Disruption of medial prefrontal synchrony in the subchronic phencyclidine model of schizophrenia in rats.

Subchronic treatment with the N-methyl-D-aspartate (NMDA) antagonist phencyclidine (PCP) produces behavioral abnormalities in rodents which are considered a reliable pharmacological model of neurocognitive deficits in schizophrenia. Alterations in prefrontal neuronal firing after acute PCP administration have been observed, however enduring changes in prefrontal activity after subchronic PCP treatment have not been studied. To address this we have recorded cortical oscillations and unit responses in putative cortical pyramidal cells in subchronic PCP-treated rats (2mg/kg twice daily for 7 days) under urethane anesthesia. We found that this regimen reduced theta oscillations in the medial prefrontal cortex. It further produced abnormal cortical synchronization in putative cortical pyramidal cells. These alterations in prefrontal cortex functioning may contribute to cognitive deficits seen in subchronic NMDA antagonist pre-treated animals in prefrontal-dependent tasks.

Disruption of overshadowing and latent inhibition in high schizotypy individuals.

Deficits in selective attention are seen in positively symptomatic schizophrenia sufferers, and in normal people displaying schizotypal traits. We investigated the relationship between selective attention and schizotypy in undergraduate students, by comparing participants' performance in two models of selective attention, overshadowing and latent inhibition, with psychoticism scores derived from the Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE). Using a novel within-subject overshadowing task, we showed that the unusual experiences dimension of schizotypy, but not the other three O-LIFE dimensions, was negatively related to overshadowing score. We also replicated findings that the unusual experiences dimension of schizotypy was negatively related to latent inhibition score. These experiments provide evidence that selective attention is disrupted in normal individuals showing traits relating to positive-like schizophrenic symptoms, and has implications for interpreting selective attention deficits measured in schizophrenia patients.

Allopregnanolone protects against dopamine-induced striatal damage after in vitro ischaemia via interaction at GABA A receptors.

Sex steroid hormones, such as progesterone, have been shown to display neuroprotective properties after various models of central nervous system injury, including cerebral ischaemia, although the mechanism(s) of action remain largely undetermined. Allopregnanolone, an active progesterone metabolite, may explain some of the protective actions of progesterone. We utilised an in vitro model of ischaemia to evaluate the neuroprotective potential of allopregnanolone and examine its interaction at the GABA(A) receptor, which is hypothesised to be its main neuroprotective mechanism. In adult male mouse coronal caudate slices exposed to oxygen glucose deprivation (OGD), we measured aspects of OGD-induced dopamine release, which is neurotoxic during ischaemia, using fast cyclic voltammetry and also assessed tissue viability. The GABA(A) agonist, muscimol, displayed a neuroprotective profile in terms of delaying the OGD-evoked dopamine efflux (P < 0.05) and reducing the amount of dopamine released after OGD (P < 0.05). Allopregnanolone, at a concentration of 10(-6) m, also displayed a neuroprotective profile because it significantly reduced the amount of dopamine efflux (P < 0.05) and reduced the loss of viable tissue after OGD compared to slices exposed to vehicle during OGD (P < 0.05). However, the effect of 10(-6) m allopregnanolone on dopamine efflux was prevented in the presence of bicuculline, a competitive GABA(A) receptor antagonist. These results describe the use of an in vitro model of ischaemia with respect to determining that allopregnanolone is neuroprotective during the acute phase of ischaemia, and also demonstrate that such actions are dependent, at least in part, upon interaction at the GABA(A) receptor.

Modelling ischaemia in vitro: effects of temperature and glucose concentration on dopamine release evoked by oxygen and glucose depletion in a mouse brain slice.

Current pharmacological interventions for acute stroke are largely ineffective or confounded by adverse effects, emphasising the need to develop new pharmacological treatments for neuroprotection. We have developed a robust in vitro model previously used in rats to assess dopamine release in mouse caudate nucleus brain slices, measured by fast cyclic voltammetry, during oxygen and glucose deprivation (OGD) as a model for cerebral ischaemia: this model will allow the study of transgenic mouse strains. During the pre-OGD equilibration period we found that a temperature of 33°C, with solution containing 10 mM glucose provided the optimum baseline conditions from which reliable OGD-induced changes in dopamine efflux could be measured, without being susceptible to spontaneous release events. During OGD we found no significant difference in any of the parameters measured between perfusion with glucose-free solution, and perfusion with solution containing 2 mM glucose. We therefore suggest, in agreement with previous work, that using 2 mM glucose during OGD is appropriate, and using these conditions we were able to reliably produce OGD-evoked dopamine release.

Dopamine antagonist modulation of amphetamine response as detected using pharmacological MRI.

Functional magnetic resonance imaging (fMRI), employing BOLD-contrast, was used to measure changes in regional brain activation following amphetamine administration, either alone or after pre-treatment with the dopamine D1 receptor antagonist SCH23390, or the dopamine D2 receptor antagonist, sulpiride, in anaesthetised rat. After obtaining baseline data, rats (n=8) were given amphetamine (3 g/kg i.v) and volume data sets collected for 90 mins. Acute amphetamine challenge caused widespread increases in BOLD signal intensity in many subcortical structures with rich dopaminergic innervation, with decreases in BOLD contrast observed in the superficial layers of the cortex. Pretreatment with SCH23390 (n=8, 0.5 mg/kg, i.v) substantially attenuated the increases in BOLD activity in response to amphetamine, with lesser effects on the amphetamine-evoked decreases in BOLD signal. In contrast, sulpiride (n=8, 50 mg/kg, i.v) predominantly blocked the decrease in BOLD signal, having a smaller effect on the increases in BOLD signal. In summary, these data are supportive of the notion that different dopamine receptor types are responsible for separate components of the full amphetamine response. Furthermore the utility of BOLD contrast fMRI as a means of characterising the mechanisms of drug action in the whole brain has been demonstrated. Such studies may be of particular use for investigation of localised action and interaction of different dopaminergic agents.

GABA transmission in the ventral pallidum is not involved in the control of latent inhibition in the rat.

Latent inhibition describes a process of learning to ignore stimuli of no consequence, and is disrupted in acute, positive-symptomatic schizophrenia. Understanding the neural basis of latent inhibition in animals may help to elucidate the neural dysfunction underlying positive schizophrenic symptoms in man. Evidence suggests a crucial role for dopamine transmission in the nucleus accumbens in the control of latent inhibition. The present studies investigated the role of the GABA-ergic efferent from the nucleus accumbens to the ventral pallidum in latent inhibition. The GABA(A) agonist muscimol (4.56 ng/microl), and antagonist picrotoxin (0.2 microg/microl), were infused into the ventral pallidum, and effects on latent inhibition were assessed using a conditioned suppression procedure. Neither drug produced specific effects on latent inhibition when given alone and, in the case of muscimol, failed to reverse the disruption of latent inhibition induced by systemic amphetamine. In addition to significant non-specific drug effects, a positive control experiment revealed that intra-pallidal picrotoxin significantly enhanced locomotion, suggesting that our manipulations of ventral pallidal GABA function were behaviourally effective. We conclude that modulating ventral pallidal GABA transmission does not affect latent inhibition. The implications of this finding for theories of the neural circuitry mediating latent inhibition and for understanding the functional role of ventral pallidal GABA transmission are discussed.

The effect of amphetamine on Kamin blocking and overshadowing.

Schizophrenic patients show deficits on stimulus salience tasks such as latent inhibition and blocking, which measure the ability to disregard irrelevant stimuli. Amphetamine-treated animals show similar deficits in analogous tasks, thereby providing a model of the stimulus-selection deficits observed in schizophrenia. In two experiments, the effect of the indirect dopamine (DA) agonist D-amphetamine sulphate (1.0 mg/kg, i.p.) on Kamin blocking and overshadowing were examined and compared, in the rat, using the conditioned lick suppression procedure. The aim was to provide some insight into the behavioural and pharmacological mechanisms underlying amphetamine effects in both paradigms. In experiment 1, it was shown that amphetamine selectively disrupted Kamin blocking, when given either at stage 2 alone, or at both stages of the task. In experiment 2, amphetamine treatment significantly abolished Kamin blocking and overshadowing, when administered prior to compound conditioning in both tasks. These data suggest that dopamine may play a critical role in mediating performance in tasks measuring stimulus salience processes. The results are discussed in the framework of the role of DA in stimulus-selection performance.

Conditioned appetitive stimulus increases extracellular dopamine in the nucleus accumbens of the rat.

This study used in vivo microdialysis to examine the release of dopamine (DA) in the nucleus accumbens (nAc) during the performance of a previously learned, signalled sucrose reward task, and during conditioning of a neutral tone stimulus to this reward. Behavioural measures (magazine entries) confirmed that stimuli associated with sucrose presentation became secondary rewarding stimuli, and DA release was also monitored during subsequent presentation of these stimuli alone. Perhaps surprisingly, during magazine entry for consumption of sucrose, i.e. in conditions similar to routine training, dialysate DA levels in the nAc did not increase. In contrast, during conditioning of the tone with light-sucrose, dopamine levels increased consistently and significantly. Interestingly, DA levels were somewhat, but significantly, increased when tone alone was presented in a test session, i.e. two hours after conditioning, and even more so when tone was combined with the light previously associated with sucrose. In this latter case the number of magazine entries increased to a level similar to that seen during conditioning. Presentation of light alone resulted in a similar level of magazine entries to tone alone, but no significant increase in DA. In summary, these studies confirm that a neutral stimulus can acquire the behavioural properties of reward when conditioned. The neurochemical data, on the other hand, suggest that increases of DA in nAc are more likely to be related to new associative learning than to established incentive or consumatory processes. The increase in DA release in the test session may be related either to the secondary reinforcing properties acquired by the stimulus, or to the change in contingencies, or to the aversive effects of the omission of reward.