Desipramine-treated Rats Research Articles

Progressive attenuation of the firing activity of locus coeruleus noradrenergic neurons by sustained administration of selective serotonin reuptake inhibitors.

Sustained administration of the selective serotonin (5-HT) reuptake inhibitors (SSRIs) citalopram for 2, 14, and 21 d, and paroxetine for 2 and 21 d (20 and 10 mg/kg.d, respectively, s.c. using osmotic minipumps) produced a gradual decrease in spontaneous firing activity of locus coeruleus (LC) noradrenergic neurons. In contrast, sustained desipramine administration for 2 and 21 d (10 mg/kg.d) robustly reduced LC firing activity, though only to the same extent, following these two treatment periods. The enhancement of the firing rate of LC neurons produced by the 5-HT1A agonist 8-OH-DPAT (10-50 &mgr;g/kg, i.v.) in desipramine- and citalopram-treated rats was abolished, indicating a desensitization of 5-HT1A receptors. However, the attenuation of the firing rate of LC neurons induced by the 5-HT2 agonist DOI (5-50 &mgr;g/kg, i.v.) was decreased approx. 2-fold in citalopram-treated rats but not significantly altered in desipramine-treated rats. Since 5-HT neurons exert a tonic inhibitory effect on LC neurons, it appears that enhancing 5-HT neurotransmission by sustained SSRI administration leads to a reduction of the firing rate of noradrenergic neurons. In conclusion, SSRIs attenuate the activity of noradrenergic neurons with a delay that is consistent with their beneficial effect in depression and some anxiety disorders, such as panic, generalized and social anxiety disorders. However, given the hyperadrenergic state often observed in anxiogenic conditions the latter phenomenon is believed to contribute more to the anxiolytic effect of SSRIs than to their antidepressant action.

Activation and desensitization by cyclic antidepressant drugs of alpha2-autoreceptors, alpha2-heteroreceptors and 5-HT1A-autoreceptors regulating monamine synthesis in the rat brain in vivo.

The effects of antidepressant drugs on the synthesis of noradrenaline and serotonin (5-HT) were assessed using the accumulation of 3,4-dihydroxyphenylalanine (dopa) and 5-hydroxytryptophan (5-HTP) after decarboxylase inhibition as a measure of the rate of tyrosine and tryptophan hydroxylation in the rat brain in vivo. Three inhibitory synthesis-modulating receptors were investigated simultaneously: the alpha2C-autoreceptor modulating dopa/noradrenaline synthesis, and the alpha2A-heteroreceptor and 5-HT1A-autoreceptor modulating 5-HTP/5-HT synthesis. Acute treatment (2 h, i.p.) with desipramine (1-10 mg/kg), protriptyline (0.3-10 mg/kg) and nisoxetine (3-10 mg/kg), selective NA reuptake blockers, dose-dependently decreased dopa synthesis in cortex (15%-40%) and hippocampus (20%-53%). Fluoxetine (1-10 mg/kg) and zimelidine (1-10 mg/kg), selective 5-HT reuptake blockers, did not alter dopa synthesis. Fluoxetine and zimelidine dose-dependently decreased 5-HTP synthesis in cortex (14%-43%) and hippocampus (27%-54%). Desipramine and protryptyline did not alter 5-HTP synthesis in cortex but in hippocampus it was decreased (36%). Repeated desipramine (10 mg/kg for 1-21 days) or fluoxetine (3 mg/kg for 3-21 days) treatment resulted in a time-dependent loss in their ability to decrease dopa or 5-HTP synthesis. Desipramine (1-21 days) did not alter 5-HTP synthesis in cortex, but in hippocampus it was decreased (21%-37%, days 1-14) followed by recovery to control values (day 21). Fluoxetine (3-21 days) did not alter brain dopa synthesis. To further assess the desensitization of alpha2C-autoreceptors, alpha2A-heteroreceptors and 5-HT1A autoreceptors regulating the synthesis of dopa/NA or 5-HTP/5-HT after chronic desipramine and fluoxetine, the effects of clonidine (agonist at alpha2-auto/heteroreceptors) and 8-OH-DPAT (agonist at 5-HT1A-autoreceptors) were tested. In saline-treated rats, clonidine (1 mg/kg, 1 h) decreased dopa and 5-HTP synthesis in cortex (58% and 54%) and hippocampus (54% and 42%). In desipramine-treated rats (10 mg/kg, 21 days), but not in fluoxetine-treated ones (3 mg/kg, 14 days), the effect of clonidine was attenuated in cortex (12% and 18%) and only for dopa synthesis in hippocampus (31%). In saline-treated rats, 8-OH-DPAT (1 mg/kg, 1 h) decreased 5-HTP synthesis in cortex (63%) and hippocampus (75%). In fluoxetine-treated rats, but not in desipramine-treated ones, this inhibitory effect was markedly attenuated in cortex (26%) and hippocampus (9%). These findings indicate that acute treatment with cyclic antidepressant drugs results in activation of inhibitory alpha2C-autoreceptors, alpha2A-heteroreceptors and/or 5-HT1A-autoreceptors regulating the synthesis of dopa/NA and/or 5-HTP/5-HT in brain, whereas chronic treatment with these drugs is followed by desensitization of these presynaptic receptors.

Effect of 3,4-Methylenedioxymethamphetamine (MDMA) on Hippocampal Dopamine and Serotonin

The 3,4-methylenedioxymethamphetamine (MDMA)-induced increase in the extracellular concentration of dopamine and the long-term depletion of 5-HT were studied in the hippocampus of the rat brain. MDMA produced a dose-dependent increase in the extracellular concentration of dopamine in the hippocampus, as well as in the striatum. The MDMA-induced increase in the extracellular concentration of dopamine in the hippocampus, but not in the striatum, was suppressed in rats treated with the norepinephrine uptake inhibitor, desipramine, and in rats in which noradrenergic neurons in the hippocampus were lesioned with DSP 4 ( N-(2- chloroethyl)- N-ethyl-2-bromo benzylamine). However, the long-term depletion of 5-HT in the hippocampus produced by MDMA was unaltered in desipramine-treated rats. These results are supportive of the view that the MDMA-induced increase in the extracellular concentration of dopamine in the hippocampus is the result of an enhanced release of dopamine from noradrenergic neurons. In addition, the MDMA-induced depletion of 5-HT in the hippocampus appears not to involve dopamine-initiated processes, because suppression of MDMA-induced dopamine release did not attenuate the long-term depletion of 5-HT in the hippocampus.

Chronic desipramine treatment desensitizes the rat to anesthetic and antinociceptive effects of the alpha2-adrenergic agonist dexmedetomidine.

The effects of long-term administration of the tricyclic antidepressant agent desipramine on the hypnotic, antinociceptive, anesthetic-sparing, and central norepinephrine turnover suppressant action of short-term dexmedetomidine, a highly selective alpha2-adrenergic agonist, were studied in rats. Rats were given a 3- or 4-week course of twice daily administration of desipramine, 10 mg/kg, or saline. The effect of a hypnotic dose of dexmedetomidine, 250 microg/kg given intraperitoneally, on the duration of loss of righting reflex was determined. The tail flick latency response was determined before and after 50 microg/kg dexmedetomidine. The minimum anesthetic concentration of halothane and the central norepinephrine turnover rate were determined before and after administration of 30 microg/kg dexmedetomidine. Changes in the affinity and density of the alpha2-adrenergic receptor in locus coeruleus and spinal cord also were determined. Treatment with desipramine decreased dexmedetomidine-induced loss of righting reflex duration by 67% and eliminated the antinociceptive effect of dexmedetomidine. Dexmedetomidine produced a 55% decrease in minimum anesthetic concentration in the control group but no reduction in desipramine-treated rats. Desipramine did not change the receptor density or binding affinity of alpha2 receptors at the site for hypnotic (locus coeruleus) or antinociceptive (spinal cord) responses. No decrement in the central norepinephrine turnover rate was noted in the locus coeruleus of dexmedetomidine after 3 weeks of treatment with desipramine. The alpha1-adrenergic antagonist prazosin at 1 or 5 mg/kg completely (minimum anesthetic concentration reduction), almost completely (antinociceptive), or partially (hypnotic) restored responsiveness to normal. These data indicate that treatment with desipramine induces hyporesponsiveness to the hypnotic, analgesic, and minimum anesthetic concentration-reducing, but not to the suppression of central norepinephrine turnover, properties of dexmedetomidine. The hyporesponsiveness appears to involve an alpha1-adrenergic mechanism.

Amphetamine induces hydroxyl radical formation in the striatum of rats

Amphetamine-induced hydroxyl radical formation in the striatum of rats was investigated in this study. With the utilization of the microdialysis and HPLC-ECD, the striatal dopamine (DA) release and the formation of 2,3-dihydroxybenzoic acid (2,3-DHBA), derived from the reaction of hydroxyl radicals (·-OH) and salicylate in perfusion, were monitored and detected during desipramine and/or amphetamine (AMPH) administration. Our data revealed that after desipramine treatment AMPH injections not only amplified striatal DA release and 2,3-DHBA formation, but also intensified the stereotyped behaviors induced by AMPH. Furthermore, we discovered that α-methyl- para-tyrosine (α-MT) pretreatment prevented the onset of the above responses. In desipramine-treated rats, the tissue homogenization study demonstrated that a single dose of AMPH produced long-term depletion of striatal DA; this was not seen in saline-treated rats. Moreover, striatal DA depletion could be lessened by pretreatment with mannitol, a·.OH scavenger. These results indicate that AMPH-induced striatal.OH formation might be DA-related in desipramine-treated rats, and suggest that ·.OH formation might be correlated with AMPH-induced neurodegeneration.

Chronic administration of l-sulpiride at low doses reduces A10 but not A9 somatodentritic dopamine autoreceptor sensitivity

The effect of chronic treatment (twice daily for 21 days) with low doses of l-sulpiride (2 mg/kg i.p.) on the apomorphine-induced inhibition of A10 and A9 dopaminergic neurons was compared with the effect of chronic administration of the classic antidepressant desipramine (20 mg/kg i.p. daily for 21 days). Intravenous administration of apomorphine (0.01–0.04 mg/kg), to rats treated chronically with l-sulpiride, produced a reduction of the spontaneous firing rate of A9 dopaminergic neurons not significantly different from that observed in control (saline-treated) rats. In contrast, apomorphine at the same doses was more potent in inhibiting A10 firing in control rats than in l-sulpiride-treated subjects. On the other hand, desipramine-treated rats were found normosensitive (as compared to saline-treated rats) to the inhibitory properties of apomorphine in both A9 and A10 dopaminergic neurons. It is suggested that chronic l-sulpiride-induced reduction of autoreceptor sensitivity in the A10 region may contribute to its clinical antidepressant effect.

The effects of desipramine on thyroid hormone concentrations in rat brain.

The effects of the antidepressant desipramine on the tissue concentrations of thyroxine and triiodothyronine in 9 different regions of the brain and also in the pituitary and liver were investigated in male rats. The investigations were carried out at three different times of the light/dark cycle: 5 a.m., 1 p.m. and 11 p.m. After fourteen days' treatment with 20 mg/kg/day desipramine by gavage the concentrations of triiodothyronine in the frontal and parieto-occipital cortex were significantly higher than in the saline-treated controls, those in the hippocampus lower and those in the 6 remaining brain regions the same. In 8 areas of the brain the concentrations of thyroxine were lower in the desipramine-treated rats and the tissue ratios of triiodothyronine to thyroxine were enhanced in 6 regions. These effects are most likely the result of the action of desipramine on the activity of the isoenzyme 5'II deiodinase. This enzyme catalyzes the deiodination of thyroxine to triiodothyronine in rat brain and its activity has recently been reported to be enhanced by desipramine. The observed effects were dose-dependent and also strongly dependent upon the time within the 24 h light/dark cycle at which the hormone concentrations were measured. No effects of desipramine were seen in the pituitary or liver after 14 days' treatment, or in various areas of the central nervous system 24 h after administration. In view of the psychotropic properties of thyroid hormones, it seems possible that the observed increases in triiodothyronine concentrations, particularly in cortical areas, are involved in the mechanisms of action of desipramine.

Effects of clonidine on desipramine- and desmethylclomipramine- induced 3-methoxy-4-hydroxyphenylglycol levels in rat brain

Rats received repeated i.p. administrations of desipramine (20 mg/kg) or desmethylclomipramine (10 mg/kr). The steady state concentration of each drug in the brain was attained a few days after the start of the treatment. The treatments with desipramine and desmethylclomipramine for more than 10 and 2 days, respectively, induced significant elevation of 3-methoxy-4-hydroxyphenylglycol (MHPG) level in the brain. After repeated administration of each drug, rats were given a single i.p. injection of clonidine (50 μg/kg). This treatment decreased the elevated MHPG level in the brain of desmethylclomipramine-treated rats, whereas it had no effect on the increased MHPG level in desipramine-treated rats.

Effect of low alcohol dose on behavioral “despair” in rats neonatally treated with antidepressant drugs

Rat pups were treated with monoamine uptake inhibiting antidepressant drugs, desipramine, imipramine or nomifensine (5 mg/kg) during the second and third postnatal weeks, and their later behavioral “despair,” measured by Porsolt's swim test, was examined. At the age of two months, the desipramine-treated rats showed lengthened immobility in the swim test, and thus probably increased behavioral “despair.” They also responded to 1 g/kg alcohol by shortening the immobility to the level of control rats. Neonatal treatment with either imipramine or nomifensine did not affect the swim test behavior. The results suggest that a low, stimulatory dose of alcohol was able to reverse the lengthened immobility in the swim test of rats treated with desipramine during the early postnatal period.

Effects of desipramine of rat behavior are prevented by concomitant treatment with ethanol

Ethanol prevents the decease of the number of β-adrenoceptors in the cerebral cortex induced by chronic treatment of rats with desipramine. The activation of the adenylate cyclase, the second messenger, by β-adrenergic agonists is reduced somewhat less than after treatment with desipramine alone. The present paper examined the hypothesis that ethanol inhibits the neuronal adaption to desipramine chronic treatment at the fucntional level as well. Desipramine reduced exploratory behavior (crossings, rearings) as did ethanol. Combined treatment attnenuate the effect of desipramine. Cognitive performace was investigated using an active avoidance paradigm. Desipramine-treated rats did not learn the task in contrast to control animals. Again, combination treatment with ethanol improved the ability of the rats to perform the task. The activity of cerebral β-adrenergic mechanisms was assessed by injection of sulbutamol, a β-adrenoceptor agonist in rats pretreated with 5-hydroxytryptophan (5-HTP). The augmentation of the 5-HTP-induced wet dog shake behavior by salbutamol was observed in all animals independent of the chronic treament. However, rat treated with desipramine were less active than those treated with tap water or ethanol. The effect of desipramine of a high concentration of salbutamol was attnuated by ethanol. The observed increased of the number of wet dog shakes correlates with the funtion of these receptors. In two paradigms, spontaneous motility and apomorphine-induced hypothermia, ethanol did not effect the action of desipramine. It is noteworthy that desipramine acted in both situations within a short time period (minutes to hours). The findings strongly suggest that ethanol can prevent adaptive changes in the brain induced in the brain by chronic treatment with the antidepressant desipramine. This is of special interest since the adaption of β-adrenoceptors is thought to be critical for the antidepressant efficacy of cvarious therapeutic interventions applied in psychiatric practice.

Forced swimming test in rats: effect of desipramine administration and the period of exposure to the test on struggling behavior, swimming, immobility and defecation rate

The effect of desipramine administration and the duration of the daily exposure to forced swimming on some variables has been studied in adult male rats. Desipramine administration (15 mg/kg) significantly increased struggling behavior in the first and second 5-min periods of a single exposure to forced swimming. Swimming was reduced in the first 5 min and remained unchanged thereafter. Immobility was decreased in the second and the third 5-min periods. After a pre-exposure to forced swimming for 15 min the day before, the drug was effective in increasing struggling behavior and reducing immobility during a subsequent 5-min test. Swimming was not modified. Daily exposure to forced swimming for 3 days caused a decline in struggling behavior and swimming, while increasing immobility and the defecation rate. The duration of daily exposure to forced swimming,did not alter the changes in the variables measured. The present results indicate that a one-day test can be used to discriminate between saline- and desipramine-treated rats, and that struggling behavior could be a reliable measure of the positive action of antidepressants. The finding that behavioral changes over the 3 days were independent of the duration of exposure to swimming argues against the interpretation of the results which suggest that the responses are caused by the appearance of a behavioral despair state, and suggests that these behaviors might be trait-markers in the rat. In addition, the changes in struggling behavior and immobility over the 3 days cannot be attributed to a behavioral adaptation to the test because the defecation rate increased rather than decreased during successive forced swimming tests.

Neonatal treatment with monoamine uptake inhibitors alters later response in behavioural 'despair' test to beta and GABA-B receptor agonists.

The administration of monoamine uptake-inhibiting antidepressant drugs to rats during the early postnatal period was previously shown to lengthen the duration of subsequent immobility in Porsolt's swim test, hence suggesting increased behavioural 'despair' in these animals. Because the mechanism of the antidepressant action may be related to changes in the cerebral monoamine or gamma-aminobutyric acid (GABA) function, the present study was carried out to examine the response in the swim test to a beta-receptor agonist salbutamol, or to the GABA-B receptor agonists progabide and baclofen in rats treated with antidepressant drugs during the second and third postnatal week: either desipramine 5 mg/kg, nomifensine 10 mg/kg or zimeldine 25 mg/kg. When tested a month later i.e. at the age of two months these rats were immobile in water for a longer period than the controls. Salbutamol 10 mg/kg and progabide 100 mg/kg increased the immobility time in the control rats but neither drug affected the rats treated with desipramine, nomifensine or zimeldine. When the animals were 5 months of age, salbutamol 10 mg/kg and baclofen 10 mg/kg shortened the immobility time in the desipramine-treated rats. The control rats and those treated with zimeldine were not affected by the drugs. The results indicate that in the rats which were neonatally treated with antidepressants, the immobility time in water is lengthened in adulthood. Moreover, the response to beta-receptor and GABA-B receptor agonists is increased from the response observed in the control rats.

Possible involvement of pertussis toxin substrates (Gi, Go) in desipramine-induced refractoriness of adenylate cyclase in cerebral cortices of rats.

To evaluate the efficiency of coupling between beta-receptor and adenylate cyclase catalyst via a GTP-binding protein, Gs, in the brain membrane two parameters were employed: a beta-agonist-induced increase in the membrane GTP-dependent adenylate cyclase activity and a beta-agonist-induced shortening of the lag time preceding the onset of the steady-state activation by guanyl-5'-yl-beta-gamma-imidodiphosphate [Gpp(NH)p] of the membrane cyclase. Both parameters showed lower values in membranes from desipramine-treated rats compared with untreated rats. Thus, coupling of beta-adrenergic receptors to adenylate cyclase in the brain membrane was impaired by the desipramine treatment. Rats once injected intraventricularly with islet-activating protein (IAP), pertussis toxin, were subjected to desipramine treatment, for the purpose of studying effects of another kind of the GTP-binding protein (Gi), which loses its function as a signal transducer on being ADP-ribosylated selectively by the toxin. IAP treatment did not impair the beta-receptor coupling by itself, since neither of the above two parameters for the coupling were reduced by IAP treatment. Moreover, the first parameter was normalized, though the second one was not, by superimposition of the IAP treatment upon the desipramine-treated rats. It seems likely, therefore, that Gi interacts with a Gs-adenylate cyclase coupling in an inhibitory fashion in brain membranes. The desensitization might be overcome when the inhibitory interaction of Gi on the subsequent process is attenuated by IAP treatment.

Effects of chronic amitriptyline and desipramine on food intake and body weight in rats

Long-term treatment with tricyclic antidepressant drugs (TCAs) can induce excessive body weight gain in a significant proportion of patients. Such weight gains, which appear to be largely independent of clinical improvement, are in many cases severe enough to interfere with continuation of treatment. In efforts to model this effect in experimental animals, seven experiments were performed in which two commonly used TCAs, amitriptyline and desipramine, were administered chronically to rats. Despite manipulations of drug dosages (2.5 mg−17 mg/kg), route of administration (intraperitoneal, subcutaneous, oral; daily injections vs. continuous release from osmotic pumps), diet composition and palatability (regular Purina Chow pellets or powder with or without added high fat and high carbohydrate sources; high vs. low protein diets) and animal sex and housing conditions (single vs. group housing), chronic TCA treatment was never observed to increase daily food intake or rates of body weight gain. Desipramine treatment invariably caused decreased food intake and weight loss. Amitriptyline treatment either caused no change in food intake and body weight or slightly reduced levels in comparison to vehicle-treated controls. However, both amitriptyline- and desipramine-treated rats showed a potentiation of acute caloric intake after a single systemic injection of the glucoprivic agent 2-deoxy-D-glucose. These results are considered against the background of human clinical observations. Possible reasons for the differences between human and animal data are discussed.

Changes in brain serotonin levels affect leukocytes, lymphocytes, T-cell subpopulations and natural killer cell activity in rats

The intraventricular injection of 5,6-dihydroxytryptamine into desipramine-treated rats caused a marked reduction in serotonin levels 5 and 10 days after treatment without significantly affecting catecholamine levels. In these animals, total leukocytes were increased and lymphocytes decreased. The number of helper T-cells ( W3 25 + ) was significantly decreased after 5 days, whereas the numbers of total T-cells ( W3 13 + ) and suppressor T-cells (MRC OX8) were increased after 10 days. The percentages of total T-cells, helper T-cells and suppressor T-cells were significantly reduced after 5 days. Natural killer cell (NK) activity was markedly reduced after 5 days. This finding suggests that central serotonin-containing neurons might be involved in the regulation of certain parts of the peripheral immune system.

Effect of specific serotonergic lesions on cholinergic neurons in the hippocampus, cortex and striatum

Local injection of 5, 7-dihydroxytryptamine into the median raphe nucleus of rats pretreated with desipramine decreases the serotonin content of the hippocampus and cortex. The turnover of acetylcholine, as measured by the rate of decline of acetylcholine content after hemicholinium-3, the rate of decline of acetylcholine content after hemicholinium-3, is not affected in the hippocampus or the striatum, but is increased in the cortex by such treatment. Local injection of 5, 7-dihydroxytryptamine into the dorsal raphe nucleus of desipramine-treated rats decreases the serotonin content of the hippocampus, cortex, and striatum. The turnover of acetylcholine is increased in the hippocampus and cortex, but not affected in the striatum. Thus, serotonergic neurons from the median raphe nucleus appear to tonically inhibit cholinergic neurons in the cortex, and serotonergic neurons from the dorsal raphe nucleus appear to tonically inhibit cholinergic neurons in the hippocampus and cortex. These serotonergic neurons do not appear to act tonically on striatal cholinergic neurons.

The effect of long-term chlorpromazine and desipramine treatment on adrenal corticosterone, cyclic AMP, and cholesterol distribution in rats.

1. Male rats were injected intraperitoneally with chlorpromazine (10 mg/kg) and desipramine (10 mg/kg), respectively, twice daily for 2 weeks. 2. The adrenal corticosterone concentrations were significantly lowered in chlorpromazine- and desipramine-treated rats. 3. Large dose of corticotrophin would increase the adrenal corticosterone level in chlorpromazine-treated but the adrenal response was significantly less than in the untreated controls. 4. The adrenal cyclic AMP level was similar in treated and control rats and the adrenal response to corticotrophin was not decreased at the cyclic AMP level. 5. The cholesteryl ester concentrations in the adrenals were significantly increased by drug treatment, although the free cholesterol concentrations were unchanged in the cytosol and mitochondrial cell fractions. 6. The possible site of action of chlorpromazine in suppressing corticosterone production is discussed.

Effects of chronic desipramine treatment on rat brain noradrenergic responses to α-adrenergic drugs

It has been previously reported that long-term tricyclic antidepressant treatment in the rat causes a subsensitivity of central β-receptor-stimulated adenylate cyclase along with alterations of brain norepinephrine (NE) content and metabolism. We have confirmed earlier findings that after one week of desipramine treatment (5.0 mg/kg b.i.d.) brain NE levels decline while NE metabolism is similar to control animals, but is above control after 12 days of treatment. Single cell recordings from noradrenergic neurons of the locus coeruleus (LC) show that after one week of desipramine treatment, neuronal firing rate is lower than in control rats but greater than that seen in response to acutely administered drug. Furthermore, desipramine injection in a dose which profoundly altered LC impulse flow in control rats produced little or no effect on impulse flow in chronically treated rats. Of 25 or 250 μg/kg doses of clonidine, which are equieffective for decreasing brain NE metabolism in control animals, only the larger dose decreased NE metabolism in 12 day desipramine-treated rats. The postsynaptic α-antagonist prazosin (5.0 mg/kg) increased NE metabolism in both groups. These results suggest that presynaptic ( α 2) adrenoreceptors become subsensitive during long-term desipramine treatment, thus allowing recovery of noradrenergic impulse flow in the presence of NE uptake inhibition.

Effect of central catecholamine alterations on the hypothermic response to 6-hydroxydopamine in desipramine treated rats.

The hypothermia observed in rats kept in a cold environment after the intracisternal administration of 6-hydroxydopamine was enhanced by desipramine. Since pretreatment with 6-hydroxydopamine virtually eliminated the temperature fall in response to a subsequent dose of 6-hydroxydopamine, brain catecholamines were implicated in the response. Preferential reduction of brain noradrenaline antagonized the hypothermia after 6-hydroxydopamine in desipramine-treated rats to a greater extent than did the preferential reduction of dopamine. The results indicate the importance of noradrenergic fibres in this hypothermic response, but do not exclude an involvement of brain dopaminergic pathways.