Cristiane Salum

The effect of amphetamine on Kamin blocking and overshadowing.

&NA; Schizophrenic patients show deficits on stimulus salience tasks such as latent inhibition and blocking, which measure the ability to disregard irrelevant stimuli. Amphetaminetreated 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. Behavioural Pharmacology 14:315‐322

Anxiety-like behavior in rats: a computational model

This work describes a neural network model of the rat exploratory behavior in the elevated plus-maze, a test used to study anxiety. It involves three parameters: drive to explore; drive to avoid aversive stimuli; and spontaneous locomotor activity. Each network unit corresponds to a specific location in the maze and the connections, only between closest neighbors, represent the possible adjacent places to which a virtual rat can navigate. Competitive learning is used to generate a sequence of network states that correspond to the virtual rat successive locations in the maze. To evaluate the generality of the model it was also tested for two modifications of the elevated plus-maze: one with totally closed arms and the other with totally open arms. The results are compared with data obtained with rats. The simulations are consistent with experimental evidence and may provide an efficient way of describing the anxiety-like rat behavior in the elevated plus-maze. This could be useful for researching the emotional parameters involved in this anxiety animal model.

Nitric oxide modulation of methylphenidate-induced disruption of prepulse inhibition in Swiss mice

Drugs that facilitate dopaminergic neurotransmission induce cognitive and attentional deficits which include inability to filter sensory input measured by prepulse inhibition (PPI). Methylphenidate, an amphetamine analog is used in the treatment of attention deficit hyperactivity disorder. Given that nitric oxide (NO) modulates dopamine effect our aim is to analyze the nitric oxide synthase (NOS) and soluble guanylate cyclase (sGC) inhibitors effect on PPI disruption induced by methylphenidate. The inhibitors effects were compared to those produced by haloperidol and clozapine. Male Swiss mice received a first i.p. injection (one hour before testing), of either saline, or N(G) nitro l-arginine (10, 40 or 90 mg/kg), or 7-Nitroindazole (3, 10, 30 or 60 mg/kg), or oxadiazolo-quinoxalin (5 or 10 mg/kg), or haloperidol (1 mg/kg), or clozapine (5 mg/kg). Thirty min later mice received the second injection of either saline or methylphenidate (20 or 30 mg/kg) or amphetamine (5 or 10 mg/kg). One group of mice received intracerebroventricular 7-Nitroindazole (50 or 100 nM) followed by systemic administration of saline or methylphenidate (30 mg/kg). The results revealed a methylphenidate dose-dependent disruption of PPI comparable to amphetamine. The effect was prevented by either nitric oxide synthase or guanilate cyclase inhibitors or clozapine or haloperidol. In conclusion, methylphenidate induced a dose-dependent PPI disruption in Swiss mice modulated by dopamine and NO/sGC. The results corroborate the hypothesis of dopamine and NO interacting to modulate sensorimotor gating through central nervous system. It may be useful to understand methylphenidate and other psychostimulants effects.

Modulation of dopamine uptake by nitric oxide in cultured mesencephalic neurons

Strong evidence obtained from in vivo and ex-vivo studies suggests the existence of interaction between dopaminergic and nitrergic systems. Some of the observations suggest a possible implication of nitric oxide (NO) in dopamine (DA) uptake mechanism. The present work investigated the interaction between both systems by examining the effect of an NO donor, sodium nitroprusside (SNP), associated with the indirect DA agonist, amphetamine (AMPH) on tritiated DA uptake in cultures of embryonic mesencephalic neurons. Consistent with the literature, both AMPH (1, 3 and 10 microM) and SNP (300 microM and 1 mM) inhibited DA uptake in a dose-dependent manner. In addition, the inhibition of DA uptake by AMPH (1 and 3 microM) was significantly increased by the previous addition of SNP (300 microM). The implication of NO in this interaction was supported by the fact that the free radical scavenger N-acetyl-L-Cysteine (500 microM) significantly increased DA uptake and completely abolished the effect of SNP, leaving unaffected that from AMPH on DA uptake. Further, double-labeling immunohistochemistry showed the presence of tyrosine hydroxylase- (TH, marker for dopaminergic neurons) and neuronal NO synthase- (nNOS, marker for NO containing neurons) expressing neurons in mesencephalic cultures. Some dopaminergic neurons also express nNOS giving further support for a pre-synaptic interaction between both systems. This is the first work demonstrating in mesencephalic cultured neurons a combined effect of an NO donor and an indirect DA agonist on specific DA uptake.

Nitric oxide modulates dopaminergic regulation of prepulse inhibition in the basolateral amygdala

Systemic injection of the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine (LNO) prevents the disruptive effect of amphetamine (Amph) on prepulse inhibition (PPI), a sensorimotor gating model in which the amplitude of the acoustic startle response (ASR) to a startling sound (pulse) is reduced when preceded immediately by a weaker stimulus (prepulse). Given that dopamine (DA) projections to the basolateral amygdala (BLA) are involved in the control of information processing, our aim was to investigate if intra-BLA administration of LNO would modify the disruption caused by the DA agonists, Amph, apomorphine (Apo) and quinpirole (QNP), on PPI. Male Wistar rats received bilateral intra-BLA microinjections (0.2 µL/min/side) of combined treatments (saline or LNO 11 µg followed by saline, QNP 3 µg, Apo 10 µg or Amph 30 µg). PPI was disrupted by intra-BLA Apo, QNP or Amph but not by LNO. Prior bilateral intra-BLA injection of LNO prevented the Apo- and QNP-induced disruption of PPI but did not affect that caused by Amph. APO- or QNP-induced increases in ASR to prepulse + pulse were also restored by LNO. Since local inhibition of NO formation affected the effects of direct, but not indirect, DA agonists, the results suggest that this modulation is not occurring at the level of DA release but may involve complex interactions with other neurotransmitter systems.

Striatal dopamine in attentional learning: A computational model☆

This work describes a neural network model which simulates a discrete part of the dopaminergic striatal circuitry involved in reinforcement learning. We consider the proposal that learning by reinforcement is acquired by a heterosynaptic mechanism affecting plasticity of corticostriatal synapses, under the modulatory control of DA neurons. The simulation results seem to be successful since they are consistent with the literature that shows a transfer of DA neuron firing from the primary reinforcement stimulus to the conditioned stimulus after learning. We also present some simulations, using the same model, of two learning paradigms, blocking and overshadowing, which may be mediated by this dopamine circuitry.

Dopamina, óxido nítrico e suas interações em modelos para o estudo da esquizofrenia

Experimental models based on the increase of dopaminergic neurotransmission mimic behavioral and neurochemical schizophrenia-like aspects. Psychostimulants, as amphetamine, are used with this purpose because they increase extracellular dopamine levels in mesocorticolimbic and mesostriatal pathways. The limitations of direct manipulation uniquely based on the dopamine system in animal models have encouraged the use of new approaches. Nitric oxide (NO), an atypical neurotransmitter which inhibits dopamine reuptake and stimulates its release, seems to modulate dopamine-controlled behaviors. The prepulse inhibition test reveals deficits on the sensorimotor filter found in schizophrenics or after psichotomimetic treatments. This review presents evidences for the interaction between NO and DA systems on schizophrenia models as a new tool for the investigation of this pathology.

A model for the rat exploratory behavior in the elevated plus-maze

Address: 1Department of Psychology and Education, School of Philosophy, Sciences and Letters of Ribeirão Preto, University of São Paulo, 14040901 Ribeirão Preto, SP, Brazil, 2Computational and Experimental Neuroplasticity Laboratory, Krasnow Institute, George Mason University, Rockfish Creek Lane, Fairfax, VA 22030-4444, USA, 3Department of Morphology, Stomatology and Physiology, School of Odontology of Ribeirão Preto, University of São Paulo, 14040-901 Ribeirão Preto, SP, Brazil and 4Department of Physics and Mathematics, School of Philosophy, Sciences and Letters of Ribeirão Preto, University of São Paulo, 14040-901 Ribeirão Preto, SP, Brazil

Modelling rat behavior in an elevated plus-maze confronted with experimental data

This work describes a neural network model of rat exploratory behavior in the elevated plus-maze, a test used to study anxiety. It involves three parameters: drive to explore, drive to avoid aversive stimuli and spontaneous locomotive activity. Competitive learning is used to generate a sequence of network states each corresponding to a place in the maze. The work also presents experiments made with real rats providing data to be compared with the simulation results. The simulations are consistent with the experimental evidence, and may provide an efficient way of describing anxiety-like behaviors of rats in the elevated plus-maze.