A. Wren

Olfactory projection systems, drugs and behaviour: a review.

Abstract (1) Bilateral olfactory bulbectomy (OB) produces a series of behavioural changes in the rat, characterised by hyperactivity and hyper-reactivity. It also produces an elevation of plasma 11-hydroxycorticosterone (11-OHCS). (2) Chronic treatment (10–14 days) of OB rats with anti-depressant drugs (amitriptyline, mianserin, viloxazine, nomifensine and iprindole) normalises the behavioural change and the 11-OHCS elevation. The mono-amine oxidase inhibitor, tranylcypromine, does not normalise these parameters. (3) Using two behavioural parameters (step-down avoidance testing and irritability), plus 11-OHCS measurements, it has proved possible to differentiate between anti-depressants, anti-anxiety agents, tranquilisers and central stimulants. OB therefore has potential as a screening method for differentiating between various classes of psychotropic drugs. (4) The quadracyclic anti-depressant, mianserin, proved negative in standard anti-depressant screening and a new derivative, GB-6582 proved positive in the OB model. GB-6582 is an efficient inhibitor of 5-hydroxytryptamine (5-HT) uptake. (5) The neurotoxin, 5–6 DHT, will mimic the behavioural and physiological effects of bulbectomy as will 5–7 DHT with prior treatment of the rat with desmethyl-imipramine, when these neurotoxins are injected directly into the olfactory bulb. The neurotoxin, 6-OHDA, injected into the bulb does not mimic the effects of OB. (6) GB-6582 when injected into the bulb prior to intra-bulbar 5–6 DHT, prevents the appearance of the behavioural and physiological effects of bulbectomy. (7) All the anti-depressants which normalise surgical bulbectomy, show the same effect with chemical bulbectomy induced by 5–6 DHT. (8) Following bulbectomy, neuroanatomical studies demonstrated degenerating fibres in: (a) the anterior hippocampus; (b) the corticomedial nucleii of the amygdala; (c) the bed nucleus of the stria terminalis and (d) the pre-optic area of the hypothalamus. (9) These brain areas are concerned with behavioural arousal, hypothalamic-adrenohypophyseal modulation and sexual behaviour. All these are adversely affected by bulbectomy. (10) The significance of these observations is discussed in terms of 5-HT-catecholamine interaction in the development of diseases of affect.

Olfactory bulb ablation in the rat: behavioural changes and their reversal by antidepressant drugs.

1 The effects of bilateral olfactory bulbectomy, sham‐operation and inducement of peripheral anosmia were studied on locomotor activity, passive avoidance acquisition and irritability.

Effects of olfactory bulbectomy and domicile on stress-induced corticosterone release in the rat.

Abstract Following bilateral olfactory bulbectomy or sham surgery, rats were housed either in groups of 5 or individually. After 10 days the animals were sacrificed and plasma corticosterone levels were measured. Half the animals in each group received predictable stress in the form of footshock immediately prior to exsanguination. Two levels of corticosterone elevation were noted, an intermediate level (circa 40 μg/100 ml plasma), in bulbectomised animals without stress and in sham operated animals with stress. Extreme corticosterone elevation (circa 80 μg/100 ml plasma) occurred in bulbectomised rats with stress. The type of housing had no effect on corticosterone elevation. The results are discussed in terms of a non olfactory function for the olfactory bulb, and the role of corticosterone and ACTH in acquisition learning.

A new model for the detection of antidepressant drugs: Olfactory bulbectomy in the rat compared with existing models

Abstract A new model for the detection of antidepressant drugs has been described and compared with two other tests. This new model depends on the ability of the antidepressant drugs to selectively modify some behavioral and biochemical changes which occur following bilateral ablation of the olfactory bulbs in rats. The bulbectomy syndrome has been characterized as a learning deficit on a step-down passive-avoidance test; hyper-reactivity; and as an increase in circulating 11-hydroxycorticosteroids (11-OHCS). The antidepressants, amitriptyline (10 mg kg ), mianserin (10 mg kg ), and viloxazine (10 mg kg ) administered i.p. daily for 7 days corrected the learning deficit, reduced the hyper-reactivity, and the elevated plasma (11-OHCS) in a reproducible manner. Thus this test indicates the potential antidepressant activity of mianserin, a drug which, although used in the clinic, was not detected by conventional screening tests. The present study not only confirms the apparent lack of activity of mianserin in two other tests (reserpine reversal and potentiation of noradrenaline) but also shows that, in the relatively low doses used in the bulbectomy model, the established antidepressants may also fail to give positive responses in these other tests.

The effect of psychoactive drugs on plasma corticosterone levels and behaviour in the bulbectomised rat

Abstract Bilateral olfactory bulbectomy (OB) in the rat produces a rise in circulating 11-hydroxycorticosterone (11-OHCS) to intermediate levels (40–50 μg/100 ml plasma). Following footshock extreme corticosterone elevation occurs (65–80 μg/100 ml plasma). Bulbectomy also produces behavioural changes which include hyper-reactivity and an acquisition deficit in a step-down passive avoidance test. Treatment of the bulbectomised rat with amitriptyline (5 and 10 mg/kg), mianserin (5 and 10 mg/kg) and viloxazine (2 and 5 mg/kg) administered IP for at least 7 days corrected the acquisition deficit, reduced the hyper-reactivity and the elevated corticosterone levels in a reproducible manner. This reduction in 11-OHCS concentrations occurred in bulbectomised rats with and without footshock. In contrast, the antidepressant drugs did not produce these changes in sham-operated controls (SO). The central stimulant, amphetamine (1 and 3 mg/kg/day for 7 days, IP), increased 11-OHCS concentrations in unstressed OB and SO rats. There was no further elevation in the 11-OHCS concentrations of stressed rats of both OB and SO groups. This drug further impaired the acquisition of both OB and SO rats and increased the reactivity scoring of both groups. The major tranquillizer, chlorpromazine (1 and 3 mg/kg IP for 7 days), reduced plasma 11-OHCS levels and the hyperreactivity of both OB and SO groups. It did not reduce the acquisition deficit exhibited by the OB rats. Chlordiazepoxide (5 and 15 mg/kg IP for 7 days), had a profile similar to that of chlorpromazine except that it impaired acquisition in the SO group. Thus using the techniques described above it is possible to separate the antidepressants from other major classes of psychotropic drugs.