V. Klimek

Parallel changes in dopamine D2 receptor binding in limbic forebrain associated with chronic mild stress-induced anhedonia and its reversal by imipramine

Chronic sequential exposure to a variety of mild stressors has previously been found to cause an antidepressant-reversible decrease in the consumption of palatable sweet solutions, associated with abnormalities of dopaminergic neurotransmission in the nucleus accumbens. In the present study, 5 weeks of treatment with imipramine (10 mg/kg b.i.d.) reversed the decreased sucrose intake of rats exposed to chronic mild stress. Stress also caused a decrease in D2-receptor binding in the limbic forebrain (but not the striatum), which was completely reversed by imipramine. In nonstressed animals, imipramine decreased D1-receptor binding in both regions. However, in stressed animals, imipramine did not significantly alter D1-receptor binding in either area. Stress alone slightly increased D1-receptor binding, in striatum only. Scatchard analysis showed that all changes in receptor binding resulted from changes in receptor number (Bmax) rather than receptor affinity (KD). The results support the hypothesis that changes in D2-receptor function in the nucleus accumbens are responsible for chronic mild stress-induced anhedonia and its reversal by antidepressant drugs. They do not support the hypothesis that the sensitization of D2-receptors seen following chronic antidepressant treatment is caused by a down-regulation of D1-receptors.

Drugs affecting dopamine neurons and yawning behavior

Drugs stimulating the dopamine (DA) neurons in different ways (apomorphine, piribedil, amphetamine, nomifensine, L-DOPA) given in low doses (not producing behavioral excitation) induced yawning in rats. Blockade of DA receptors with neuroleptics counteracted DA-agonists induced yawning which may indicate a dopaminergic component of this behavior.

Chronic treatment with antidepressants decreases the number of [3H]SCH 23390 binding sites in the rat striatum and limbic system

Binding of [3H]SCH 23390 to dopamine D-1 receptors and of [3H]spiperone to D-2 sites was measured in identical membrane preparations of the striatum and limbic system of rats treated chronically (twice daily, for two weeks) with antidepressants. Chronic administration of imipramine, amitriptyline, mianserin, citalopram, bupropion, iprindole and electroconvulsive shocks, but not benztropine or cyproheptadine (non-antidepressants) decreased the number of [3H]SCH 23390 binding sites, while no change in the parameters of [3H]spiperone binding was observed. The serotonin2 receptor antagonist ketanserin when added to the incubation medium had no effect on [3H]SCH 23390 binding to D-1 sites. The results suggest that D-1 receptor subsensitivity is a component of the therapeutic effect of antidepressants.

Effects of imipramine on serotonergic and beta-adrenergic receptor binding in a realistic animal model of depression.

Chronic exposure to mild unpredictable stress (CMS) has previously been found to cause an antidepressant-reversible decrease in the consumption of palatable sweet solutions. In the present study, in addition to confirming these behavioural observations, the binding properties of cortical beta-adrenergic and 5HT2 receptors, and hippocampal 5HT1A receptors were studied (using the ligands [3H]-dihydroalprenolol, [3H]-ketanserin and [3H]-8-OH-DPAT, respectively), following 7 weeks of CMS and 4 weeks of imipramine treatment (10mg/kg per day). CMS increased Bmax for all three receptor systems. Impramine decreased Bmax, reversing the effect of CMS, for beta-adrenergic and 5HT2 receptor binding, but increased Bmax for 5HT1A receptor binding. KDs were unaffected by either treatment. The beta-receptor and 5HT2 receptor binding data are consistent with accounts of antidepressant action derived from studies in normal animals, but the 5HT1A receptor binding data are more difficult to reconcile. In no case was there a good correlation between receptor binding and behavioural data.

MK-801 elevates the etracellular concentration of dopamine in the rat prefrontal cortex and increases the density of striatal dopamine D1 receptors

In the present study we found that MK-801 (dizocilpine), given peripherally in doses (0.2 and 0.4 mg/kg) which evoked locomotor activation in rats, enhanced in a dose-dependent manner the extracellular concentration of dopamine (DA) in the rat prefrontal cortex (PFC). MK-801 used in similar range of doses (0.2, 0.4 mg/kg) failed to alter the DA content in superfusates of the rat striatum (STR). It was also found that single doses of MK-801 enhanced the density of D1 receptors, assessed by the [3H]SCH 23390 binding in the rat STR, but not in the limbic forebrain. An increase in the density of D1 receptors was observed at 24, but not 2, h after MK-801 administration. MK-801 failed to alter the density of D2 receptors in the STR and limbic forebrain. The available data indicate that MK-801 may enhance the dopaminergic neurotransmission by at least two separate mechanisms: a fast one, associated with the release of DA in PFC, and a slow one, resulting from the increase in the D1 receptor density.

Antidepressant drugs given repeatedly increase binding to α1-adrenoceptors in the rat cortex

The effect of antidepressant drugs, administered repeatedly, on binding to α 1 -adrenoceptors in the rat cerebral cortex was studied using [ 3 H]prazosin as a ligand. Imipramine, amitriptyline, citalopram and mianserin increased the binding (B max ) assessed at 8:00 h. At 20:00 h such an effect was produced by imipramine, citalopram and mianserin. [ 3 H]Prazosin binding in control rats was higher at 20:00 h than at 8:00 h. An increase in the density of α 1 -adrenoceptors may be associated with the therapeutic activity antidepressant drugs.

Changes in mesolimbic dopamine may explain stress-induced anhedonia

The mesolimbic dopamine projection to the limbic forebrain is known to be critically involved in responsiveness to rewards. In two experiments, the consumption of palatable weak sucrose solutions by rats was reduced by chronic exposure to mild unpredictable stress. Increases in the levels of dopamine and serotonin and their metabolites were found in the limbic forebrain of stressed rats; these changes were not present in the caudate nucleus or septal area, or in the brains of meal-fed control animals. In the first experiment (7 weeks of stress), specific binding to dopamine D2 receptors was decreased in limbic forebrain; this change was not seen in the second experiment (3 weeks of stress). We discuss the possible role of these changes in mesolimbic dopamine function in the reduced sensitivity to reward that follows exposure to chronic mild stress.

The effect of repeated administration of antidepressant drugs on the responsiveness of rats to catecholamine agonists.

The antidepressant drugs, imipramine (10mg/kg s.c.), amitriptyline (10 mg/kg s.c.), mianserin (2 mg/kg i.p.), danitracen (3 mg/kg i.p.) or the vehicle were administered to rats twice a day for 4 or 10 days. Clonidine (0.5 mg/kg s.c.) induced in rats chronically treated with the compounds studied an increase in locomotor activity but, at the same time, did not affect or decreased this activity in rats chronically treated with the vehicle or a single dose of an antidepressant. This refers, in particular, to imipramine, amitriptyline and danitracen which have a similar effect. This effect, an increase in motility, was most pronounced and common for all the three drugs (after a 4- and 10-day treatment) when clonidine was administered 72 hours after the last dose of an antidepressant. Only in a few cases the amphetamine-induced hypermotility was enhanced by a chronic administration of antidepressants (a 4-day amitriptyline treatment, 72 hours after the last injection; a 4-day mianserin or danitracen treatment, 48 hours after the last injection). The results obtained seem to suggest that a chronic administration of the antidepressant drugs may cause a change in the sensitivity of the central noradrenaline receptors.

Chronic treatment with antidepressants: Potentiation of clonidine-induced aggression in mice via noradrenergic mechanism

The chronic (10mg/kg i.p. twice daily, 10 days)-and not the acute-administration of amitriptyline, maprotiline or zimelidine enhances aggressiveness induced by clonidine in mice. An analogous potentiation of clonidine-induced aggressiveness was obtained with chronic administration (the schedule as above) of levomepromazine (2 mg/kg) or thioridazine (5 mg/kg) but not of spiperone (0.2 mg/kg). Fluoxetine (10 mg/kg), atropine (5 mg/kg), propranolol (10 mg/kg) or metergoline (0.5 mg/kg) given chronically (the schedule as above) also had no effect. The enhancement of clonidine aggressiveness induced by prolonged treatment with imipramine (10 mg/kg) was prevented by cycloheximide, an inhibitor of protein synthesis. The results supply further evidence for the previously proposed hypothesis that chronic administration of antidepressants enhances the responsiveness of central postsynaptic noradrenaline receptors.

Desipramine given repeatedly enhances behavioural effects of dopamine and d-amphetamine injected into the nucleus accumbens.

The effect of desipramine (DMI) was studied after its repeated administration (10 mg/kg p.o., twice daily, 14 days) to rats, on the action of dopamine and d-amphetamine injected bilaterally into the nucleus accumbens. DMI, applied repeatedly but not acutely, prevented the sedative effect of dopamine and enhanced its stimulating action, as assessed by the open-field test. Repeated administration of DMI also enhanced d-amphetamine-induced locomotor hyperactivity. The number of [3H]SCH 23390 binding sites (D-1) in the limbic system decreased while the number of [3H] spiperone ones (D-2) remained unchanged. The results indicate that, like other antidepressant drugs studied earlier, DMI enhances neurotransmission in the dopamine mesolimbic system (nucleus accumbens) of the rat.