Roger W. Horton

Brain 5-HT2 receptor binding sites in depressed suicide victims

5-HT2 receptor binding sites were measured (by saturation binding of [3H]ketanserin) in brain tissue obtained at postmortem from 19 suicide victims with definite evidence of depression and 19 sex and age-matched control subjects. Five of the suicide victims were receiving antidepressant drugs prior to death; 13 suicide victims had not been prescribed antidepressant or other psychoactive drugs recently and none were found in their blood at postmortem. The number of serotonin-2 (5-HT2) binding sites in frontal, temporal and occipital cortex and amygdala did not differ significantly between the depressed suicide victims and controls, either in the total suicide group or in the antidepressant drug-free suicides. The number of 5-HT2 binding sites in the hippocampus did not differ from controls in the total suicide group but was significantly lower (by 23%) in the antidepressant-free suicide group. The affinity of [3H]ketanserin binding did not differ from controls in the antidepressant-free suicides but was lower (increased Kd) in those subjects receiving antidepressant drugs. No correlation was found between the time of death and storage of tissue or the duration of tissue storage prior to assay and the number or affinity of 5-HT2 binding sites. A significant negative correlation was found between age of the subject and the number of 5-HT2 binding sites in the frontal and occipital cortex. The present study of suicide victims with definite evidence of depression do not confirm previous studies of increased numbers of 5-HT2 binding sites in suicide victims and suggest that these previous findings may be related to factors other than depression.

Brain 5-HT1 binding sites in depressed suicides

Abstract5-HT1 and 5-HT1A binding sites were measured in brain tissue obtained at postmortem from 19 suicides, with definite evidence of depression, and 19 sex and age-matched controls. Thirteen of the depressed suicides had not been prescribed psychoactive drugs recently (drug-free suicides); six had been receiving antidepressant drugs, alone or in combination with other drugs (antidepressant-treated suicides). No significant differences were found in the number or affinity of 5-HT1 and 5-HT1A binding sites in frontal or temporal cortex between drug-free suicides and controls. The number of 5-HT1 sites was significantly lower (by 20%), affinity unaltered, in hippocampus and the affinity significantly lower (by 33%), number unaltered, in amygdala of drug-free suicides than controls. The number of 5-HT1 binding sites tended to be higher and the affinity lower in the antidepressant-treated compared to drug-free suicides, and significantly so in hippocampus. The present results, together with our previous studies, provide no evidence of altered cortical 5-HT markers in depressed suicides, but further emphasise abnormalities in the hippocampus.

Monoamine and GABA metabolism and the anticonvulsant action of DI-n-propylacetate and ethanolamine-O-sulphate

The time course of changes in behaviour, seizure response and cerebral monoamine and gamma-aminobutyric acid (GABA) metabolism has been studied in relation to the anticonvulsant actions of di-n-propylacetic acid (DPA) and ethanolamine-O-sulphate (EOS) on sound-induced seizures in DBA/2 mice. Changes in cerebral monoamine metabolism after EOS (75 or 150 mug, intracerebroventricularly) were not related to its anticonvulsant action. The primary effect was GABA-transaminase inhibition (by 50-70%) leading to a 2-4 fold increase in cerebral GABA concentration. Increases in brain GABA concentration (maximally 36%), 5-hydroxyindoleacetic acid (5HIAA, maximally 134%) and homovanillic acid (HVA, maximally 183%) were seen after DPA (400-600 mg/kg, i.p.). The time course of the increases in HVA and 5HIAA did not correlate with the anticonvulsant effect. Elimination of these increases by the use of inhibitors of monoamine synthesis (alpha-methyl-p-tyrosine and p-chlorophenyl-alanine) did not alter the anticonvulsant effect of DPA. Experiments using probenecid suggested that the increases in 5HIAA and HVA after DPA result from inhibition of their active transport out of the brain.

Brain alpha-adrenoceptors in depressed suicides.

alpha1-Adrenoceptors and alpha2-adrenoceptors were measured by radioligand binding to homogenates of brain samples obtained at post-mortem from suicides with a retrospective diagnosis of depression, and age and gender-matched controls. Suicides were subdivided into those who had been free of antidepressant drugs for at least three months, and those in whom prescription of antidepressant drugs was clearly documented. The number of alpha1-adrenoceptors (or alpha1A + alpha1D-adrenoceptors) did not differ significantly between antidepressant-free or antidepressant-treated suicides and controls. In antidepressant-free suicides, the number of alpha2-adrenoceptors was significantly higher in temporal cortex (Ba 21/22). alpha2A-Adrenoceptors did not differ significantly from controls in this brain region, suggesting the involvement of other alpha2-adrenoceptor subtypes. In antidepressant-treated suicides, significantly lower numbers of alpha2-adrenoceptors were found in occipital cortex and hippocampus (and for alpha2A-adrenoceptors in caudate and amygdala) compared to controls.

5-HT1A receptor binding sites in post-mortem brain samples from depressed suicides and controls.

5-HT1A receptor binding sites were measured, by saturation binding with [3H]8-OH-DPAT, in frontal and occipital cortex, hippocampus and amygdala obtained at post-mortem examination from suicide victims with a firm retrospective diagnosis of depression, and matched controls. The number of 5-HT1A binding sites did not differ significantly between suicides and controls, either in the total sample or when the suicides were divided on the basis of violence of death or recent antidepressant treatment.

Brain 5-HT2 receptors in suicide victims: violence of death, depression and effects of antidepressant treatment

5-HT2 binding sites were quantitated, by saturation binding with [3H]ketanserin, in six brain regions from 73 subjects who died by suicide and 70 sudden death controls. There were no significant differences in the number of 5-HT2 binding sites between suicides and controls in any brain region within the total suicide group or when suicides were divided on the basis of violence of death. Similar results were found when suicides were divided into those with a firm retrospective diagnosis of depression, whether they had been receiving antidepressants or not, and those who were heterogeneous in respect of psychiatric diagnosis and drug treatment. The present findings contrast with previous reports of higher cortical 5-HT2 binding sites in suicides; possible reasons for these differences are discussed.

Brain β-adrenoceptor binding sites in antidepressant-free depressed suicide victims

beta-Adrenoceptor binding sites were quantitated by saturation binding of [3H]CGP 12177 in 9 brain regions from 21 suicide victims, with a firm retrospective diagnosis of depression, who had not recently received antidepressant drugs, and 20 age- and sex-matched controls. In depressed suicides the number of total beta-adrenoceptors was significantly lower in temporal cortex (Brodmann area 38, by 19%) and beta 1-adrenoceptors (Brodmann area 21/22, by 17%) compared to controls. Suicides who died by violent means had significantly lower numbers of total beta- and beta 1-adrenoceptors in frontal cortex than matched controls (by 23 and 25%, respectively) and than non-violent suicides (by 20 and 22%, respectively) and lower numbers of beta 1-adrenoceptors in temporal cortex (Brodmann area 21/22) than matched controls (by 16%). Depressed suicides who died by non-violent means had lower numbers of total beta-adrenoceptors in occipital cortex than matched controls (by 24%) and than violent suicides (by 18%), and lower numbers of total beta- and beta 1-adrenoceptors in temporal cortex (Brodmann area 38) than matched controls (by 27 and 24%, respectively). Depression in suicide victims is associated with deficits in beta-adrenoceptor binding sites, largely restricted to cortical areas.

Brain GABAA/benzodiazepine binding sites and glutamic acid decarboxylase activity in depressed suicide victims

We have investigated the involvement of gamma-aminobutyric acid (GABA) in depression by quantitating benzodiazepine (BZ) binding sites, the ability of GABA to stimulate BZ binding and glutamic acid decarboxylase activity in frontal and temporal cortex obtained at postmortem examination from 21 suicide victims and 21 age- and sex-matched controls. We limited our study to suicide victims with clear evidence of depression, in the absence of symptoms of other psychiatric disorders. Thirteen of the depressed suicide victims had not been prescribed psychoactive drugs recently and none were found in their blood at postmortem; of the remaining 8 suicides, 6 were receiving antidepressant drugs, alone or in combination with other drugs. The number of BZ binding sites was significantly greater (by 18%) in the frontal cortex of the total group of depressed suicides compared to controls, but did not differ in the temporal cortex. The increase in the number of BZ binding sites in the frontal cortex was of similar magnitude when drug-free (16%), drug-treated (21%) and antidepressant-treated suicides (16%) were compared to matched controls, although the increase was only statistically significant for the drug-treated suicides. The Kd of BZ binding and the ability of GABA to stimulate BZ binding did not differ significantly between controls and the total, drug-free, drug-treated or antidepressant-treated suicides in either cortical area. Glutamic acid decarboxylase activity did not differ significantly between control and suicide groups, but was markedly reduced in subjects dying by carbon monoxide poisoning. The present study provides evidence for a greater number of BZ binding sites in the frontal cortex of depressed suicide victims, which could not clearly be attributed to drug treatment.

Brain 5-HT uptake sites, labelled with 3H.paroxetine, in antidepressant-free depressed suicides

Brain serotonin (5-HT) uptake sites were quantitated, by saturation binding of [3H]paroxetine, in 10 brain regions from 22 suicide victims and 20 control subjects. Suicide victims were restricted to those subjects in whom a firm retrospective diagnosis of depression was established and who had not recently been prescribed antidepressant drugs. The Kd and Bmax of [3H]paroxetine did not differ significantly between controls and depressed suicides in any of the brain regions. In putamen, Bmax values of suicides who died non-violently were lower than controls, whereas those who died by violent methods did not differ from controls. No significant differences between violent or non-violent suicides and their matched controls were found in other brain areas. These results offer little support for the view that suicide/depression is associated with an abnormality in 5-HT uptake.

Convulsant and anticonvulsant actions in DBA/2 mice of compounds blocking the reuptake of GABA

Compounds blocking the uptake of GABA into neurons or glia have been injected intracerebroventricularly (icv) or intraperitoneally (ip) in DBA/2 mice, age 21-28 days. Protection against audiogenic seizures was seen 30 min after the icv injection of (+)-2,4-diaminobutyric acid (0.5-2.0 mumoles), (+/-)-nipecotic acid (1.6-3.2 mumoles), (+)-ethyl nipecotate (0.4-0.8 mumoles), (-)-piperazic acid (4 mumoles) and putrescine (2 mumoles) or the ip injection of (+)-2,4-diaminobutyric acid (4-8 mmoles/kg and (+)-ethyl nipecotate (0.24-0.32 mmoles/kg). Of these ethyl nipecotate and nipecotic acid were the most effective anticonvulsants icv, but nipecotic acid was ineffective ip. Limb myoclonus and other epileptic manifestations (rearing, wild running, tonic clonic seizures) occurred in the absence of auditory stimulation after (+)-2,4-diaminobutyric acid (0.5-2.0 mumoles), (+/-)-cis-3-aminocyclohexane carboxylic acid (3.2-6.4 mumoles) and putrescine (2 mumoles). beta-Alanine (2-4 mumoles, icv) depressed respiration but did not protect against audiogenic seizures or induce myoclonus.