Jaanus Harro

Chronic mild unpredictable stress after noradrenergic denervation: attenuation of behavioural and biochemical effects of DSP-4 treatment

Chronic mild unpredictable stress, which reduces rewarded behaviour in rats, is becoming increasingly popular as an animal model of depression. The effect of chronic mild stress (applied to animals housed five per cage for 15 days) on forced swimming and open field behaviour, and on beta-adrenoceptor binding was studied in naive rats and after the denervation of the locus coeruleus projections by DSP-4 (50 mg kg(-1)) treatment. In the forced swimming test, chronic mild stress reduced the immobility time on the second day of testing in both vehicle- and DSP-4-treated rats, indicating rather an antidepressant-like effect. This antidepressant-like effect of chronic mild stress in the forced swimming test was not present in individually housed rats which suggests that this paradigm is sensitive to housing conditions. Stress had no clear effect on the open field locomotion in naive animals (but caused a reduction in defecations), but completely blocked the DSP-4-induced decrease in the exploratory activity. As measured by 3H-dihydroalprenolol binding, DSP-4 treatment increased the beta-adrenoceptor affinity in the frontal cortex and the number of binding sites in the hippocampus and in the cerebral cortex (total-frontal cortex). Stress had no effect on the beta-adrenoceptor binding in the frontal cortex and cerebral cortex, but prevented the increase in affinity caused by DSP-4 treatment in the frontal cortex. In the hippocampus, chronic mild stress and DSP-4 treatment increased the number of beta-adrenoceptor binding sites. Neither chronic mild stress nor DSP-4 treatment had any effect on CCK(B) receptor binding in the cerebral cortex and striatum. These results show that chronic mild stress applied to group-housed rats can prevent the development of certain behavioural and biochemical changes caused by the denervation of the locus coeruleus projection areas.

Impaired exploratory behaviour after DSP-4 treatment in rats: implications for the increased anxiety after noradrenergic denervation

The effect of DSP-4, a neurotoxin selectively affecting the projections of the locus coeruleus, upon exploratory behaviour of rats was studied in a complex exploration test, including a choice between open and enclosed areas and both inquisitive and inspective exploration elements. One week after DSP-4 (50 mg/kg i.p.) administration, the neurotoxin-treated rats did not explore a novel open area to any extent on the first exposure to the apparatus; however, on the third day of testing, these animals began to explore the area and the novel objects. Diazepam (0.5 mg/kg) treatment did not change the behaviour of control rats, but significantly increased the exploratory activity of the DSP-4-treated animals. LY 288513, a selective CCKB receptor antagonist (0.01 mg/kg), prevented the increase in exploratory activity in the DSP-4-treated rats, but increased the exploratory activity of controls on the third exposure to the test situation. The results of this investigation suggest that DSP-4 treatment reduces neotic behaviour by increasing neophobia rather than by decreasing exploratory drive. The divergence reported between the relative potencies of CCKB receptor antagonists in exploratory activity and other anxiety tests may in part be due to the effects of these drugs on exploratory drive.

Anxiolytic-like effect of the GABA-transaminase inhibitor vigabatrin (gamma-vinyl GABA) on rat exploratory activity

Vigabatrin (gamma-vinyl GABA, GVG) is an irreversible inhibitor of GABA-transaminase (GABA-T). This study addressed the question of whether or not the inhibition of GABA-T has an anxiolytic effect in rats. Diazepam (1.5 mg/kg) and GVG (50 and 500 mg/kg) increased the tendency of rats to explore in the elevated plus-maze test, whereas the effect of general locomotor activity was diminished. The sedative effect of GVG (500 mg/kg) was more pronounced 6 h than 2 h after IP administration. The present findings suggest that even a partial inhibition of GABA-T results in a reduction of anxiety measures in a novel environment.

Alterations in brain cholecystokinin receptors in suicide victims

Cholecystokinin (CCK) and benzodiazepine receptor binding characteristics were analyzed in the brain tissue samples from 19 suicide victims and 23 control cases. In the frontal cortex, significantly higher apparent number of CCK receptors and affinity constants were found in the series of suicide victims. These differences between suicides and controls were present in similar proportions when the suicide cases with depressive syndrome or violent or non-violent means of self-killing were compared to matched controls. However, when the samples were split into subgroups consisting of persons either below or over the age of 60 years, significant differences in the CCK receptor characteristics in the frontal cortex were observed only between younger suicides and controls. Furthermore, the younger suicide victims had a higher density of CCK receptors in the cingulate cortex, whereas in older suicides the value was lower as compared to age-matched controls. No difference in benzodiazepine receptor binding was found between control and suicide groups. The results of this investigation suggest that CCK-ergic neurotransmission is linked to self-destructive behaviour, probably through its impact on anxiety and adaptational deficits.

Cholecystokinin in CSF from depressed patients: possible relations to severity of depression and suicidal behaviour

Levels of cholecystokinin (CCK) peptides were measured in the CSF from 105 patients suffering from major depressive disorders admitted to a research psychiatric ward for diagnostic evaluation, by a radioimmunoassay method using two different antibodies. Relations between CCK levels and parameters of depression, anxiety, and suicidal behaviour were investigated. Significant inverse correlations were found between CCK levels and certain depression and anxiety parameters. Patients who had made one or more suicide attempts tended to have higher CSF CCK levels than those who had not. No correlations were found between CSF CCK and 5-HIAA or HVA, or with plasma cortisol.

Lesioning of locus coeruleus projections by DSP-4 neurotoxin treatment : Effect on amphetamine-induced hyperlocomotion and dopamine D2 receptor binding in rats

DSP-4 is a neurotoxin highly selective for the noradrenergic nerve terminals of the locus coeruleus projections. Data on the effect of DSP-4 treatment on amphetamine-induced hyperlocomotion are contradictory. In this study, DSP-4 (50 mg/kg) caused reduction of noradrenaline levels by 70% in the cerebral cortex and by 79% in the cerebellum. This treatment resulted in upregulation of dopamine D2 receptors in the striatum as evidenced by [3H]-raclopride binding. In an open field test, DSP-4 reduced locomotor activity. D-Amphetamine (1.5 mg/kg) caused a similar increase in locomotor activity in control and DSP-4-pretreated animals not familiar to the apparatus. However, when the rats were habituated to the test apparatus, the effect of amphetamine on horizontal activity was significantly larger in the DSP-4-pretreated animals. These data suggest that supersensitivity of D2 receptors develops after locus coeruleus denervation, but that the enhanced efficacy of amphetamine in DSP-4-treated rats is masked by neophobia.

Cholecystokinin receptors and memory: A radial maze study

CCK receptor agonists and antagonists have repeatedly been demonstrated to improve and impair, respectively, learning and memory functions. However, all studies to date have exploited avoidance paradigms. In the present study, the effect of some CCK receptor agonists and antagonists on the ability to learn an appetitively motivated task and to influence spatial working memory was investigated. In the first experiment, drugs were given immediately after each training session in the radial maze and the animals were tested, drug-free, during a 2-week period. After the initial treatments with caerulein, an unselective CCK receptor agonist (100 ng/kg SC), the animals were slightly less successful to obtain food pellets during the sessions on the first 2 days; whereas proglumide, an unselective CCK receptor antagonist (1 mg/kg SC) was without any effect. However, on the following days, all the three groups of rats (saline, caerulein, and proglumide) performed in a similar way. In the second experiment, drugs were given before each test session to well-trained animals. Scopolamine (0.15 and 0.3 mg/kg IP), the reference amnestic drug, produced dose-dependent impairment of working memory in the radial maze test. Proglumide (1 and 10 mg/kg SC) and devazepide, (a selective CCK-A receptor antagonist; 0.01 and 1 mg/kg SC), as well as caerulein (0.01, 0.1 and 1 microgram/kg SC) and CCK-4 (a selective CCK-B receptor agonist; 25 and 50 micrograms/kg SC) had no reliable effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Neuropeptide Y attenuates the effect of locus coeruleus denervation by DSP-4 treatment on social behaviour in the rat.

Noradrenaline (NA) has been implicated in both increase and reduction of anxiety. Selective destruction of nerve endings of the locus coeruleus projections by DSP-4 has been shown to reduce active behaviour in novel situations by enhancing anxiety. In the present study, DSP-4 (50 mg/kg) treatment reduced locomotor activity and time spent in social interaction in rats placed into a novel environment together with an unfamiliar rat, indicating an anxiogenic-like effect. The effect of DSP-4 on time spent in social interaction was completely antagonized by intracerebroventricular administration of neuropeptide Y (NPY) (1 microg) which had no effect of its own on this measure. The present study thus supports the idea that DSP-4 pretreatment is anxiogenic in novel situations and suggests a functional relationship of NA- and NPY-using neural mechanisms in the regulation of social behaviour.

DEPRESSION AS A SPREADING NEURONAL ADJUSTMENT DISORDER

The outlines of a theory of the pathophysiology of depression are presented. The classic monoamine theory of depression as well as its more recent elaborations suggests that a deficit in monoamine neurotransmitters in the synaptic cleft is the primary cause of depression. We suggest that the primary defect emerges in the regulation of firing rates in brainstem monoaminergic neurons, which brings about a decrease in the tonic release of neurotransmitters in their projection areas, an increase in postsynaptic sensitivity and, concomitantly, exaggerated responses to acute increases in presynaptic firing rate and transmitter release. We propose that the initial defect involves, in particular, the noradrenergic innervation from the locus coeruleus, which in turn leads to dysregulation of 5-HT-ergic and dopaminergic neurotransmission.

Changes in cholecystokinin receptor binding in rat brain after selective damage of locus coeruleus projections by DSP-4 treatment

SummaryBrain cholecystokinin (CCK)- and noradrenergic activities are two neurochemical systems implicated in anxiety and deficits in novelty-related behaviour. In order to clarify a possible interaction between CCK- and noradrenergic neurotransmission in the brain, DSP-4 [N(2-chloroethyl)-N-ethyl-2-bromobenzylamine], a neurotoxin that selectively destroys noradrenaline-containing nerve terminals originating from the locus coeruleus, was administered to rats IP (10 and 50 mg/kg) seven days before decapitation. Noradrenaline uptake was very markedly reduced in the frontal cortex and hippocampus of the DSP-4 treated animals, whereas the decrease in the hypothalamus was smaller but still statistically significant. Dopamine uptake in the corpus striatum, as well as serotonin uptake in the frontal cortex, hippocampus and hypothalamus, were not influenced by DSP-4 treatment. Concomitantly, CCK receptor binding in certain brain regions was markedly affected. Thus, CCK receptor density was significantly higher in the frontal cortex and hippocampus of DSP-4-treated rats. If desipramine (25 mg/kg) was administered before DSP-4 treatment, the DSP-4-induced changes both in noradrenaline uptake and CCK receptor binding were not present, suggesting that both effects were exerted after uptake of the neurotoxin by the nerve terminals. The time-course of the development of changes in CCK-8 binding paralleled with some lag the development of changes in noradrenaline uptake. These findings demonstrate the denervation of noradrenergic input from the locus coeruleus induces certain alterations in the CCK-ergic neurotransmission. These alterations are similar to those seen in rats with deficits in response to novel stimuli, and may therefore mediate the neophobic responses observed in animals after lesions of noradrenergic innervation of the forebrain.