Acute and chronic effects of desipramine and clorgyline on alpha(2)-adrenoceptors regulating noradrenergic transmission in the rat brain: a dual-probe microdialysis study.

1. The effects of desipramine (3 mg kg(-1) i.p.) and clorgyline (1 mg kg(-1) i.p.) on extracellular noradrenaline (NA) in the locus coeruleus (LC) and cingulate cortex were assessed in freely-moving rats by dual-probe microdialysis. Functional activities of alpha(2)-adrenoceptors regulating NA release in the LC and cingulate cortex were determined by systemic (0.3 mg kg(-1) i.p.) or local (0.1 - 100 microM) clonidine administration. 2. Extracellular NA was increased in the LC and cingulate cortex following acute desipramine but not clorgyline treatment. Systemic clonidine decreased NA similarly in desipramine-, clorgyline-, and saline-treated animals, in both brain areas. 3. Long-term (twice daily, 14 days) but not short-term (twice daily, 7 days) desipramine, and long-term clorgyline (once daily, 21 days) treatments increased NA (3 fold) in cingulate cortex but not in the LC. Following long-term treatments, responses of NA to systemic clonidine were attenuated in the LC and cingulate cortex. 4. Clonidine perfusion by reverse dialysis into the cingulate cortex decreased local NA (-55 +/- 9%). The effect was attenuated by long-term desipramine (-31 +/- 9%) and clorgyline (-10 +/- 2%) treatments. 5. Clonidine perfusion by reverse dialysis into the LC decreased NA in the LC (-89 +/- 2%) and in cingulate cortex (-52 +/- 12%). This effect was attenuated in the LC following long-term desipramine (-72 +/- 4%) and clorgyline (-62 +/- 12%) treatments but it was not modified in the cingulate cortex (-57 +/- 10% and -68 +/- 6%, respectively). 6. These findings demonstrate that chronic desipramine or clorgyline treatments increase NA in noradrenergic terminal areas and desensitize alpha(2)-adrenoceptors modulating local NA release at somatodendritic and terminal levels. However, somatodendritic alpha(2)-adrenoceptors that control LC firing activity are not desensitized.

Effects of central noradrenaline depletion by the selective neurotoxin DSP-4 on the behaviour of the isolated rat in the elevated plus maze and water maze.

RATIONALE: Social isolation of the rat from weaning influences behaviour following central noradrenaline (NA) depletion by the selective neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4). OBJECTIVES: The study characterised the effects of DSP-4 on the behaviour of isolates in the elevated plus maze and water maze. METHODS: Male Lister hooded rats were reared singly or in groups after weaning. Two weeks postweaning, the rats were injected with DSP-4 (25 mg/kg, i.p.) or saline. From week 4, rats were tested in the plus maze and in the water maze. RESULTS: DSP-4 significantly reduced cortical and hippocampal NA but had no effect on hypothalamic NA. Isolation rearing alone had no significant effects on behaviour in the elevated plus maze but enhanced retention of platform placement in the water maze as measured by increased entries to the platform annulus during the probe test. DSP-4 in group-reared rats increased activity in the open arms and increased general activity in the elevated plus maze with no effect on water maze performance. DSP-4-treated isolates spent less time in the open arms and were hypoactive in the plus maze compared to group-reared DSP-4-treated rats, and had impaired retention of spatial memory in the water maze compared to isolate controls. CONCLUSIONS: DSP-4 treatment had an 'anxiolytic' effect in group-reared rats in the elevated plus maze. In the water maze, isolation rearing enhanced retention of spatial information, an effect normalised by NA depletion. The results demonstrate the importance of noradrenergic function in the regulation of responsiveness to environmental cues.

Effects of noradrenaline depletion in the brain on response on novelty in isolation-reared rats.

RATIONALE: Social isolation from weaning in the rat produces a variety of neurochemical and behavioural effects in the adult that in part parallel changes seen in human schizophrenia. OBJECTIVES: The study investigated the effects of central noradrenaline (NA) depletion by the selective neurotoxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), on the behaviour of isolation-reared rats. METHODS: Male Lister hooded rats were reared singly or in groups after weaning. During week 2, the rats were tested in photocell activity cages and were then injected with DSP-4 (25 mg/kg, IP). During week 4, rats were tested in the open field under the following conditions: open field alone, with two novel stimuli (T1), and with a familiar and a novel object (T2), and in the activity cages. RESULTS: DSP-4 significantly reduced cortical and hippocampal NA levels with no effect on the hypothalamus. Isolation-reared rats exhibited locomotor hyperactivity and reduced habituation to the testing arena, although their exploration of the novel objects in T1 was not significantly different from group-reared rats. DSP-4 treatment in group-reared rats increased inner zone activity in the open field but did not significantly affect the exploration of novel objects. DSP-4 treatment in isolates reduced exploration of objects at T2 while increasing exploration of the general environment. CONCLUSIONS: Isolation rearing influences the behavioural effects of central NA depletion. The results suggest isolation-induced changes in the central noradrenergic system in the isolated rat, supporting the view that early environmental factors can have long-term effects on central noradrenergic function as well as other neurotransmitter systems.

Inhibition of 5-hydroxytryptamine reuptake by the antidepressant citalopram in the locus coeruleus modulates the rat brain noradrenergic transmission in vivo.

The in vivo effect of the serotonin (5-HT) reuptake inhibitor antidepressant citalopram, administered in the locus coeruleus (LC), on noradrenergic transmission was evaluated in the rat brain. In dual-probe microdialysis assays, citalopram (0.1-100 microM), in a concentration-dependent manner, increased extracellular noradrenaline (NA) in the LC and simultaneously decreased extracellular NA in the cingulate cortex (Cg). These effects of citalopram were abolished by pretreatment with the 5-HT synthesis inhibitor p-chlorophenylalanine (400 mg/kg, i.p.). When the alpha(2)-adrenoceptor antagonist RS79948 (1 microM) was perfused in the LC, local citalopram increased NA dialysate in the LC but no longer modified NA dialysate in the Cg. In electrophysiological experiments, the administration of citalopram (100 microM) in the LC by reversal dialysis, decreased the firing rate of LC neurones. The results demonstrate in vivo that local administration of citalopram in the LC leads to a decreased release of NA in the Cg. This modulation seems to be the result of an increase in NA concentration in the LC and the subsequent inhibition of LC neurones via alpha(2)-adrenoceptors. The effects of citalopram are dependent on the presence of endogenous 5-HT in the LC.

Determination of the somatodendritic alpha2-adrenoceptor subtype located in rat locus coeruleus that modulates cortical noradrenaline release in vivo.

The regulation of extracellular noradrenaline levels in the cingulate cortex by somatodendritic alpha2-adrenoceptors located in the locus coeruleus was evaluated in the rat by using dual-probe microdialysis. The concentration of noradrenaline in the cingulate cortex was decreased (37%-40%) by administration into the locus coeruleus (1microM) of the agonists clonidine and UK14304 (bromoxidine), whereas it was increased by similar administration of the nonselective antagonist RX821002 (2-methoxyidazoxan) (+ 103%) and the selective alpha2A-adrenoceptor antagonist BRL44408 (2-[2H-(1-methyl-1,3-dihydroisoindole)methyl]-4,5-dihydroimidaz ole) (+ 148%). The selective alpha2B/C-adrenoceptor antagonist ARC239 (2-[2[4-(o-methoxyphenyl)piperazin-1-yl]ethyl]-4,4-dimethyl-1,3-(2 H,4H)-isoquinolimedione) did not induce changes. In the presence of BRL44408, the effects of clonidine and UK14304 were abolished, but they were not modified in the presence of ARC239. The data demonstrate that noradrenaline release in terminal areas is tonically modulated by somatodendritic alpha2A-adrenoceptors.

Somatodendritic alpha2-adrenoceptors in the locus coeruleus are involved in the in vivo modulation of cortical noradrenaline release by the antidepressant desipramine.

The effect of the antidepressant and selective noradrenaline reuptake blocker desipramine (DMI) on noradrenergic transmission was evaluated in vivo by dual-probe microdialysis. DMI (1, 3, and 10 mg/kg, i.p.) dose-dependently increased extracellular levels of noradrenaline (NA) in the locus coeruleus (LC) area. In the cingulate cortex (Cg), DMI (3 and 10 mg/kg, i.p.) also increased NA dialysate, but at the lowest dose (1 mg/kg, i.p.) it decreased NA levels. When the alpha2-adrenoceptor antagonist RX821002 (1 microM) was perfused in the LC, DMI (1 mg/kg, i.p.) no longer decreased but rather increased NA dialysate in the Cg. In electrophysiological experiments, DMI (1 mg/kg, i.p.) inhibited the firing activity of LC neurons by a mechanism reversed by RX821002. Local DMI (0.01-100 microM) into the LC increased concentration-dependently NA levels in the LC and simultaneously decreased NA levels in the Cg. This decrease was abolished by local RX821002 administration into the LC. The results demonstrate in vivo that DMI inhibits NA reuptake at somatodendritic and nerve terminal levels of noradrenergic cells. The increased NA dialysate in the LC inhibits noradrenergic activity, which in part counteracts the effects of DMI on the Cg. The modulation of cortical NA release by activity of DMI at the somatodendritic level is mediated through alpha2-adrenoceptors located in the LC.