Kaoru Takenouchi

Effects of D1 and D2 dopamine receptor antagonists on cocaine-induced self-stimulation and locomotor activity in rats

To clarify the involvement of D1 and D2 dopamine systems in intracranial self-stimulation (ICSS) and locomotor activity in rats, we studied the acute effects of cocaine and the interaction between cocaine and dopamine antagonists with respect to these behaviors. Although cocaine (5.0, 10.0, or 20.0 mg/kg) dose-dependently increased locomotor activity, it augmented the rate of ICSS only at 5.0 mg/kg. The failure of high doses of cocaine to augment purpose-oriented behavior such as ICSS may result from its induction of a manic-like state. The D1 dopamine receptor antagonist SCH23390 (0.02, 0.1, or 0.5 mg/kg) or the D2 antagonist nemonapride (0.04, 0.2, or 1.0 mg/kg) significantly decreased cocaine augmentation of ICSS. The higher two doses of either antagonist also produced a significant decrease in cocaine-induced locomotor activity. We therefore suspect that cocaines augmentative effect on those behaviors, especially ICSS, requires activation of both D1 and D2 dopamine receptors.

Metabolite changes with age measured by proton magnetic resonance spectroscopy in normal subjects.

Abstract  To determine whether there are metabolite changes in the left medial temporal and frontal lobes with aging, we performed proton magnetic resonance spectroscopy in 36 normal subjects. The N‐acetylaspartate/creatine‐phosphocreatine ratio in the medial temporal lobe tended to be decreased in subjects over 60 years of age. The ratio decrease in the frontal lobe related to aging was lower than that in the medial temporal lobe. There were no significant differences in the metabolite ratios between males and females. These findings suggest that structures in the medial temporal lobe may be more susceptible to neuronal dysfunction associated with aging than those in the frontal lobe.

Hippocampal volume asymmetry and age at illness onset in males with schizophrenia.

To determine whether there are disturbances of hippocampal volume asymmetry in schizophrenic patients, we obtained contiguous, I-mm-thick magnetic resonance images in 28 males with chronic schizophrenia and in 28 age-matched healthy males. The schizophrenic patients showed a bilateral reduction in volume of the hippocampal formation (HF; left 7.0%; right 8.7%). This reduction was significantly associated with the severity of disorganization syndrome (P < 0.0005). A significant asymmetry in the HF volume was found in the control subjects (P = 0.006), but not in the patients (P = 0.40). There was a significant positive correlation between the asymmetry index and the patient’s age at the onset of schizophrenia (r = 0.46,P = 0.01). Results indicate that a disturbance in the normal asymmetry of the HF may be a characteristic in schizophrenia, particularly in patients with an early onset of the illness.

Shortening of the hippocampal formation in first‐episode schizophrenic patients

Abstract Shortening of hippocampal formation (HF) in chronic schizophrenic patients have been demonstrated in our previous study. The purpose of the present study is to test if shortening of the HF occurs in schizophrenic patients suffering their initial psychotic episode. We performed contiguous, 1 mm thick, magnetic resonance imaging scans in 20 first‐episode schizophrenic patients, 21 chronic schizophrenic patients, and 25 healthy subjects. Both groups of schizophrenic patients demonstrated significant shortening of the HF compared with normal controls (first‐episode schizophrenia, 5.3%; chronic schizophrenia, 8.0%). However, the HF length was not significantly different between the first‐episode and chronic schizophrenic patients. No significant correlation was seen between the HF length and the duration of illness in chronic schizophrenic patients. These results suggest that the HF shortening observed in schizophrenic patients may be genetic and/or developmental in origin.

Directed Coherence of EEG on ICSS Rats with Methamphetamine‐induced Hyperactivity and Stereotyped Behavior

Methamphetamine (MAP) can reinforce intracranial self-stimulation (ICSS) in rats, that is, reward-seeking behavior. However, the ICSS can be inhibited by the stereotyped behavior induced by MAP. This study was designed to observe the mutual information flow between prefrontal cortex (PFC) and ventral tegmental area (VTA) using directed coherence (DC) analysis during the hyperactivity and stereotyped behavior induced by administration of MAP (a derivative of amphetamine). The DC from PFC to VTA increased at 5-7 Hz in the hyperactivity as compared to the stereotypy. In contrast, enhanced information flow from VTA to PFC was observed in the stereotypy as compared to the hyperactivity. We found a reciprocal information flow between PFC and VTA corresponding to the hyperactivity and stereotyped behavior that was induced by administration of MAP.

Reciprocal information flow between prefrontal cortex and ventral tegmental area in an animal model of schizophrenia.

The medial prefrontal cortex (PFC) is anatomically and functionally connected with the ventral tegmental area (VTA), the neuronal source of mesocorticolimbic system that is pathophysiologically related to schizophrenia-like symptoms. Methamphetamine (MAP) was applied to examine the functional relationship between PFC and VTA in an animal model of schizophrenia. Hyperactivity and stereotyped behavior were observed accompanied by a distinctive direction of information flow. In hyperactivity, information flow in the direction from PFC to VTA was dominant. Contrarily, dominant information flow from VTA to PFC was found in stereotyped behavior. These results indicate that dysfunctional interaction between PFC and VTA is the neuronal basis of MAP-induced schizophrenia-like psychosis. The information flow and its direction can be useful tool to explain the neurogenesis of these abnormal behaviors.

Metabolite changes with age measured by proton magnetic resonance spectroscopy in normal subjects

To determine whether there are metabolite changes in the left medial temporal and frontal lobes with aging, we performed proton magnetic resonance spectroscopy in 36 normal subjects. The N-acetylaspartate/creatine-phosphocreatine ratio in the medial temporal lobe tended to be decreased in subjects over 60 years of age. The ratio decrease in the frontal lobe related to aging was lower than that in the medial temporal lobe. There were no significant differences in the metabolite ratios between males and females. These findings suggest that structures in the medial temporal lobe may be more susceptible to neuronal dysfunction associated with aging than those in the frontal lobe.

Alterations of accumbens neuronal activity in freely moving rats following methamphetamine.

Abstract: Multiple unit activity in the nucleus accumbens, locomotor activity, and stereotyped behavior were simultaneously recorded in freely moving rats. An intra‐peritoneal injection of 1.5 mg/kg methamphetamine produced an increase in the firing rate while a decrease in the discharge rate occurred following an administration of 4.5 mg/kg methamphetamine. In addition, the unit activity was positively correlated with the locomotor activity and negatively correlated with the stereotypy score. These results suggest that accumbens neuronal activation during locomotor hyperactivity may partly depend on the feedback from locomotion.