Altered modulation of prefrontal and subcortical brain activity in newly diagnosed schizophrenia and schizophreniform disorder. A regional cerebral blood flow study.

To measure prefrontal and subcortical activity during a cognitive task, we examined 19 newly diagnosed schizophrenics and patients with schizophreniform psychosis. Seven healthy volunteers served as controls. The patients were drug naive or had received neuroleptics for a few days only. Cerebral blood flow distribution was depicted by single photon emission computed tomography at rest and during activation with the Wisconsin Card Sorting Test. A significant relative activation deficit in the left inferior-prefrontal region was revealed during the Wisconsin Card Sorting Test in the patient group. Furthermore, the patients had impaired striatal suppression on the left side during the cognitive task. The test performance was significantly impaired in the patients. The inability to reduce striatal activity may be due to a lack of corticostriatal feedback during prefrontal activation.

Neural networks as models of psychopathology.

Neural network modeling is situated between neurobiology, cognitive science, and neuropsychology. The structural and functional resemblance with biological computation has made artificial neural networks (ANN) useful for exploring the relationship between neurobiology and computational performance, i.e., cognition and behavior. This review provides an introduction to the theory of ANN and how they have linked theories from neurobiology and psychopathology in schizophrenia, affective disorders, and dementia.

Cerebral blood flow in rats with renal and spontaneous hypertension: resetting of the lower limit of autoregulation.

The effect of chronic hypertension on cerebral blood flow (CBF) was studied in anaesthetised rats. CBF was measured with the intracarotid 133Xe injection method. Rats with spontaneous and renal hypertension were compared with normotensive controls. The lower limit of autoregulation was determined during controlled haemorrhage. In the normotensive rats, CBF remained constant until mean arterial pressure (MAP) had decreased to the range of 50-69 mm Hg. Thereafter, CBF decreased with each further decrease in MAP. In both types of hypertensive rats, CBF remained constant until MAP had decreased to the range of 70-89 mm Hg. Thus, a 20-mm Hg shift of the lower limit of CBF autoregulation was found in both spontaneous and renal hypertensive rats. A neuropathological study revealed ischaemic brains lesions in half of the hypertensive rats following hypotension, whereas only a single lesion was found in one of six normotensive rats. No ischaemic brain lesions were found in a control study in which CBF was shown to be stable over a 21/2-h period. In conclusion, hypertensive rats showed a shift of the lower limit of CBF autoregulation as well as an increased susceptibility to ischaemic brain damage during hypotension. These findings presumably reflect hypertensive structural changes in the cerebral circulation.

Cerebral blood flow during delirium tremens and related clinical states studied with xenon-133 inhalation tomography.

The regional cerebral blood flow of 12 patients with severe alcohol withdrawal reactions (delirium tremens or impending delirium tremens) was measured during the acute state before treatment and after recovery. Greater cerebral blood flow was significantly correlated with visual hallucinations and agitation during the acute withdrawal reaction. The results suggest that delirium tremens and related clinical states represent a type of acute brain syndrome mainly characterized by CNS hyperexcitability.

Effects of acute ethanol intoxication, chronic ethanol intoxication, and ethanol withdrawal on magnesium and calcium metabolism in the rat.

Effects of ethanol intoxication and withdrawal on magnesium and calcium metabolism were studied in rats. During acute ethanol intoxication, plasma [Mg2+] was increased and plasma [Ca2+] decreased. During chronic intoxication, plasma [Mg2+] was normalized whereas plasma [Ca2+] was persistently subnormal. Ethanol withdrawal was followed by a decrease in plasma [Mg2+] and a normalization of plasma [Ca2+]. These various changes are probably related to changes in systemic pH and to the biochemical effects of ethanol and ethanol withdrawal on intermediary metabolism. Cerebrospinal fluid [Mg2+] was unchanged during intoxication and withdrawal and it was concluded that no etiological role can presently be ascribed to the magnesium ion as far as cerebral signs of ethanol intoxication and withdrawal in the rat are concerned. No consistent changes in erythrocyte [Mg2+] were encountered during ethanol intoxication and withdrawal in rats.

Convulsive behaviour during alcohol dependence: discrimination between the role of intoxication and withdrawal.

Male Wistar rats were subjected to repeated weekly episodes of 2 days severe alcohol intoxication (intragastric intubation) and 5 days of withdrawal. In half of the animals the withdrawal reaction was attenuated during the first nine weekly episodes by intragastric intubations with phenobarbital. During episodes 10-14 both phenobarbital treated and phenobarbital untreated animals were allowed to develop a withdrawal reaction; all animals were video-recorded during withdrawal and the records were rated blindly for the occurrence of convulsive seizures. The results were analyzed by step-wise logistic analysis of regression including phenobarbital treatment, alcohol dose and intoxication score as explanatory variables for the occurrence of convulsive seizures. The animals that had been in withdrawal during all episodes developed significantly more convulsive seizures compared with animals that had their first nine withdrawal episodes attenuated by phenobarbital. The development of withdrawal seizures depended on repeated episodes of withdrawal, whereas repeated alcohol intoxication per se did not explain the development of seizures. There were no differences between the groups in the severity of the non-convulsive signs of alcohol withdrawal. Thus the development of seizures and the non-convulsive signs of alcohol withdrawal may result from two pathogenetically different mechanisms: 1) seizures from a cumulative kindling-like effect over long time periods and 2) physical signs of alcohol withdrawal may reflect the degree of physical dependence during the most recent drinking bout.

The GABA/benzodiazepine receptor chloride channel complex during repeated episodes of physical ethanol dependence in the rat.

The GABA/benzodiazepine (BZ) receptor chloride channel complex was investigated during repeated episodes of ethanol intoxication and withdrawal in the rat; the intragastric intoxication technique was applied and the severity of intoxication, withdrawal and number of seizures were recorded. The following groups were studied after decapitation during withdrawal 10-16 h after the last ethanol feeding: A) isocalorically fed controls not receiving ethanol; B) isocalorical controls subjected to a single ethanol intoxication period; C) animals subjected to 15 intoxication-withdrawal episodes (spontaneous seizures); D) same as C, but without developing seizures. A radio receptor technique was applied in the characterization of the receptor complex comprising specific binding to the BZ-receptor, the chloride channel and the GABA receptor by 3H-diazepam, 35S-TBPS and 3H-muscimol, respectively. The allosteric couplings among the components of the receptor complex were studied by 3H-diazepam and 35S-TBPS binding enhancement tests involving muscimol, ZK 93423 and DMCM. Cortex, hippocampus and cerebellum were the brain regions studied. Except for a reduced specific binding of 3H-diazepam in cerebellum, there were no indications of changes in specific binding to any part of the receptor complex. The allosteric coupling of BZ and GABA receptors as well as chloride channel-BZ receptors were unchanged in all groups. It is notable that no changes at all could be related to number of intoxication-withdrawal episodes or to the development of seizures. Thus, the present study gave no indication that the GABA/benzodiazepine receptor chloride channel complex is directly involved in the augmentation of cerebral nervous system excitability (seizures) during repeated episodes of physical ethanol dependence.

The effect of phenobarbital and carbamazepine on the ethanol withdrawal reaction in the rat.

The effects of phenobarbital (PB) and carbamazepine (CZ) on the ethanol withdrawal reaction in the rat were investigated in a blind study including an untreated control group. Physical ethanol dependence was established by intragastric intubation during a 4-day period. Both the degree of intoxication and the withdrawal reaction were assessed by standardised assessment instruments. Treatment with PB (40-60 mg/kg) and CZ (80-120 mg/kg) was initiated 10 h after the last ethanol dose and continued during the first 24 h of withdrawal. Serum concentrations of the drugs were measured. Both PB and CZ significantly reduced the ethanol withdrawal reaction compared to controls, and PB was significantly more effective than CZ. The degree of drug intoxication signs assessed by the same rating scale as the degree of ethanol intoxication indicated that maximum tolerable drug doses were used. PB probably exerts its treatment effect through the mechanism of cross dependence with ethanol, while CZ may exert a more specific effect on limbic structures responsible for central nervous system excitability.

Diazepam prevents progression of kindled alcohol withdrawal behaviour.

The purpose of the present experiment was to study the "kindling" hypothesis of alcohol withdrawal stating that exposure to repeated episodes of alcohol withdrawal results in an increased severity of subsequent withdrawal reactions. Two groups of male Wistar rats were subjected to 13 episodes of 2 days severe alcohol intoxication and 5 days alcohol withdrawal. Animals in the control group (n = 80) developed clinical withdrawal signs following each intoxication episode. In the diazepam group (n = 80) the withdrawal reactions during episodes 1-9 were blocked by intraperitoneal diazepam administration (0-30 mg/kg) 8, 11 and 15 h into withdrawal. During episode 10-13 diazepam treatment was terminated and convulsive withdrawal behaviour was observed 9-15 h after last alcohol dose. The probability of seizure activity during these four withdrawal episodes was calculated as 0.239 and 0.066 in the control and the diazepam groups, respectively. Based on Monte Carlo simulation techniques, this difference was found to be statistically significant (P < 0.05). No differences in the non-convulsive alcohol withdrawal symptoms tremor, hyperactivity and rigidity were detected between controls and diazepam animals after diazepam treatment. It was concluded that the increased convulsive behaviour in the control group was caused by cumulated kindling-like cerebral alterations during the previous repeated alcohol withdrawal phases.

Serotonin1A receptor autoradiography during alcohol-withdrawal kindling.

A series of autoradiography experiments were conducted in order to test the theory that the serotonin (5-HT) receptor subtype 5-HT(1a) is involved in alcohol-withdrawal kindled convulsive behaviour. Alcohol-withdrawal kindling was performed by subjecting male Wistar rats to multiple episodes consisting of 2 days of alcohol intoxication and 5 days of alcohol withdrawal. In the first episode alcohol intoxication led to focal downregulation of [3H]-8-hydroxy-2-(di-n-propylamino)tetralin ([3H]-8-OH-DPAT) binding sites in septum and subregions of frontal cortex, hippocampus, and entorhinal cortex. This alcohol-induced response was blunted in both alcohol-withdrawal kindled animals and in animals exposed to repeated alcohol dependence in which the previous withdrawal reactions were blocked by diazepam administration. A paradoxical upregulation of [3H]-8-OH-DPAT binding sites was found in septum and subregions of frontal cortex, hippocampus, and entorhinal cortex in control animals which were fed isocalorically with the alcohol-withdrawal kindled animals and subsequently exposed to 2 days of alcohol intoxication. It was concluded that the alterations in the alcohol induced 5-HT(1a) receptor regulation after multiple episodes of alcohol dependence were not caused by alcohol-withdrawal kindling processes per se, but were due to both alcohol specific and alcohol non-specific effects.

Glutamate and benzodiazepine receptor autoradiography in rat brain after repetition of alcohol dependence.

During repeated alcohol withdrawal, convulsive withdrawal behavior has been shown to be increased in a kindling-like manner in both clinical and experimental studies. In the present experiment, quantitative autoradiography was used to investigate binding of tritiated ligands to glutamate receptor subtypes and the benzodiazepine/GABA (BZ/GABA) receptor complex in rats exposed to 14 episodes of alcohol withdrawal. Seizures were detected in 25% of the animals during withdrawal episode 10-13. Repeated alcohol withdrawal resulted in a decrease in the number of [3H]-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ([3H]-AMPA) binding sites in striatum and sub-regions of the entorhinal cortex, the cerebellum and the hippocampus, while the [3H]-flunitrazepam binding was down-regulated in the frontal cortex. There was no differences between the controls and the multiple withdrawal animals regarding the [3H]-dizocilpine ([3H]-MK801) binding and the [3H]-kainic acid binding. However, within the latter group, those animals in which withdrawal seizures were observed had increased [3H]-MK801 binding sites in focal regions of entorhinal cortex and hippocampus, compared to those in which seizures were not observed. The decreased AMPA binding suggested impaired glutamate neurotransmission. As such, this receptor probably did not contribute to alcohol withdrawal kindling, but rather was involved in seizure protective mechanisms during this process.

Brain marker protein changes after short- and long-term ethanol intoxication and withdrawal in the rat.

The brain marker proteins, D1, D2, and D3, localised to neuronal membranes, and mitochondrial and cytoplasmic marker proteins (MM and CM), were studied during 1-6 days (short term) intragastrically-induced severe ethanol intoxication and during 1 month (long-term) ethanol intoxication established by a liquid diet regimen. The concentrations of the same brain proteins were also measured during withdrawal from the ethanol intoxication periods. Three categories of effect were encountered: decreased concentration of brain marker proteins during severe short-term intoxication the effect being most marked for D3, possibly indicating degradation of mature synapses; increased concentration of proteins D2 and MM during withdrawal, the D2 changes possibly indicating formation of new synapses; increased concentration of D1 protein and MM during long-term intoxication. We suggest that the changes in brain marker proteins reflect dynamic changes of subcellular neuronal structures which may form a part of the basis of functional tolerance to and physical dependence upon ethanol or the reversion of these states after withdrawal of ethanol.

Local cerebral glucose consumption during ethanol withdrawal in the rat: effects of single and multiple episodes and previous convulsive seizures.

Local cerebral glucose consumption (l-CMRgl) was studied using [14C]2-deoxyglucose autoradiography in minimally restrained rats during acute (12 or 18 h postwithdrawal (p.w.] and late (14 days p.w.) ethanol withdrawal, as well after 10 previous, weekly withdrawal episodes as after a similar period of isocalorical feeding. A period of two days of intoxication was established by gastric intubation. Spontaneous incomplete convulsive seizures were observed during the 8th to 10th withdrawal episode. Audiogenic seizures occurred following stimulation during the 6th and 10th withdrawal episode. Animals with previous spontaneous or audiogenic seizure were distributed randomly and evenly among the groups. l-CMRgl values were adjusted to a temperature of 38 degrees C. During acute withdrawal, l-CMRgl was significantly reduced by 18-32% in cortical and most limbic regions, but unchanged in cerebellum and subcortical structures as compared with the neutral state (late withdrawal and control groups). l-CMRgl was relatively more lowered in the amygdala in animals with previous spontaneous withdrawal seizures and in structures belonging to the auditory system in animals with previous audiogenic seizures. l-CMRgl did not differ among neutral groups. The lowered l-CMRgl in cortical and limbic regions during withdrawal contrasts to the results of previous studies. This difference may be attributed to the minimal restraint of animals in this study. The pattern of l-CMRgl in acute and late withdrawal animals with previous spontaneous withdrawal seizures is consistent with a mechanism comparable to electrical amygdala kindling contributing to seizure genesis.

Convulsive and non-convulsive ethanol withdrawal behaviour in rats with lesions of the noradrenergic locus coeruleus system.

The ascending noradrenergic pathways from the locus coeruleus were lesioned bilaterally in 10 rats by intracerebral 6-hydroxydopamine injections. Ten rats were sham-operated. All animals were subjected to a 4-day ethanol intoxication period using intragastric intubation. Intoxication and withdrawal assessments were performed blindly. The 6-hydroxydopamine lesions did not appear to affect tolerance to ethanol. During withdrawal, however, lesioned animals showed minor, but statistically significant changes in scores of certain non-convulsive withdrawal signs, but incidence and intensity of spontaneous and audiogenic convulsive seizures were not different between the groups.

Electrical sensitization of the meso-limbic dopaminergic system in rats: a pathogenetic model for schizophrenia.

To study whether it was possible to modify mesolimbic dopaminergic activity by intermittent electrical stimulations (IES), 44 rats were either electrically stimulated or sham-stimulated in the ventral tegmental area (VTA) once daily for 70 days. This was done through chronically implanted intracranial electrodes. The intensity of electrical stimulation was determined by the lowest current that elicited a definite motor response. Stimulated rats demonstrated a significantly potentiated behavioral response after 70 stimulations. Seven months after IES rats still demonstrated an increased sensitivity to electrical stimulations in the VTA. A new stimulation period only resulted in a modest additional fall in threshold values. There was a highly significant difference between the current needed to provoke a given response in sensitized rats and in sham-stimulated rats. The behavioral response to stimulation was suppressed both by the dopamine (DA) D2 receptor antagonists haloperidol and raclopride and by the DA D1 receptor antagonist SCH 23390. Furthermore, stimulated rats showed an enhanced response to stimulation with amphetamine and to a lesser extent with apomorphine. Between stimulation periods sensitized animals demonstrated a reduced social interaction. In conclusion intermittent electrical stimulations of the VTA resulted in a syndrome characterized by a hypersensitive response to electrical and pharmacological DA provocation combined with abnormal social interaction. This animal model has points of resemblance with recent interpretations of the DA hypothesis for schizophrenia.

Cerebral blood flow and oxygen consumption during ethanol withdrawal in the rat.

The ethanol withdrawal syndrome in man and animals is characterized by signs of CNS hyperactivity although a direct measurement of a physiological variable reflecting this CNS hyperactivity has never been performed in untreated man or in animals. We induced ethanol dependence in the rat by means of intragastric intubation with a 20% w/v ethanol solution, thus keeping the animals in a state of continuous severe intoxication for 3--4 days; during the subsequent state of withdrawal characterized by tremor, rigidity, stereotyped movements and general seizures a 25% increase in cerebral oxygen consumption (CMRO2) could be measured; this increase was not due to catecholamines originating from adrenal medulla as adrenomedullectomized animals showed a similar increase in CMRO2 (28%); the withdrawing animals showed a corresponding cerebral blood flow (CBF) increase. The elevated CMRO2 and CBF could be reduced to normal by administration of a beta-adrenergic receptor blocker (propranolol 2 mg/kg i.v.), and hence the increased CMRO2 during ethanol withdrawal could be related to catecholaminergic systems in the brain, e.g. the noradrenergic locus coeruleus system which is anatomically well suited as a general activating system. This interpretation is supported by the earlier neurochemical finding of an increased cerebral noradrenaline turnover during ethanol withdrawal. The exact mechanism underlying the increased cerebral oxygen consumption during ethanol withdrawal and the effect of propranolol on cerebral function during this condition remains to be clarified.

Intermittent neuroleptic treatment induces long-lasting abnormal mouthing in the rat.

Rats were treated either discontinuously or continuously with haloperidol. Only discontinuous treatment caused a long-lasting abnormal rise in the number of mouth movements. After termination of medication the animals were kindled electrically in the nucleus amygdala. The results suggest cross-sensitivity between discontinuous neuroleptic treatment and amygdala kindling. Our results are consistent with the hypothesis of a kindling-like sensitization to the dyskinetic-inducing side-effects of neuroleptic drugs following intermittent antidopaminergic treatment.

Effects of chronic discontinuous and continuous treatment of rats with a dopamine D1 receptor antagonist (NNC-756).

Rats were treated intermittently or continuously with the dopamine D1 receptor antagonist NNC-756 for 15 weeks. Two weeks after withdrawal they were challenged with the dopamine D1 receptor agonist SK&F 38393, either alone or after pretreatment with NNC-756. Neither treatment regimen resulted in irreversible increases in oral activities when treated rats were compared with controls; however, transient elevations were observed in the beginning of treatment in the continuously treated group and in the withdrawal phase in the discontinuously treated group. Furthermore, discontinuous treatment resulted in within-group elevations in vacuous chewing movements and tongue protrusions after withdrawal. Dopamine D1 receptor supersensitivity was not observed after challenge with the dopamine D1 receptor agonist. NNC-756 efficiently blocked the behavioural response to stimulation with SK&F 38393. Both treatment regimens resulted in the development of rigidity and catalepsy. The present study suggests that treatment with selective dopamine D1 receptor antagonists is less likely to cause irreversible oral dyskinesia than is treatment with classical neuroleptic drugs.

Intermittent versus continuous neuroleptic treatment in a rat model.

The treatment schedule for neuroleptic therapy is of relevance when evaluating the development of side-effects. Seventy-five rats were treated discontinuously or continuously with the predominantly dopamine D2 receptor blocker haloperidol or the combined dopamine D1/D2 receptor blocker zuclopenthixol for 15 weeks. During and after treatment, a broad spectrum of behavioural parameters including vacuous chewing movements and tongue protrusions were observed. Discontinuous neuroleptic treatment as opposed to continuous neuroleptic treatment produced a significant long-lasting increase in oral activity. The changes were most pronounced in haloperidol-treated rats. The differences observed may have methodological implications for animal models of neuroleptic-induced movement disorders. Our findings are consistent with the hypothesis that pharmacological sensitization to the dyskinetic side-effects of neuroleptics develops when the drug effect is allowed to wear off between repeated administrations.

Electrical kindling of rats treated discontinuously or continuously with haloperidol.

Intermittent as opposed to continuous treatment of rats with haloperidol resulted in a long-lasting potentiation of oral activity. To examine if this behavioural sensitization to discontinuous neuroleptic treatment facilitates seizure development in electrical kindling, rats treated either intermittently or continuously with haloperidol for 15 weeks were kindled in the nucleus amygdala. Development of kindled seizures was significantly faster in the intermittently treated group (P < 0.01) than in controls or continuously treated rats. Furthermore, discontinuously treated animals displayed electroencephalographic afterdischarges in the substantia nigra from the beginning of treatment. The findings of cross-sensitivity between electrical amygdala kindling and pharmacological sensitization and of early appearance of epileptiform nigral activity have implications for the pathogenesis of both conditions. We suggest that depressed gamma-aminobutyric acid activity in substantia nigra could be a common mechanism.