Effects of local infusions of dopaminergic drugs into the medial prefrontal cortex of rats on latent inhibition, prepulse inhibition and amphetamine induced activity

Impaired ability to 'gate out' sensory and cognitive information is considered to be a central feature of schizophrenia and is manifested, among others, in disrupted prepulse inhibition (PPI) and latent inhibition (LI). The present study investigated in rats the effects of increasing or decreasing dopamine (DA) receptor activation within the medial prefrontal cortex (mPFC) by local administration of the indirect DA receptor agonist amphetamine (AMPH; 10.0 microg/side) or the DA antagonist cis-flupenthixol (FLU; 12.0 microg/side) on PPI and LI as well as on systemic AMPH-induced activity. The effects of intra-mPFC apomorphine (APO; 10.0 microg/side) on PPI were also tested. AMPH infusions decreased systemic AMPH-induced increase in locomotor activity in the open field, whereas FLU infusion was ineffective. Both infusions had no effect on LI and PPI. However, APO infusions induced a disruption of PPI. These results provide additional evidence that the mPFC is a component of the neural circuitry mediating PPI but plays no role in LI. In addition, they show that the behavioral outcomes produced by DA receptor activation/blockade in the mPFC of the rat cannot be explained by postulating a simple reciprocal relationship between the cortical and subcortical DA systems.     

Amphetamine-induced disruption of prepulse inhibition in mice with reduced NMDA receptor function

Genetically altered mice with reductions in the NR1 subunit of the N-methyl-d-aspartate (NMDA) receptor have been proposed as a model for the intrinsic NMDA hypofunction hypothesized for schizophrenia. The following study investigated whether NR1-deficient mice have enhanced susceptibility for the effects of amphetamine, similar to the exaggerated responsivity to dopamine agonists observed in many schizophrenia patients. NR1-/- mice and wild-type controls were tested for the effects of amphetamine (2-10 mg/kg) on prepulse inhibition of acoustic startle responses. The results showed that mice with reduced NMDA receptor function demonstrated consistent deficits in prepulse inhibition (PPI), as well as higher startle response amplitudes. In comparison to normal controls, the NR1-/- mice were more sensitive to the disruptive effects of amphetamine on PPI, but not to the drug effects on startle magnitude without a prepulse stimulus. Wild-type mice only showed decreased PPI at the highest dose of amphetamine tested (10 mg/kg) and demonstrated small increases in PPI at lower amphetamine doses (2 and 6 mg/kg). The NR1-/- mice did not show enhanced PPI in response to amphetamine at low doses, with reductions in PPI apparent at doses of 4-10 mg/kg. Overall, these findings suggest that the NR1-/- mouse may provide a model for enhanced sensitivity to dopamine agonist-induced disruption of PPI.     

Withdrawal from repeated amphetamine administration leads to disruption of prepulse inhibition but not to disruption of latent inhibition

Summary. The present study represents a continuous effort to develop an animal model of schizophrenia based on the “endogenous dopamine sensitization” hypothesis. To achieve this goal, withdrawal from an escalating amphetamine (AMPH) regime administration [three injections per day over a period of 4 days and increasing doses from 1 to 10 mg/kg of AMPH or an equivalent volume of saline (SAL)] was employed. Animals exposed to this treatment were evaluated on their performance in attentional (Latent inhibition, LI) and sensorimotor gating (Prepulse inhibition, PPI) tasks in a drug free state and tested for locomotor sensitization following a low dose of AMPH challenge administration. LI using active avoidance, tested on withdrawal day 4, was unaffected. PPI of the acoustic startle response, measured on withdrawal days 6 and 70, was disrupted. On the 76th day of withdrawal, a low challenge dose of AMPH (1 mg/kg) led to a clear locomotor sensitization effect. Present address: Brain Research Institute, University of Zurich/ETH Zurich, Switzerland     

Dissociation between the effects of pre-weaning and/or post-weaning social isolation on prepulse inhibition and latent inhibition in adult Sprague--Dawley rats

Human attentional impairments can be modelled in the rat using the prepulse inhibition (PPI) or the latent inhibition (LI) paradigm. The present study investigated the consequences of a combination of pre-weaning maternal separation (MS) and post-weaning social isolation (SI) on both PPI and LI in male and female Sprague--Dawley rats tested as adults. We report here a double dissociation between the effects of MS (repeated 4 h daily separations) and SI on PPI and LI: MS did not modify PPI, but enhanced LI. In contrast, SI disrupted PPI, the deficits being restricted to male rats, but left LI intact. There were no additive effects of MS and SI on PPI or LI. While MS improved avoidance learning, SI impaired it. Although both PPI and LI assess processes of selective attention, our results support the contention, already stated in the literature, that they involve differing neuro-psychological mechanisms. Furthermore, the fact that only males exhibited PPI deficits following SI has implications for the well-known differential vulnerability of human males to certain psychiatric disorders (e.g. schizophrenia). Finally, the combination of MS and SI could represent a relevant animal model for some aspects of schizophrenia, since both PPI and LI were altered.     

Effects of fencamfamine on latent inhibition

The effects of fencamfamine (FCF), an indirect dopamine (DA) agent, were investigated using the latent inhibition (LI) model of schizophrenia. In the LI procedure, rats preexposed (PE) to an unreinforced stimulus show difficulty in subsequent learning of an association in which that stimulus is predictive of an unconditioned stimulus (US). FCF (1.75, 3.5 and 7.0 mg/kg i.p.) yielded an inverse dose-response relationship regarding LI. At 3.5 mg/kg, LI was abolished and no effect was observed at 1.75 and 7.0 mg/kg. The effect of FCF (3.5 mg/kg) on LI was blocked by the antipsychotic risperidone (RIS; 4.0 mg/kg), a D2/5HT2 antagonist. These results confirm the similarity of the behavioral profile of FCF and amphetamine (AMPH). In addition, they provide a further validation of the LI model for psychosis, since RIS was shown to prevent a psychostimulant-induced disruption of LI.     

Prenatal dexamethasone exposure, postnatal development, and adulthood prepulse inhibition and latent inhibition in Wistar rats

Prenatal stress is an important risk factor in schizophrenia, and the aetiological factors mediating this relationship are central to the neurodevelopmental hypothesis of schizophrenia. The glucocorticoid receptor (GR) agonist dexamethasone (DEX) is commonly prescribed for prenatal conditions, and results in GR activation, which is part of the stress response. To investigate animal evidence for whether prenatal DEX leads to development of schizophrenia-like phenotypes, Wistar rats were prenatally exposed to DEX (0.1mg/kg/day) between the gestational days 15 and 21, and tested in two paradigms known to be disrupted in schizophrenia patients: prepulse inhibition (PPI) and latent inhibition (LI). A cross-fostering design was used to allow dissociation of any direct prenatal effects on offspring from effects dependent on DEX exposure of the rearing dam. Pup birth weight was reduced by prenatal DEX treatment. DEX-treated dams demonstrated increased pup-directed behaviour. There were additive effects of prenatal DEX treatment and DEX treatment of rearing dam in terms of reduced body weight in adulthood. In one of two replications, PPI was increased by prenatal DEX in males only and specific to the highest prepulse intensity. There was no evidence that LI was disrupted by prenatal DEX treatment. This study does not provide support for the hypothesis that prenatal DEX exposure leads to schizophrenia-like deficits in PPI or LI, suggesting that GR prenatal programming is not a mechanism of direct relevance to the neurodevelopmental hypothesis of schizophrenia.     

Delayed onset of prepulse inhibition deficits following kainic acid treatment on postnatal day 7 in rats

Abnormal activity in corticolimbic circuits during development may be a predisposing factor for schizophrenia. Permanent or temporary lesions of limbic structures such as the ventral hippocampus and basolateral amygdala in rats on postnatal day (PND) 7 result in functional changes similar to some behavioural and cognitive signs of schizophrenia. The present experiments tested whether transient increases in the neural activity of corticolimbic circuits on PND 7 would result in similar behavioural changes. Long-Evans rats were treated with either kainic acid (KA, 1.5 mg/kg, i.p.) or saline on PND 7 and tested for prepulse inhibition (PPI) of the acoustic startle response and spontaneous locomotor activity both in a novel environment and following amphetamine treatment before puberty (PND 35) and in early adulthood (PND 56). In subgroups of animals PPI was also measured following apomorphine administration (0.2 mg/kg) and spatial learning and memory were tested in the water maze. Rats treated with KA were indistinguishable from saline-treated animals on PND 35. However, on PND 56, KA-treated animals showed a subtle consistent decrease in PPI relative to control animals, but did not show increased sensitivity to the disruptive effects of a low dose of apomorphine on PPI. Locomotor responses to novelty or amphetamine were not reliably altered in the KA-treated animals. KA- and saline-treated animals performed similarly in the water maze. These results support the hypothesis that neural hyperactivity on PND 7 in rats causes behavioural changes in early adulthood that resemble some symptoms of schizophrenia. These pharmacological data suggest that the changes are not mediated by postsynaptic alterations in mesolimbic dopamine transmission.     

Spontaneously Hypertensive Rats (SHR) present deficits in prepulse inhibition of startle specifically reverted by clozapine

Deficits in an operational measure of sensorimotor gating - the prepulse inhibition of startle (PPI) - are presented in psychiatric disorders such as schizophrenia, bipolar disorder, and attention deficit/hyperactivity disorder (ADHD). Some previous studies showed that the spontaneously hypertensive rats (SHR) present PPI deficit. Although SHR is suggested as an animal model to study ADHD, we have suggested that the behavioral phenotype of this strain mimics some aspects of schizophrenia. The aim of this study was to characterize the PPI response in SHR. Pharmacological characterization consisted in the evaluation of the effects of the following drugs administered to adult Wistar rats (WR) and SHR previously to the PPI test: amphetamine (used for ADHD and also a psychotomimetic drug), haloperidol and clozapine (antipsychotic drugs), metoclopramide (dopamine antagonist without antipsychotic properties) and carbamazepine (mood stabilizer). Our results showed that SHR presented reduced PPI. This deficit was similar to that induced by amphetamine in WR. Only the atypical antipsychotic clozapine improved the PPI deficit observed in SHR. These findings reinforce the SHR strain as an animal model to study several aspects of schizophrenia, including the abnormalities in sensorimotor gating associated with this disease.     

A putative animal model of the "prodromal" state of schizophrenia.

BACKGROUND: There is growing interest in detecting and treating schizophrenia during the "prodrome," before the symptoms are fully manifested. The objective of this study was to develop a putative model of the prodrome and study the effects of medications on it. METHODS: Rats were treated with different regimens of amphetamine to produce full sensitization (full syndrome) and partial sensitization (to model the prodromal state) and were then treated with typical and atypical antipsychotics and a D1 antagonist to mimic early intervention. After several weeks of withdrawal, locomotor activity in response to amphetamine and behavioral deficits (prepulse inhibition [PPI] and latent inhibition [LI]) were examined. RESULTS: Animals that received the full sensitization showed significant increase in locomotor activity and a disruption in both PPI and LI. Animals treated with a partial regimen showed only a muted phenotype. The animals that received "early intervention" did not show progression from the prodromal to the full-blown phenotype. CONCLUSIONS: The partial regimen of amphetamine injections provided a modified phenotype that could be regarded as a representative of the "prodromal" state. Early intervention, instituted once the prodromal state was already developed, prevented further progression into the full phenotype analogous to schizophrenia.     

Role of the substantia nigra pars reticulata in sensorimotor gating, measured by prepulse inhibition of startle in rats

The substantia nigra pars reticulata (SNR) is one of the major output nuclei of the basal ganglia. It connects the dorsal and ventral striatum with the thalamus, superior colliculus and pontomedullary brainstem. The SNR is therefore in a strategic position to regulate sensorimotor behavior. We here assessed the effects of SNR lesions on prepulse inhibition (PPI) of the acoustic startle response (ASR), stereotypy and locomotion in drug-free rats, as well as after systemic administration of the dopamine agonist DL-amphetamine (2 mg/kg), and the NMDA receptor antagonists dizocilpine (0.16 mg/kg) and CGP 40116 (2 mg/kg). SNR lesions reduced PPI, enhanced spontaneous sniffing and potentiated the locomotor stimulation by dizocilpine and CGP 40116. PPI was impaired by dizocilpine and CGP 40116 in controls. The ASR was enhanced in controls by dizocilpine and amphetamine. SNR lesions prevented the enhancement of the ASR by amphetamine. A second experiment tested the hypothesis that the SNR mediates PPI via a GABAergic inhibition of the startle pathway. Infusion of the GABA(B) antagonist phaclofen but not the GABA(A) antagonist picrotoxin into the caudal pontine reticular nucleus reduced PPI. Hence, lesion of the SNR reduces sensorimotor gating possibly by elimination of a nigroreticular GABAergic projection interacting with GABA(B) receptors. Moreover, destruction of the SNR enhances the motor stimulatory effects of amphetamine and of the NMDA antagonists dizocilpine and CGP 40116. We conclude that the SNR exerts a tonic GABAergic inhibition on sensorimotor behavior that is regulated by the dorsal and the ventral striatum.     

Amphetamine dose dependently disrupts prepulse inhibition of the acoustic startle response in rats within a narrow time window

Prepulse inhibition (PPI) of the acoustic startle response refers to the reduction in startle amplitude when a weak prepulse precedes a startle-inducing pulse. Prepulse inhibition has been shown to be disrupted by amphetamine at doses that also stimulate locomotor activity, and it has been suggested that the same neuroanatomical substrate, mesolimbic dopamine activation, mediates the effects of amphetamine on locomotor activity and PPI. Amphetamine stimulates locomotor activity and mesolimbic dopamine release over a 1- to 3-h period, whereas PPI is typically measured within the first 30 min following amphetamine treatment. The present study therefore determined whether delays in testing would alter the PPI-disruptive effect of amphetamine in male Wistar rats. Amphetamine dose dependently disrupted PPI when the test session occurred 10 min following amphetamine treatment and only when the prepulse intensity was 5-10 dB above background. Delays of 40 and 60 min post-amphetamine injection, however, resulted in a loss of the ability of amphetamine to disrupt PPI although locomotor activity was significantly stimulated by amphetamine at these time points. The data from the present study therefore do not readily fit with the notion that the effects of amphetamine on locomotion and PPI are mediated by the same substrate.     

Reduction of latent inhibition by D-amphetamine in a conditioned suppression paradigm in humans

The sensitivity of latent inhibition (LI) to amphetamine has been tested in humans with a paradigm close to the conditioned emotional response suppression currently used in experimental animals. The conditioned stimulus (CS) was a tone, the unconditioned stimulus (US) a strong white noise, and the response a transient delay in a regular sequence of hand movements in the resolution of the Tower of Toronto puzzle. The aim of this study was to verify whether the previously reported, disruptive effect of CS preexposure on conditioning really represents LI, by examining its sensitivity to amphetamine. Three groups of healthy volunteers received placebo, 5 or 10 mg of dexamphetamine sulphate, respectively, in a double-blind experimental design. The preexposure, conditioning and test phases were carried out under either amphetamine or placebo. The non preexposed groups treated with amphetamine were not different from the non preexposed placebo group, indicating that amphetamine did not affect conditioning. Among the preexposed groups, those receiving 10 mg of amphetamine showed normal rates of conditioning, whereas those treated with either 5 mg of amphetamine or placebo showed LI. Similar results have been reported in experimental animals. This sensitivity to amphetamine suggests that the present paradigm may be used to study LI in humans.     

Developmental vitamin D deficiency alters MK 801-induced hyperlocomotion in the adult rat: An animal model of schizophrenia.

BACKGROUND: Developmental vitamin D (DVD) deficiency has been proposed as a risk factor for schizophrenia. The behavioral phenotype of adult rats subjected to transient low prenatal vitamin D is characterized by spontaneous hyperlocomotion but normal prepulse inhibition of acoustic startle (PPI). The aim of this study was to examine the impact of selected psychotropic agents and one well-known antipsychotic agent on the behavioral phenotype of DVD deplete rats. METHODS: Control versus DVD deplete adult rats were assessed on holeboard, open field and PPI. In the open field, animals were given MK-801 and/or haloperidol. For PPI, the animals were given apomorphine or MK-801. RESULTS: DVD deplete rats had increased baseline locomotion on the holeboard task and increased locomotion in response to MK-801 compared to control rats. At low doses, haloperidol antagonized the MK-801 hyperactivity of DVD deplete rats preferentially and, at a high dose, resulted in a more pronounced reduction in spontaneous locomotion in DVD deplete rats. DVD depletion did not affect either baseline or drug-mediated PPI response. CONCLUSIONS: These results suggest that DVD deficiency is associated with a persistent alteration in neuronal systems associated with motor function but not those associated with sensory motor gating. In light of the putative association between low prenatal vitamin D and schizophrenia, the discrete behavioral differences associated with the DVD model may help elucidate the neurobiological correlates of schizophrenia.     

Rat strain differences in the ability to disrupt sensorimotor gating are limited to the dopaminergic system, specific to prepulse inhibition, and unrelated to changes in startle amplitude or nucleus accumbens dopamine receptor sensitivity.

Previous studies indicate that a variety of pharmacological agents interfere with the prepulse inhibition of the acoustic startle (PPI) response including phencyclidine (PCP), 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), amphetamine, and apomorphine. Strain differences have been observed in the ability of apomorphine to disrupt PPI, although the degree to which these strain differences occur after administration of nondopaminergic drugs or the degree to which differences can be observed in other models of dopamine (DA) receptor activation has not been elucidated. The present study tested the effects of apomorphine, amphetamine, 8-OH-DPAT, and PCP on PPI in the Sprague Dawley and Wistar rat strains. Because apomorphine disrupts PPI via activation of DA receptors in the nucleus accumbens, apomorphine-induced hyperlocomotion, also a behavioral model of nucleus accumbens DA receptor activation, was measured in both rat strains. Administration of PCP or 8-OH-DPAT attenuated PPI in both strains, whereas apomorphine and amphetamine only attenuated PPI in Wistar rats. The ability of apomorphine to increase motor activity in the absence of a startle-eliciting stimulus was similar in the two strains, as was apomorphine-induced hyperlocomotion. A time course analysis of the effects of apomorphine on startle response in Sprague Dawley rats found that changes in the magnitude of PPI followed changes in basic startle amplitude. Similarly, no apomorphine-induced attenuation of PPI was observed in Sprague Dawley rats after 6-OHDA-induced DA receptor supersensitivity in the nucleus accumbens. These data suggest a dissociation between the effects of DA receptor agonists in PPI and other behavioral models of DA receptor activation.     

Effects of microinjections of apomorphine and haloperidol into the inferior colliculus on the latent inhibition of the conditioned emotional response

Electrical or chemical stimulation of the inferior colliculus (IC) induces fear-like behaviors. More recently, consistent evidence has shown that electrical stimulation of the central nucleus of the IC supports Pavlovian conditioning and latent inhibition (LI). LI is characterized by retardation in conditioning and also by an impaired ability to ignore irrelevant stimuli, after a non-reinforced pre-exposure to the conditioned stimulus. LI has been proposed as a behavioral model of cognitive abnormalities seen in schizophrenia. The aim of the present study was to determine whether dopaminergic mechanisms in the IC are involved in LI of the conditioned emotional response (CER). To induce LI, a group of rats was pre-exposed (PE) to six tones in two sessions, while rats that were not pre-exposed (NPE) had two sessions without tone presentations. The conditioning consisted of two tone presentations to the animal, followed immediately by a foot shock. PE and NPE rats received IC microinjections of physiological saline, the dopaminergic agonist apomorphine (9.0 μg/0.5 μL/side), or the dopaminergic antagonist haloperidol (0.5 μg/0.5 μL/side) before both pre-exposure and conditioning. During the test, the PE rats that received saline or haloperidol had a lower suppression of the licking response compared to NPE rats that received vehicle or haloperidol, indicating that latent inhibition was induced. There was no significant difference in the suppression ratio in rats that received apomorphine injections into the IC, indicating reduced latent inhibition. These results suggest that dopamine-mediated mechanisms of the IC are involved in the development of LI.     

Nicotine and clozapine actions on pre-pulse inhibition deficits caused by N-methyl-D-aspartate (NMDA) glutamatergic receptor blockade

Pre-pulse inhibition (PPI) is a phenomenon of neurobehavioral plasticity in which the motor response to a startling stimulus is inhibited by a preceding stimulus of a lower intensity. Most often this is tested in the auditory mode. PPI is impaired in a variety of clinical states, most notably schizophrenia. PPI is easily modeled in experimental animals and serves as a useful basis for determining the neural bases for behavioral plasticity. In the current study we examined the interactions of N-methyl-D-aspartate (NMDA) glutamate and nicotinic cholinergic receptor systems in the expression of PPI. Female Sprague-Dawley rats were tested for auditory PPI after s.c. injections of the NMDA antagonist dizocilpine (also known as MK-801), the prototypic nicotinic agonist nicotine or both. Vehicle (saline) injections served as the control. Nicotine (0.2-0.8 mg/kg) by itself caused a modest but significant dose-related improvement in PPI. Dizocilpine (25-100 microg/kg) caused a dramatic dose-related impairment in PPI. Interestingly, the low to moderate doses of nicotine potentiated the PPI impairment by dizocilpine. In a second experiment nicotine and dizocilpine interactions with the atypical antipsychotic drug clozapine were assessed. As in the first experiment, nicotine potentiated the adverse effects of dizocilpine on PPI. The combination of nicotine with clozapine effectively attenuated the PPI impairment caused by dizocilpine when neither alone was effective. Inasmuch as PPI is impaired in schizophrenia, its reversal by the antipsychotic drug clozapine may depend on co-administration of nicotine by smoking in the patients. Development of nicotinic-based co-treatments for schizophrenia may achieve this benefit of nicotine without the hazards of smoking. Sensory modulation deficit, which is a syndrome of sensory over-responsiveness may also benefit from such combination therapy.     

Prepulse inhibition deficits of the startle reflex in neonatal ventral hippocampal-lesioned rats: reversal by glycine and a glycine transporter inhibitor.

BACKGROUND: Neonatal ventral hippocampal (NVH) lesions in rats induce behavioral abnormalities at adulthood thought to simulate some aspects of the positive, negative, and cognitive deficits classically observed in schizophrenic patients. Such lesions induce a postpubertal emergence of prepulse inhibition (PPI) deficits of the startle reflex reminiscent of the sensorimotor gating deficits observed in a majority of schizophrenic patients. To study the potential involvement of the glycinergic neurotransmission in such deficits, we investigated the capacity of glycine (an obligatory N-methyl-D-aspartate [NMDA] receptor co-agonist) and ORG 24598 (a selective glycine transporter 1 inhibitor) to reverse NVH lesion-induced PPI deficits in rats.METHODS: Ibotenic acid was injected bilaterally into the ventral hippocampus of 7-day-old pups. Prepulse inhibition of the startle reflex was measured at adulthood. RESULTS: Glycine (.8 and 1.6 g/kg IP) and ORG 24598 (10 mg/kg IP) fully and partially reversed lesion-induced PPI deficits, respectively. CONCLUSIONS:These findings confirm that an impaired glutamatergic neurotransmission may be responsible for PPI deficits exhibited by NVH-lesioned rats and support the hypoglutamatergic hypothesis of schizophrenia. They also suggest that drugs acting either directly at the NMDA receptor glycine site or indirectly on the glycine transporter 1 could offer promising targets for the development of novel therapies for schizophrenia.     

Amphetamine-sensitized animals show a sensorimotor gating and neurochemical abnormality similar to that of schizophrenia

The aim of these studies was to examine whether amphetamine-induced sensitization in rats could be used as an animal model to study the basis of certain abnormalities seen in schizophrenia. Specifically, these experiments examined whether rats subjected to a sensitizing regimen of amphetamine would show the sensorimotor gating and greater amphetamine-induced displacement of radio-raclopride binding deficit that is observed in schizophrenia. In the first experiment, animals were divided into two groups with each rat receiving an intraperitoneal injection of amphetamine (AMPH) or saline (SAL) (1 ml/kg) three times per week for 3 weeks for a total of nine injections. AMPH dose was increased weekly from 1 mg/kg in the first week to 3 mg/kg in the third. Twenty-two days after the last injection, prepulse inhibition (PPI) of the acoustic startle response was tested. In addition, rats were tested for the effects of a challenge dose of 0.5 mg/kg AMPH on locomotor activity and [3H]raclopride (RAC) binding potential (BP) in the striatum. The tests for PPI confirmed that sensorimotor gating was disrupted in the AMPH-induced sensitized-state rats at baseline. The AMPH-sensitized rats also exhibited higher locomotor response to AMPH and a lower binding of striatal [3H]raclopride when challenged with the drug. The results were replicated and even more pronounced in rats that were treated with AMPH for 5 weeks, with doses ranging from 1mg/kg in the first week to 5 mg/kg in the fifth. These sensorimotor gating deficits and neurochemical (greater AMPH-induced displacement of radio-raclopride binding) abnormalities show similarities with the pathophysiology of schizophrenia and suggest that the AMPH-sensitized-state rats could be used to model certain aspects of schizophrenia.     

Amphetamine sensitization in rats as an animal model of schizophrenia

Based on the 'endogenous dopamine sensitization' hypothesis of schizophrenia the present study employed a repeated amphetamine administration regime in order to investigate the behavioral, neurochemical and neuroanatomical consequences following short- and long-term withdrawal periods. The escalating amphetamine administration schedule consisted of three injections per day over a 6-day period with the dosage ranging from 1 to 8 mg/kg. It was demonstrated that following both short- (4 days) and long-term (66 days) withdrawal periods latent inhibition (LI) and prepulse inhibition (PPI), two translational paradigms highly relevant to schizophrenia, were disrupted. A challenge injection verified sensitization in two different cohorts of animals at 40 and 70 days following cessation of treatment. Neurochemical evaluation demonstrated a reduction in dopamine levels in the caudate-putamen and nucleus accumbens core and shell as well as an enhanced utilization ratio in the caudate-putamen after both withdrawal periods. Similar to the findings from post-mortem studies of brains of schizophrenic patients, a downregulation of glutamic acid decarboxylase 67 (GAD67) immunoreactivity was found in the hippocampus, prefrontal cortex, thalamus, and amygdala in amphetamine pretreated animals following longer withdrawal periods. This was not accompanied by enhanced neurotoxicity or reactive gliosis as demonstrated by the immunohistological analysis using the apoptotic marker activated Caspase-3 and GFAP (glial fibrillary acidic protein; a marker for astrocytes) following both short- and long-term withdrawal periods. In conclusion, it is suggested that these findings constitute a highly reliable and valid animal model of schizophrenia.     

Effects of metabotropic glutamate receptor 5 on latent inhibition in conditioned taste aversion

Latent inhibition (LI) is a phenomenon by which pre-exposure of a conditioned stimulus (CS) prior to the CS-unconditioned stimulus (US) pairings retards conditioned responding (CR). LI has been demonstrated in a variety of learning tasks including conditioned taste aversion (CTA). Earlier work has shown that systemic administration of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a selective metabotropic glutamate receptor 5 (mGlu5) antagonist, is able to disrupt classical conditioning in CTA. The present study investigated the involvement of mGlu5 receptors in LI using a CTA procedure. In the first experiment, rats received either water (non-pre-exposed, NPE) or a saccharin solution (pre-exposed, PE) on 2 consecutive days. The animals then received conditioning in which a fixed amount of saccharin was paired with lithium chloride and then the CR to the taste was tested. Either MPEP (3, 6, 12 mg/kg) or vehicle was injected intraperitoneally prior to taste pre-exposure or testing. Animals in the vehicle control groups displayed LI. MPEP injections before pre-exposure trials attenuated LI but also reduced consumption during pre-exposure, which obscured interpretation of the LI effect. The second experiment used four pre-exposure trials and controlled access to fixed amount of the solutions during the pre-exposure as well as the conditioning trials. Rats were injected before pre-exposure trials but not before the test trial. The results found that MPEP attenuates latent inhibition suggesting that the mGlu5 receptor exerts an influence on the processes that underlie the effects of taste pre-exposure on conditioning.