Brain serotonin 2A receptor binding: relations to body mass index, tobacco and alcohol use.

Manipulations of the serotonin levels in the brain can affect impulsive behavior and influence our reactivity to conditioned reinforcers. Eating, tobacco smoking, and alcohol consumption are reinforcers that are influenced by serotonergic neurotransmission; serotonergic hypofunction leads to increased food and alcohol intake, and conversely, stimulation of the serotonergic system induces weight reduction and decreased food/alcohol intake as well as tobacco smoking. To investigate whether body weight, alcohol intake and tobacco smoking were related to the regulation of the cerebral serotonin 2A receptor (5-HT(2A)) in humans, we tested in 136 healthy human subjects if body mass index (BMI), degree of alcohol consumption and tobacco smoking was associated to the cerebral in vivo 5-HT(2A) receptor binding as measured with (18)F-altanserin PET. The subjects' BMI's ranged from 18.4 to 42.8 (25.2+/-4.3) kg/m(2). Cerebral cortex 5-HT(2A) binding was significantly positively correlated to BMI, whereas no association between cortical 5-HT(2A) receptor binding and alcohol or tobacco use was detected. We suggest that our observation is driven by a lower central 5-HT level in overweight people, leading both to increased food intake and to a compensatory upregulation of cerebral 5-HT(2A) receptor density.

No association between the -399 C > T polymorphism of the neuropeptide Y gene and schizophrenia, unipolar depression or panic disorder in a Danish population.

OBJECTIVE: A polymorphism in the promoter region of the NPY gene at position -399 C > T was recently reported to be associated with schizophrenia in a Japanese population and with treatment refractory unipolar depression in a Swedish population. The objective of this study was to investigate potential associations between the polymorphism and three psychiatric disorders in a Danish population. METHOD: We investigated the occurrence of the polymorphism in patients with schizophrenia (n = 291), unipolar depression (n = 256) and panic disorder (n = 142) compared with controls (n = 716). RESULTS: We detected the polymorphism -399 C > T at a frequency of 48% in controls. No significant differences were found between genotype or allele frequencies in controls vs. the patient groups. CONCLUSION: The lack of association between the -399 C > T polymorphism and schizophrenia, unipolar depression or panic disorder, respectively, suggests that the polymorphism is not involved in the etiology of these disorders in the Danish population.

Irreversibility of kindled alcohol-withdrawal behaviour in rats.

In order to investigate whether alcohol-withdrawal kindling is an irreversible process, male Wistar rats were exposed to 12 episodes, each consisting of 2 days of severe alcohol intoxication and 5 days of alcohol withdrawal. Spontaneous withdrawal seizures were found in 15% of the animals during episodes 10-12. After an alcohol-free period of 26 days, the animals were subjected to three more episodes of alcohol dependence (i.e. episodes 13-15) in which 12% of the animals developed spontaneous withdrawal seizures. Based on several statistical tests, we concluded that there was no true difference between the seizure activity in episodes 10-12 and episodes 13-15, indicating that alcohol-withdrawal kindling is a long-lasting and perhaps irreversible process. In a second experiment, an alcohol-withdrawal kindled group was first exposed to seven episodes of alcohol dependence. A diazepam group went through the same alcohol regimen, but each withdrawal reaction was blocked by diazepam treatment. Finally, a single episode group was included which was fed isocalorically with the kindled animals. After an alcohol-free period of 11 days, all three groups were subjected to 4 days of severe alcohol intoxication. During the subsequent withdrawal reaction seizures were observed in 22-26% of the animals with no significant differences across the groups. These results call for a modification of the kindling hypothesis of alcohol withdrawal and suggest that kindling-induced alterations may be overlooked if convulsive behaviour is tested during a relatively strong withdrawal reaction.

Electrical amygdala kindling in alcohol-withdrawal kindled rats.

Repeated alcohol withdrawal has been shown to kindle seizure activity. The purpose of the present investigation was to study electrical amygdala kindling in rats previously exposed to alcohol-withdrawal kindling. In three independent experiments, male Wistar rats were subjected to multiple episodes each consisting of 2 days of severe alcohol intoxication and 5 days of alcohol withdrawal. In the first experiment, the alcohol-withdrawal kindled animals were divided into two groups depending on whether spontaneous alcohol-withdrawal seizures were observed in episodes 10-13. In the second and third experiments, the alcohol-withdrawal kindled animals were compared to a group in which alcohol-withdrawal kindling was prevented by diazepam treatment during the withdrawal reactions in order to discriminate between the effect of withdrawal and intoxication. Electrical kindling was initiated 28-35 days after the last alcohol dose by exposing the animals to daily electrical stimulations of the right amygdala. The results showed that amygdala kindling was facilitated in alcohol-withdrawal kindled animals which showed spontaneous withdrawal seizure activity, compared with animals exposed to multiple episodes of alcohol withdrawal which did not develop withdrawal seizures or with animals exposed to a single episode of alcohol intoxication. When compared to the control group, the alcohol-withdrawal kindled group with seizures also kindled at a faster rate, but the difference did not reach statistical significance and therefore the results must be regarded as preliminary at present.

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.

No loss of somatostatin-immunoreactive neurons in the hippocampal dentate hilus of alcohol-withdrawal-kindled rats.

The neuropeptide somatostatin has been suggested to play a role in seizure genesis, electrical kindling and the neurotoxic effects of alcohol. The purpose of the present experiment was to study somatostatin-immunoreactive (SS-IR) neurons in hippocampus during alcohol-withdrawal kindling. Alcohol-withdrawal kindling was performed by subjecting male Wistar rats to seven weekly episodes consisting of 2 days of severe alcohol intoxication and 5 days of alcohol withdrawal. Then the kindled animals (multiple withdrawal group) and a single withdrawal group, which was fed isocalorically with the kindled animals during episodes 1-7, were exposed to 4 days of severe alcohol intoxication (episode 8). During the following withdrawal, the seizure activity was observed 9-15 h after last alcohol dose, in order to subdivide the animals from these two groups into groups with and without seizures. Subsequently, SS-IR neurons were visualized immunocytochemically and counted in the hilus of the dentate gyrus (hippocampus). The number of SS-IR neurons per unit area of the hilus was neither affected by a single nor by multiple episodes of alcohol withdrawal. We therefore concluded that a loss of these neurons is not involved in the development of alcohol-withdrawal-kindled seizures.