquired a selective response on the drug lever at a slower rate than socially reared controls. In experiment 3, a full cocaine dose-response function was examined. Isolation rearing shifted the cocaine dose-response function to the right. In addition, isolation rearing impaired the selectivity of the response on the drug lever at lower doses of cocaine. In experiment 4, the effect of isolation rearing upon the response to a conditioned reinforcer associated previously with cocaine delivery was observed. In the absence of cocaine, the contingent presentation of the conditioned reinforcer enhanced selectively the rate of response by socially reared controls. However, isolation reared animals were unresponsive to this manipulation. These data are discussed with reference to dysfunctional cortico-limbic-striatal systems, and their interactions with the mesoaccumbens dopamine projection.

Animals↗

PubMed1994

Isolation rearing impairs the reinforcing efficacy of intravenous cocaine or intra-accumbens d-amphetamine: impaired response to intra-accumbens D1 and D2/D3 dopamine receptor antagonists.

Male Lister hooded rats were raised from weaning either alone (isolation reared) or in groups of five (socially reared controls). At 5 months of age, bilateral guide cannulae were implanted within the nucleus accumbens, and experiments began. The effect of isolation rearing upon the reinforcing efficacy of the intravenous self-administration of cocaine (experiment 1), or the bilateral intra-accumbens self-administration of d-amphetamine (experiment 2) was assessed. Self-administration was made contingent upon the acquisition of a novel lever-pressing response. Two identical levers were available within each operant chamber. Responding on one lever resulted in the delivery of drug (experiment 1: cocaine, 1.5 mg/kg per infusion; experiment 2: d-amphetamine, 0.25 micrograms/side), responding on the second, control lever was recorded but had no programmed consequences. Animals were not "primed" with noncontingent infusions at any time. For experiment 1, animals received intra-accumbens infusions of the D1 dopamine receptor antagonist SCH-23390, or the D2 dopamine receptor antagonist sulpiride over two test sessions. Within each session, animals received a cumulative series of doses of each dopamine receptor antagonist. A validation group received doses of each antagonist according to more conventional methods (one dose per session). In either case, intra-accumbens infusions of SCH-23390 or sulpiride enhanced the rate of the self-administration of cocaine in socially reared controls. However, isolation rearing impaired this response to intra-accumbens infusions of the dopamine receptor antagonists. Experiment 2a examined the acquisition of the intra-accumbens self-administration of d-amphetamine. Socially reared controls acquired readily a selective response upon the drug lever. However, isolation reared animals acquired a selective response at a greatly retarded rate. In experiment 2b, a full d-amphetamine dose-response function was examined. Isolation rearing impaired the response to a range of doses of d-amphetamine. In experiment 2c, the infusate (1 microgram d-amphetamine per infusion) was adulterated with either SCH-23390 or sulpiride. Adulteration with either dopamine receptor antagonist enhanced the rate of response by socially reared controls. Isolation rearing impaired this response to SCH-23390, and blocked the response to sulpiride. These data are discussed in relation to the functioning of cortico-limbic-striatal systems, with particular reference to the mesoaccumbens dopamine projection.

Animals↗

PubMed1994

Glutamate-dopamine interactions in the ventral striatum: role in locomotor activity and responding with conditioned reinforcement.

Previous evidence suggests that glutamatergic limbic afferents participate in the potentiation of responding with conditioned reinforcement produced by intra-accumbens d-amphetamine. The present experiments were designed to investigate glutamate-dopamine interactions in the ventral striatum in both conditioned reinforcement and locomotor activity. Glutamate receptor agonists and antagonists were infused into the nucleus accumbens both alone and in combination with 3 micrograms d-amphetamine, and the effects of these interactions on responding with conditioned reinforcement and locomotor activity were measured. The glutamate receptor agonists NMDA, AMPA and quisqualate (agonists at the NMDA, AMPA and metabotropic glutamate receptor subtypes, respectively) and the antagonists AP5 and CNQX, (antagonists at the NMDA and AMPA receptor subtypes, respectively) were used in these investigations. These compounds were used in a dose range of 0.3 to 3 nmol, except CNQX, which was used in 0.2 to 2 nmol doses. While all agonists and antagonists increased locomotor activity when administered alone, the antagonists attenuated the locomotor response to d-amphetamine. In contrast, the agonists AMPA and quisqualate enhanced d-amphetamine-induced locomotor activity, although NMDA interfered with the effects of d-amphetamine. In the conditioned reinforcement paradigm, both the agonists and the antagonists abolished amphetamine's potentiation of responding with conditioned reinforcement, suggesting that the glutamatergic transmission of information about the conditioned reinforcer could be blocked by glutamate receptor antagonists and disrupted by administration of the agonists. The dissociation between the effects of these excitatory amino acids on amphetamine-induced locomotor activity versus their effects on amphetamine's potentiation of responding with conditioned reinforcement provides insight into the nature of the reward enhancement by accumbens dopamine versus its locomotor stimulant effects.

Animals↗

PubMed1994

Bilateral intra-accumbens self-administration of d-amphetamine: antagonism with intra-accumbens SCH-23390 and sulpiride.

The efficacy of d-amphetamine to support a selective bilateral intra-accumbens self-administration response was examined. Bilateral intra-accumbens infusions of d-amphetamine were made contingent upon the acquisition of a lever-pressing response. Two identical levers were available within the operant chamber. Depression of the drug lever resulted in the intra-accumbens delivery of 1 microgram d-amphetamine; responses upon the second, control lever were recorded but had no programmed consequences. Animals were not 'primed' with non-contingent infusions of d-amphetamine at any time during these experiments. Nonetheless, animals readily acquired a selective response upon the drug lever. Removal of the d-amphetamine moiety from the infusate resulted in a large decline in responding, and the abolition of the selectivity of the response for the drug lever. Adulteration of the infusate with either the D1 dopamine receptor antagonist SCH-23390 or the D2 dopamine receptor antagonist sulpiride enhanced the rate of response selectively upon the drug lever. Reductions in the dose of d-amphetamine also increased the rate of response. The effect of co-adulteration of the infusate with both SCH-23390 and sulpiride together was purely additive. The implications of these data for the methodology of intracranial drug self-administration, and the relationship between D1 and D2 dopamine receptors within the nucleus accumbens are discussed.

Animals↗

PubMed1994

Evidence for executive dysfunction in autism.

A group of young people with autism (ranging in ability from high functioning to moderately learning disabled), and ability-matched control groups of (i) non-autistic individuals with moderate learning disabilities, and (ii) normally developing children, were presented with two tests of executive function: the Intra-dimensional/Extra-dimensional set-shifting task and the Tower of London planning task. These tests were graded in difficulty and included internal control measures. On each task, the autistic group was differentially impaired with respect to both control groups. Moreover, this impairment was specific to the stages of each task which placed greatest demands upon executive control. This evidence for executive dysfunction in autism is discussed in the context of Norman and Shallice's (Centre for Human Information Processing Technical Report 99, 1980) "Supervisory Attentional System" model of frontal function.

Adolescent↗

PubMed1994

Intra-amygdala infusion of the N-methyl-D-aspartate receptor antagonist AP5 impairs acquisition but not performance of discriminated approach to an appetitive CS.

The present experiments investigated the effects of blocking glutamate transmission in the amygdala on the learning and subsequent performance of a discriminated approach response to food, as well as on locomotor activity and a test of neophobia to food. In the appetitive conditioning experiment, three separate groups of rats received intra-amygdala infusions of PBS (phosphate-buffered saline) or 1.0 or 3.0 nmol of AP5, an antagonist at the NMDA glutamate receptor subtype, immediately before each conditioning session. The effects of AP5 on the performance of the discriminated approach response were tested in a fourth group of animals. AP5 dose-dependently impaired the discriminated approach response during the acquisition of the stimulus-reward association but had no effect on the performance of this response after this association was learned. These results suggest that glutamate transmission in the amygdala at the NMDA glutamate receptor subtype is important in the learning process. In separate experiments, intra-amygdala AP5 increased locomotor activity and attenuated the neophobia to food in a novel environment by increasing approaches to the food. Together, these findings parallel the effects of lesions to the basolateral amygdala. In addition, the specific effects on learning are consistent with the hypothesis that NMDA-receptor-mediated LTP underlies specific forms of learning within the amygdala.

2-Amino-5-phosphonovalerate↗

PubMed1994

Social isolation in the rat produces developmentally specific deficits in prepulse inhibition of the acoustic startle response without disrupting latent inhibition.

A series of experiments examined the effects of 8 weeks of social isolation on spontaneous locomotor activity, prepulse inhibition (PPI) of the acoustic startle response, latent inhibition (LI) in a conditioned suppression paradigm, and basal and d-amphetamine stimulated dopamine (DA) release in the ventral striatum, as measured by in vivo microdialysis. Both isolation-reared animals (those isolated from the weaning age) and isolation-housed animals (those isolated as adults) were hyperactive when placed in a novel environment. Social isolation also led to deficits in PPI of the acoustic startle response that were specific to isolation-reared animals. Isolation rearing was without effect on the expression of LI but did lead to an enhanced response to systemic d-amphetamine in terms of striatal DA release. The data are discussed with respect to the involvement of ventral striatal DA mechanisms in the expression of PPI and LI, differences in the impact of social isolation in young and adult animals, and the utility of social isolation model as a nonlesion, nonpharmacologic means of perturbing ventral striatal DA function.

Acoustic Stimulation↗

PubMed1994

Cognitive deficits in progressive supranuclear palsy, Parkinson's disease, and multiple system atrophy in tests sensitive to frontal lobe dysfunction.

Groups of patients with idiopathic Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy or Steele-Richardson-Olszewski syndrome, matched for overall clinical disability, were compared using three computerised cognitive tests previously shown to be sensitive to frontal lobe dysfunction. On a test of planning based on the Tower of London task, all three groups were impaired, but in different ways. The groups with palsy and Parkinson's disease were slower in the measure of initial thinking time, whereas the group with multiple system atrophy was only slower in a measure of thinking time subsequent to the first move, resembling patients with frontal lobe damage. On a test of spatial working memory, each group showed deficits relative to their matched control groups, but the three groups differed in their strategy for dealing with this task. On a test of attentional set shifting, each group was again impaired, mainly at the extradimensional shifting stage, but the group with Steele-Richardson-Olszewski syndrome exhibited the greatest deficit. The results are compared with previous findings in patients with Alzheimer's disease or frontal lobe damage. It is concluded that these basal ganglia disorders share a distinctive pattern of cognitive deficits on tests of frontal lobe dysfunction, but there are differences in the exact nature of the impairments, in comparison not only with frontal lobe damage but also with one another.

Aged↗

PubMed1994

Effects of excitotoxic lesions of the septum and vertical limb nucleus of the diagonal band of Broca on conditional visual discrimination: relationship between performance and choline acetyltransferase activity in the cingulate cortex.

Four experiments examined the role of the cholinergic projections from the septum and vertical limb nucleus of the diagonal band of Broca (VDB) in acquisition and performance of a conditional visual discrimination. In experiments 1-3, excitotoxic lesions were made of the septum and VDB in rats using quisqualic acid, which resulted in significant reductions in ChAT activity in the hippocampus and cingulate cortex, but with no effects on cortical monoamines. In experiment 1, there were significant impairments in acquisition of the conditional discrimination, which did not result from motivational impairments. Experiment 2 repeated these results with lesion parameters, which produced variable effects on hippocampal and cingulate ChAT activity. Those rats with reductions in predominantly cingulate ChAT were most impaired in acquisition, but those with predominantly hippocampal reductions were relatively unimpaired. Experiment 3 showed that quisquate-induced lesions of the VDB, but not of the more caudal VDB and horizontal limb nucleus of the diagonal band, produced deficits, and a model incorporating the results of experiments 1-3 showed a highly significant correlation between errors of commission and cingulate cortical ChAT activity (r = -0.82, p < 0.001). Experiment 4 used the excitotoxin AMPA to lesion the VDB in rats pretrained on a modified form of the conditional discrimination task. In one subgroup of rats this excitotoxin produced profound and regionally selective reductions in ChAT activity. This subgroup was also impaired in relearning the discrimination to criterion. Again, there was a significant inverse relationship between the number of errors of commission made in relearning the discrimination and cingulate ChAT activity (r = -0.94, p < 0.001). These experiments suggest that excitotoxic lesions of the septum/VDB produce deficits in conditional discrimination learning and performance, and that the integrity of the projection to the cingulate cortex is more crucial than that to the hippocampus in this effect. Moreover, there is a close relationship between discrimination performance and cholinergic function in the cingulate cortex. In conjunction with other results, these data suggest that different aspects of cognition and memory are modulated by cholinergic activity in different cortical regions.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1994

AMPA-induced excitotoxic lesions of the basal forebrain: a significant role for the cortical cholinergic system in attentional function.

The aim of the present study was to clarify the role of the basal forebrain (BF)-cortical cholinergic system in visual attentional function by investigating the effect of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-induced lesions of the basal forebrain on performance of a five-choice serial reaction time task. AMPA lesions in the present study produced a profound effect on performance of the task, as measured by choice accuracy and correct response latency. This deficit was significantly greater than that observed in earlier studies following ibotenate- or quisqualate-induced lesions of the BF. However, detailed histological and biochemical analysis revealed three rather different BF lesions depending upon the batch of AMPA supplied. In one group of animals (BF/1) the deficits in task performance were substantially greater and longer lasting compared to another group of lesioned animals (BF/2), which showed behavioral recovery several months following the lesion. The former sustained severe pallidal damage in addition to marked reductions in cortical ChAT activity. Support for the attentional nature of these deficits was obtained by the ability to improve task performance in BF/1 lesioned animals by increasing the duration of the visual stimulus and thus reducing the attentional load placed on these animals. In contrast, performance deficits could be reinstated in those animals showing behavioral recovery (BF/2) by reducing the duration of the visual stimulus and thus increasing attentional load. In the second experiment more discrete lesions of the magnocellular cholinergic neurons were made, resulting in extensive reduction of cortical ChAT activity with considerably less neuronal loss from the dorsal pallidum compared to the BF/1 lesion group. Once again, deficits on the task were substantially greater than observed previously following either quisqualate- or ibotenate-induced BF lesions. Furthermore, the cholinergic specificity of these deficits was supported by the attenuation of behavioral impairments following administration of the anti-cholinesterase physostigmine. Taken together with our earlier work, which has failed to demonstrate mnemonic deficits following lesions to the magnocellular neurons of the nucleus basalis of Meynert, these results suggest that the most consistent deficit produced following lesions of the BF-cortical cholinergic system is attentional dysfunction Analogous deficits in visual attention are also seen in patients with Alzheimer's disease, which can also be improved by anti-cholinesterase treatment.

Analysis of Variance↗

PubMed1994

6-Hydroxydopamine lesions of the prefrontal cortex in monkeys enhance performance on an analog of the Wisconsin Card Sort Test: possible interactions with subcortical dopamine.

The effects of 6-hydroxydopamine lesions of the prefrontal cortex in monkeys were investigated on two cognitive tests of prefrontal function, spatial delayed response, and attentional set shifting. The latter test provided a componential analysis of the Wisconsin Card Sort Test, a commonly used clinical test of frontal lobe function in man. Acquisition of a visual compound discrimination requiring a shift of attention from one dimension to another (extradimensional shift), for example, shapes to lines, was significantly improved. This enhancement was behaviorally specific in that there were no effects on acquisition of a discrimination that required the continued maintenance of an attentional set toward one particular dimension (intradimensional shift), nor any effects on a series of visual or spatial discrimination reversals that involved the repeated shifting of responding between two exemplars from the same dimension. In contrast, spatial delayed response performance was impaired, in agreement with previous results. Neurochemical measures showed a marked depletion of dopamine limited to the prefrontal cortex and a smaller loss of prefrontal noradrenaline. This was accompanied by a long-term adaptive change in the striatum such that extracellular dopamine in the caudate nucleus, as measured by in vivo microdialysis, was elevated in response to potassium stimulation as long as 18 months postsurgery. It is proposed that attentional set shifting is mediated by a balanced interaction between prefrontal and striatal dopamine, and that elevated dopamine contributes to the improvement in attentional set-shifting ability. This interpretation is consistent with the impairment in attentional set-shifting ability observed in patients with Parkinson's disease or with damage to the frontal lobes using the same test as used here for infrahuman primates.

Animals↗

PubMed1993

Excitotoxic lesions of basal forebrain cholinergic neurons: effects on learning, memory and attention.

A substantial body of literature has suggested that the memory and learning deficits associated with Alzheimer's disease are attributable to degeneration of the cholinergic magnocellular neurons of the nucleus basalis of Meynert (nbM). Subsequently, lesion-induced damage to the cholinergic projections from the nbM to the neocortex has been utilized extensively as an animal model of dementia. Ibotenic acid lesions of the basal forebrain have been found, for example, to produce deficits in a wide variety of tasks involving learning and memory. However, recently, with the availability of more potent cholinergic excitotoxins such as AMPA, it has become apparent that nbM lesions do not provide a simple animal model of the cognitive deficits in ageing and Alzheimer's disease. Further analysis suggests that many of the learning and memory impairments traditionally attributed to the cholinergic corticopetal system are due not to destruction of cholinergic neurons in the nbM, but instead result from the disruption of cortico-striatal outputs passing through the dorsal and ventral globus pallidus. Furthermore, experiments utilizing quisqualic acid and AMPA have revealed that the most convincing deficit observed as a result of such lesions is in visual attention. This role for the basal forebrain-cortical cholinergic system in attentional function is further supported by results obtained from complementary pharmacological studies. This does not exclude a role for acetylcholine in learning and memory processes. Rather, such cognitive processes appear to depend not upon the integrity of the nbM itself, but upon more rostral elements of the cholinergic basal forebrain system.

Acetylcholine↗

PubMed1993

Isolation rearing of rats produces a deficit in prepulse inhibition of acoustic startle similar to that in schizophrenia.

Schizophrenic patients exhibit deficits in the prepulse inhibition of startle, an operational measure of the sensorimotor gating deficits that are theorized to contribute to cognitive disorganization. In rats, the activation of mesolimbic dopamine (DA) disrupts prepulse inhibition, providing a useful model of the similar deficits in sensorimotor gating in schizophrenic patients. Rats reared in isolation exhibit neurochemical and behavioral abnormalities suggestive of hyperactivity in mesolimbic DA systems. In the present studies, rats reared in social groups or in isolation were tested in startle response paradigms using 120 or 105 dB acoustic pulses, some of which were preceded (100 msec) by prepulses that were 2, 4, 8, or 16 dB above the 65 dB background. Isolation-reared animals were hyperreactive only in response to the initial few startle stimuli. The amount of prepulse inhibition was decreased significantly in isolation-reared animals, particularly when midrange 8 dB prepulses were used. A subsequent study replicated the effect of isolation rearing on prepulse inhibition and suggested that the deficit in sensorimotor gating exhibited by isolation-reared animals may be normalized by the administration of the DA antagonist raclopride (0.05 mg/kg). Hence, isolation rearing provides a nonpharmacological way to induce in rats a deficit in sensorimotor gating that is exhibited by schizophrenic patients.

Acoustic Stimulation↗

PubMed1993

Enhancement of amphetamine-induced locomotor activity and dopamine release in nucleus accumbens following excitotoxic lesions of the hippocampus.

This study tested the hypothesis that the hippocampus modulates dopamine-dependent function of the nucleus accumbens using behavioural and neurochemical evidence. Rats with bilateral lesions of the hippocampus induced by colchicine and kainic acid exhibited equivalent levels of spontaneous locomotor activity but a potentiation of the hyperactivity produced, dose-dependently, by D-amphetamine measured in photo-cell activity cages. The same rats subsequently received unilateral implantations of a microdialysis probe aimed at the nucleus accumbens and showed elevated levels of extracellular dopamine in response to D-amphetamine but no significant difference in basal values in comparison with sham-operated controls. The results are discussed in terms of functional interactions between the hippocampus and nucleus accumbens involving the control of mesolimbic dopamine release.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1993

Differential effects of excitotoxic lesions of the basolateral amygdala, ventral subiculum and medial prefrontal cortex on responding with conditioned reinforcement and locomotor activity potentiated by intra-accumbens infusions of D-amphetamine.

The experiments reported here have investigated the impact on reward-related processes of lesioning the basolateral amygdala, ventral subiculum and prelimbic cortex which represent the major limbic sources of afferents to the ventral striatum. The results showed that, while lesions of the prelimbic cortex were without effect on the approach to a CS predictive of sucrose reinforcement and the acquisition of a new response with conditioned reinforcement, lesions of the other two structures significantly impaired both responses. However, there were important differences between the effects of basolateral amygdala and ventral subiculum lesions. Thus, lesions of the ventral subiculum completely abolished the locomotor response to intra-accumbens infusions of D-amphetamine, in addition to blocking the potentiative effect of the same treatment on responding with conditioned reinforcement. Lesions of the basolateral amygdala, by contrast, reduced the control over behaviour by a conditioned reinforcer, but not the potentiation of that control by intra-accumbens D-amphetamine except at the highest dose. Moreover, the locomotor response to D-amphetamine-induced increases in dopamine in the nucleus accumbens was unaffected by amygdala lesions over the dose range blocked by ventral subiculum lesions. The results suggest a rather selective effect of amygdala-ventral striatal interactions on processes subserving conditioned reinforcement and a more fundamental influence of ventral subiculum-ventral striatal interactions in mediating the psychomotor stimulant effects of D-amphetamine.

Afferent Pathways↗