Chronic Administration Of Paroxetine Research Articles

Paroxetine and Low-dose Risperidone Induce Serotonin 5-HT1A and Dopamine D2 Receptor Heteromerization in the Mouse Prefrontal Cortex

Recently, it has been shown that serotonin 5-HT1A receptor interacts with dopamine D2 receptor in vitro. However, the existence of 5-HT1A–D2 heteromers in native tissue remains unexplored. In the present study, we investigated 5-HT1A–D2 receptor heteromerization in mice treated acutely or chronically with paroxetine (10 mg/kg) or risperidone (0.05 mg/kg). Receptor heteromerization was visualized and quantified in the mouse brain by in situ proximity ligation assay (PLA). Additionally, we aimed to determine the cellular localization of 5-HT1A–D2 receptor heteromers in mouse adult primary neuronal cells by immunofluorescent staining with markers for astrocytes (GFAP) and neurons (NeuN and MAP2).The results from the current study demonstrated that 5-HT1A and D2 receptor co-localization and heteromerization occurred in the mouse prefrontal cortex. Counterstaining after PLA confirmed neuronal (pyramidal and GABAergic) as well as astrocytal localization of 5-HT1A–D2 receptor heteromers. Chronic administration of paroxetine or risperidone increased the level of 5-HT1A–D2 receptor heteromers in the prefrontal cortex. These changes were not accompanied by any changes in the expression of mRNAs (measured by in situ hybridization) or densities of 5-HT1A and D2 receptors (quantified by receptor autoradiography with [3H]8-OH-DPAT and [3H]domperidone, respectively), what all indicated that paroxetine and risperidone facilitated 5-HT1A–D2 heteromer formation independently of the receptor expression. In vitro homogenous time-resolved FRET (HTRF) study confirmed the ability of tested drugs to influence the human 5-HT1A–D2 heteromer formation.The obtained data indicate that the increase in 5-HT1A–D2 receptor heteromerization is a common molecular characteristic of paroxetine and low-dose risperidone treatment.

Hippocampal mTOR signaling is required for the antidepressant effects of paroxetine

Although thought as a selective serotonin reuptake inhibitor (SSRI), the antidepressant mechanisms of paroxetine remain unknown. Previous studies have shown the role of the mammalian target of rapamycin (mTOR) signaling in depression. In this study, we investigated whether the antidepressant effects of paroxetine require mTOR signaling. We first examined whether chronic paroxetine administration restores the effects of CUMS and CSDS on the mTOR signaling cascade in the hippocampus and prefrontal cortex. Then, the pharmacologcial inhibitors of mTOR signaling (LY294002, U0126 and rapamycin) were used to assay if the paroxetine-induced reversing effects in the CUMS and CSDS models were prevented by mTOR system blockade. Furthermore, gene knockdown of mTOR by mTOR-shRNA was also used to test whether mTOR is necessary for the antidepressant effects of paroxetine. It was found that paroxetine treatment fully reversed the effects of CUMS and CSDS on the mTOR signaling in the hippocampus, but not the prefrontal cortex. Pharmacological inhibition of the mTOR signaling significantly blocked the antidepressant effects of paroxetine in the CUMS and CSDS models. Moreover, gene silencing of hippocampal mTOR by mTOR-shRNA also abolished the antidepressant effects of paroxetine. Taken together, hippocampal mTOR signaling is necessary for the antidepressant effects of paroxetine.

Hippocampal protein expression is differentially affected by chronic paroxetine treatment in adolescent and adult rats: a possible mechanism of “paradoxical” antidepressant responses in young persons

Selective serotonin reuptake inhibitors (SSRIs) are commonly recognized as the pharmacological treatment of choice for patients with depressive disorders, yet their use in adolescent populations has come under scrutiny following reports of minimal efficacy and an increased risk of suicidal ideation and behavior in this age group. The biological mechanisms underlying these effects are largely unknown. Accordingly, the current study examined changes in hippocampal protein expression following chronic administration of paroxetine in drinking water (target dose = 10 mg/kg for 22 days) to adult and adolescent rats. Results indicated age-specific changes in protein expression, with paroxetine significantly altering expression of 8 proteins in adolescents only and 10 proteins solely in adults. A further 12 proteins were significantly altered in both adolescents and adults. In adults, protein changes were generally suggestive of a neurotrophic and neuroprotective effect of paroxetine, with significant downregulation of apoptotic proteins Galectin 7 and Cathepsin B, and upregulation of the neurotrophic factor Neurogenin 1 and the antioxidant proteins Aldose reductase and Carbonyl reductase 3. Phosphodiesterase 10A, a signaling protein associated with major depressive disorder, was also downregulated (-6.5-fold) in adult rats. Adolescent rats failed to show the neurotrophic and neuroprotective effects observed in adults, instead displaying upregulation of the proapoptotic protein BH3-interacting domain death agonist (4.3-fold). Adolescent protein expression profiles also suggested impaired phosphoinositide signaling (Protein kinase C: -3.1-fold) and altered neurotransmitter transport and release (Syntaxin 7: 5.7-fold; Dynamin 1: -6.9-fold). The results of the present study provide clues as to possible mechanisms underlying the atypical response of human adolescents to paroxetine treatment.

Activity of mitochondrial respiratory chain is increased by chronic administration of antidepressants

Depressive disorders, including major depression, are serious and disabling for affected patients. Although the neurobiological understanding of major depressive disorder focuses mainly on the monoamine hypothesis, the exact pathophysiology of depression is not fully understood. Animals received daily intra-peritoneal injections of paroxetine (10 mg/kg), nortriptyline (15 mg/kg) or venlafaxine (10 mg/kg) in 1.0 ml/kg volume for 15 days. Twelve hours after the last injection, the rats were killed by decapitation, where the brain was removed and homogenised. The activities of mitochondrial respiratory chain complexes in different brain structures were measured. We first verified that chronic administration of paroxetine increased complex I activity in prefrontal cortex, hippocampus, striatum and cerebral cortex. In addition, complex II activity was increased by the same drug in hippocampus, striatum and cerebral cortex and complex IV activity in prefrontal cortex. Furthermore, chronic administration of nortriptyline increased complex II activity in hippocampus and striatum and complex IV activity in prefrontal cortex, striatum and cerebral cortex. Finally, chronic administration of venlafaxine increased complex II activity in hippocampus, striatum and cerebral cortex and complex IV activity in prefrontal cortex. On the basis of the present findings, it is tempting to speculate that an increase in brain energy metabolism by the antidepressant paroxetine, nortriptyline and venlafaxine could play a role in the mechanism of action of these drugs. These data corroborate with other studies suggesting that some antidepressants modulate brain energy metabolism.

Effects of selective inhibitors of serotonin reuptake on the anxiety behavior and activity of the pituitary-adrenal system in prenatally stressed male rats

We studied effects of the selective inhibitors of serotonin reuptake fluoxetine and paroxetine, which were orally administered at a dose of 5.0 mg/kg from the 1st to 14th days of postnatal life, on the anxiety behavior and hormonal stress reactivity of mature prenatally stressed male rats. We found that prenatal stress decreased the anxiety level in mature male rats. Chronic treatment with paroxetine did not the alter the anxiety behavior of prenatally stressed males. In contrast, treatment with fluoxetine had an anxiogenic effect on their behavior, canceling the effect of prenatal stress on the anxiety behavior of male rats. Prenatal stress considerably affected the dynamics of the stress response of the pituitary-adrenal system, which was seen as disturbances in the regulation of system feedback under conditions of stress-induced activation. Chronic administration of paroxetine or fluoxetine corrected the dynamics of stress-induced levels of corticosterone in the blood of prenatally stressed males.

Evaluation of Krebs cycle enzymes in the brain of rats after chronic administration of antidepressants

Several works report brain impairment of metabolism as a mechanism underlying depression. Citrate synthase and succinate dehydrogenase are enzymes localized within cells in the mitochondrial matrix and are important steps of Krebs cycle. In addition, citrate synthase has been used as a quantitative enzyme marker for the presence of intact mitochondria. Thus, we investigated citrate synthase and succinate dehydrogenase activities from rat brain after chronic administration of paroxetine, nortriptiline and venlafaxine. Adult male Wistar rats received daily injections of paroxetine (10 mg/kg), nortriptiline (15 mg/kg), venlafaxine (10 mg/kg) or saline in 1.0 mL/kg volume for 15 days. Twelve hours after the last administration, the rats were killed by decapitation, the hippocampus, striatum and prefrontal cortex were immediately removed, and activities of citrate synthase and succinate dehydrogenase were measured. We verified that chronic administration of paroxetine increased citrate synthase activity in the prefrontal cortex, hippocampus, striatum and cerebral cortex of adult rats; cerebellum was not affected. Chronic administration of nortriptiline and venlafaxine did not affect the enzyme activity in these brain areas. Succinate dehydrogenase activity was increased by chronic administration of paroxetine and nortriptiline in the prefrontal cortex, hippocampus, striatum and cerebral cortex of adult rats; cerebellum was not affected either. Chronic administration of venlafaxine increased succinate dehydrogenase activity in prefrontal cortex, but did not affect the enzyme activity in cerebellum, hippocampus, striatum and cerebral cortex. Considering that metabolism impairment is probably involved in the pathophysiology of depressive disorders, an increase in these enzymes by antidepressants may be an important mechanism of action of these drugs.

Brain creatine kinase activity is increased by chronic administration of paroxetine

Major depression is a serious and recurrent disorder often manifested with symptoms at the psychological, behavioral, and physiological levels. In addition, several works also suggest brain metabolism impairment as a mechanism underlying depression. Creatine kinase (CK) plays a central role in the metabolism of high-energy consuming tissues such as brain, where it functions as an effective buffering system of cellular ATP levels. Considering that CK plays an important role in brain energy homeostasis and that some antidepressants may modulate energy metabolism, we decided to investigate CK activity from rat brain after chronic administration of paroxetine (selective serotonin reuptake inhibitor), nortriptiline (tricyclic antidepressant) and venlafaxine (selective serotonin–norepinephrine reuptake inhibitor). Adult male Wistar rats received daily injections of paroxetine (10 mg/kg), nortriptiline (15 mg/kg), venlafaxine (10 mg/kg) or saline in 1.0 mL/kg volume for 15 days. Twelve hours after the last administration, the rats were killed by decapitation, the hippocampus, striatum and prefrontal cortex were immediately removed, and activity of CK was measured. Our results demonstrated that chronic administration of paroxetine increased CK activity in the prefrontal cortex, hippocampus and striatum of adult rats. On the other hand, nortriptiline and venlafaxine chronic administration did not affect CK activity in these brain areas. In order to verify whether the effect of paroxetine on CK is direct or indirect, we also measured the in vitro effect of this drug on the activity of the enzyme. We verified that paroxetine did not affect CK activity in vitro. Considering that metabolism impairment is probably involved in the pathophysiology of depressive disorders, an increase in CK activity by antidepressants may be an important mechanism of action of these drugs.

The brain 5‐HT4 receptor binding is down‐regulated in the Flinders Sensitive Line depression model and in response to paroxetine administration

The 5-hydroxytryptamine (5-HT(4)) receptor may be implicated in depression and is a new potential target for antidepressant treatment. We have investigated the brain 5-HT(4) receptor [(3)H]SB207145 binding in the Flinders Sensitive Line rat depression model by quantitative receptor autoradiography, and related this to 5-HT transporter (S)-[N-methyl-(3)H]citalopram binding. We also determined the regulation of 5-HT(4) receptor binding by 1, 14, and 21 days of paroxetine administration and subchronic 5-HT depletion, and compared this with changes in 5-HT(2A) receptor [(3)H]MDL100907 binding. In the Flinders Sensitive Line, the 5-HT(4) receptor and 5-HT transporter binding were decreased in the dorsal and ventral hippocampus, and the changes in binding were directly correlated within the dorsal hippocampus. Chronic but not acute paroxetine administration caused a 16-47% down-regulation of 5-HT(4) receptor binding in all regions evaluated including the basal ganglia and hippocampus, while 5-HT depletion increased the 5-HT(4) receptor binding in the dorsal hippocampus, hypothalamus, and lateral globus pallidus. In comparison, the 5-HT(2A) receptor binding was decreased in the frontal and cingulate cortices after chronic paroxetine administration, and markedly reduced in several regions after 5-HT depletion. Thus, the 5-HT(4) receptor binding was decreased in the Flinders Sensitive Line depression model and in response to chronic paroxetine administration.

A pilot study of the effects of chronic paroxetine administration on hippocampal N-acetylaspartate in generalized anxiety disorder

The neural basis of generalized anxiety disorder (GAD) is poorly characterized. The effect of chronic administration (12 weeks) of paroxetine, a selective serotonin reuptake inhibitor, on N-acetylaspartate (NAA), a marker of neuronal viability, was evaluated in adults with GAD using proton magnetic resonance spectroscopic imaging ((1)H MRSI) at 1.5 T. We hypothesized that, pretreatment abnormalities in hippocampal NAA/creatine (NAA/Cr) would normalize with symptomatic improvement. Nine GAD patients (mean age = 41.7 year; 4 females) received 12 weeks of open-label paroxetine treatment, flexibly dosed up to 60 mg/day. Clinical outcome was assessed with the Hamilton Anxiety Rating Scale (HAM-A). Multislice ( 1)H MRSI scans were performed at unmedicated baseline and following 6 and 12 weeks of treatment. Ten untreated healthy volunteers (HVs) (mean age = 37.1 year; 4 females) received scans at the same intervals. All patients achieved remission (HAM-A <or= 7) by week 12. Compared to HVs, GAD patients showed persistently lower levels of bilateral hippocampal NAA/Cr (17.7% mean decrease; Cohen's d = 1.29) that were maintained across all three time points, despite marked symptom improvement. This pilot study failed to support an association between a hippocampal neuronal marker and anxiolytic response to paroxetine, and suggests further investigation of potential trait-like hippocampal abnormalities in GAD.

Effect of paroxetine on enhanced contextual fear induced by single prolonged stress in rats

Single prolonged stress (SPS) is an animal model of posttraumatic stress disorder (PTSD) that can reproduce enhanced hypothalamo-pituitary-adrenal negative feedback. We examined whether SPS can produce an enhanced psychophysiological reactivity to laboratory stressors unrelated to trauma and whether paroxetine (PRX) can alleviate the enhanced anxiety and fear response in rats subjected to SPS. Furthermore, the effect of PRX on pain sensitivity was examined in rats with and without SPS. Rats were subjected to SPS (restraint for 2 h, forced swim for 20 min, and ether anesthesia) and then kept undisturbed for 14 days. After that, contextual fear response was assessed. Twenty-four hours after foot shock conditioning, freezing behavior was measured during reexposure to the shock environment for 3 min. Pain sensitivity was assessed by the flinch-jump test. PRX (0.01, 0.03, or 0.1 mg/mL) was chronically administered orally in drinking water. Rats subjected to SPS showed a significant increase in contextual freezing compared to rats without SPS. Chronic administration of PRX at concentrations of 0.03 and 0.1 mg/mL (which produced serum concentrations similar to those that are clinically relevant) caused significant suppression of the enhanced contextual freezing. Acute administration of PRX at a dose producing clinically relevant serum concentrations did not affect the enhanced freezing. Our results suggest that SPS can reproduce behavioral alteration similar to that observed in patients with PTSD, and this elevated fear response can be alleviated by the chronic administration of PRX at doses producing clinically relevant serum concentrations.

Chronic administration of selective serotonin reuptake inhibitor (SSRI) paroxetine modulates human motor cortex excitability in healthy subjects

The aim of the study was to investigate the effect of chronic administration of paroxetine (selective serotonin reuptake inhibitor: SSRI) on motor cortex excitability in healthy subjects by means of transcranial magnetic stimulation (TMS), functional magnetic resonance imaging (fMRI) and behavioral motor tests. In a randomized, double-blind, crossover study, twenty-one right-handed subjects received 20 mg daily of either paroxetine or a placebo over a period of 30 days separated by a period of 3 months wash-out. The TMS study is presented here correlated with some results of the motor behavior study (finger tapping test) and the fMRI study (primary sensorimotor cortex (S1M1) volume of activation). TMS was used to test motor threshold (MT), motor evoked potential recruitment curve (RC), cortical silent period (CSP) and paired-pulse intracortical inhibition and facilitation (ICI, ICF). Chronic administration of paroxetine did not modulate ICI or CSP but induced a significant enhancement of mean ICF (ANOVA P = 0.04), which significantly correlated with increase of speed in a finger tapping test ( P = 0.02). This suggests a modulation of cortical interneuronal excitatory pathways without changes in the excitability of cortical inhibitory GABAergic interneurons. A decrease of RC (ANOVA P = 0.05) was also observed after 30 days intake of paroxetine in comparison with placebo and was associated with changes of fMRI activation intensity (left S1M1 hypoactivation, Loubinoux, I., Tombari, D., Pariente, J., Gerdelat, A., Pastor, J., Cassol, E., Rascol, O. and Chollet, F., Modulation of behavior and cortical motor activity in healthy subjects by a chronic administration of a serotonin enhancer. NeuroImage (in press)), without changes of S1M1 activation volume. Finally, the different modulation of RC and ICF after chronic administration of paroxetine compared to single dose (opposite effects) emphasizes the different pharmacological action of the drug at cortical level depending on its acute or long-term administration.

Modulation of behavior and cortical motor activity in healthy subjects by a chronic administration of a serotonin enhancer

SSRIs are postulated to modulate motor behavior. A single dose of selective serotoninergic reuptake inhibitors (SSRIs) like fluoxetine, paroxetine, or fluvoxamine, has been shown to improve motor performance and efficiency of information processing for simple sensorimotor tasks in healthy subjects. At a cortical level, a single dose of SSRI was shown to induce a hyperactivation of the primary sensorimotor cortex (S1M1) involved in the movement (Loubinoux, I., Boulanouar, K., Ranjeva, J. P., Carel, C., Berry, I., Rascol, O., Celsis, P., and Chollet, F., 1999. Cerebral functional magnetic resonance imaging activation modulated by a single dose of the monoamine neurotransmission enhancers fluoxetine and fenozolone during hand sensorimotor tasks. J. Cereb. Blood Flow Metab. 19 1365–1375, Loubinoux, I., Pariente, J., Boulanouar, K., Carel, C., Manelfe, C., Rascol, O., Celsis, P., and Chollet, F., 2002. A Single Dose of Serotonin Neurotransmission Agonist Paroxetine Enhances Motor Output. A double-blind, placebo-controlled, fMRI study in healthy subjects. NeuroImage 15 26–36). Since SSRIs are usually given for several weeks, we assessed the behavioral and cerebral effects of a one-month chronic administration of paroxetine on a larger group. In a double-blind, placebo controlled and crossover study, 19 subjects received daily 20 mg paroxetine or placebo, respectively, over a period of 30 days separated by a wash-out period of 3 months. After each period, the subjects underwent an fMRI (active or passive movement, dexterity task, sensory discrimination task) and a behavioral evaluation. Concurrently, a TMS (transcranial magnetic stimulation) study was conducted (Gerdelat-Mas, A., Loubinoux, I., Tombari, D., Rascol, O., Chollet, F., Simonetta-Moreau, M., 2005. Chronic administration of selective serotonin re-uptake inhibitor (SSRI) paroxetine modulates human motor cortex excitability in healthy subjects. NeuroImage 27 314–322). Results: On the one hand, paroxetine improved motor performances at the finger tapping test ( P = 0.02) without affecting choice reaction time, strength and dexterity significantly. Subjects were also faster in processing the spatial incongruency between a stimulus and the motor response ( P = 0.04). In order to differentiate behavioral components, a principal component analysis was performed on all motor tests, and several characteristics were differentiated: strength, speed, skill, attention, and motor response coding. Paroxetine would improve the efficiency of motor response coding (MANOVA on the factors; factor 3, P = 0.01). On the other hand, the chronic administration induced a significant hypoactivation of S1M1 whatever the task: motor or sensory, simple or complex (random effect analysis, P < 0.05). The hypoactivation correlated with the improvement of performances at the finger tapping test ( P < 0.05) suggesting more efficiency in cerebral motor processing. Conclusions: Our results showed a clear modulation of sensory and motor cerebral activation after a chronic paroxetine administration. An improvement in both behavior and cerebral efficiency was suggested. It could be hypothesized that monoamines, by an unspecific effect, may tune the response of pyramidal neurons to optimize performances.

Effect of Repeated Administration of Paroxetine and Electroconvulsive Shock on the Proliferative Response of Lymphocytes and the Synthesis of Nitric Oxide by Macrophages in Rats

We sought to determine whether chronic administration of paroxetine and electroconvulsive shock (ECS), given separately or jointly, changes the proliferative response of T and B lymphocytes stimulated by mitogens and affect the production of nitric oxide (NO) by peritoneal macrophages. The experiment was conducted on male Wistar rats receiving treatment once daily for 12 consecutive days. Control animals were injected intraperitoneally (ip) with sterile distilled water (2 mL/kg) and were subjected to sham ECS. Paroxetine was administered ip in a dose of 10 mg/kg of body weight. ECS (150 mA, 50 Hz, 0.5 seconds) was delivered through ear clips. For combined treatment, paroxetine was given 30 minutes before ECS. The rats were killed 24 hours after the last treatment. Then, the proliferative response of splenocytes was induced by concanavalin A (Con A), lipopolysaccharide (LPS), or pokeweed mitogen and those of thymocytes by Con A and was later assessed by a standard [H]-thymidine incorporation assay. The spontaneous or induced (with LPS) NO synthesis in peritoneal macrophages was assessed as nitrite accumulation in 24-hour culture supernatants using the Griess reaction. Only chronic treatment with ECS alone significantly increased the proliferative response of splenocytes to stimulation with Con A or LPS. The response of thymocytes was not changed in any group tested. Both the spontaneous NO synthesis and that induced with LPS in macrophages were significantly decreased only in rats receiving ECS. We suggest that the ECS-induced suppression of NO synthesis by macrophages, resulting from the noradrenergic component of ECS action, may be responsible for the enhanced proliferative response of lymphocytes. Our data are in line with the results of other authors indicating that paroxetine and/or ECS modulate the immune system indirectly via the neuroendocrine system. The relatively high efficacy of ECS in the therapy for depression may be attributable to the ECS-evoked long-lasting changes in the immune system, which supports the macrophage theory of depression.

Effects of chronic paroxetine treatment on dialysate serotonin in 5-HT1B receptor knockout mice.

The role of serotonin (5-HT)1B receptors in the mechanism of action of selective serotonin re-uptake inhibitors (SSRI) was studied by using intracerebral in vivo microdialysis in conscious, freely moving wild-type and 5-HT1B receptor knockout (KO 5-HT1B) mice in order to compare the effects of chronic administration of paroxetine via osmotic minipumps (1 mg per kg per day for 14 days) on extracellular 5-HT levels ([5-HT]ext) in the medial prefrontal cortex and ventral hippocampus. Basal [5-HT]ext values in the medial prefrontal cortex and ventral hippocampus, approximately 20 h after removing the minipump, were not altered by chronic paroxetine treatment in both genotypes. On day 15, in the ventral hippocampus, an acute paroxetine challenge (1 mg/kg i.p.) induced a larger increase in [5-HT]ext in saline-pretreated mutant than in wild-type mice. This difference between the two genotypes in the effect of the paroxetine challenge persisted following chronic paroxetine treatment. Conversely, in the medial prefrontal cortex, the paroxetine challenge increased [5-HT]ext similarly in saline-pretreated mice of both genotypes. Such a challenge produced a further increase in cortical [5-HT]ext compared with that in saline-pretreated groups of both genotypes, but no differences were found between genotypes following chronic treatment. To avoid the interaction with raphe 5-HT1A autoreceptors, 1 micro m paroxetine was perfused locally through the dialysis probe implanted in the ventral hippocampus; similar increases in hippocampal [5-HT]ext were found in acutely or chronically treated wild-type mice. Systemic administration of the mixed 5-HT1B/1D receptor antagonist GR 127935 (4 mg/kg) in chronically treated wild-type mice potentiated the effect of a paroxetine challenge dose on [5-HT]ext in the ventral hippocampus, whereas systemic administration of the selective 5-HT1A receptor antagonist WAY 100635 did not. By using the zero net flux method of quantitative microdialysis in the medial prefrontal cortex and ventral hippocampus of wild-type and KO 5-HT1B mice, we found that basal [5-HT]ext and the extraction fraction of 5-HT were similar in the medial prefrontal cortex and ventral hippocampus of both genotypes, suggesting that no compensatory response to the constitutive deletion of the 5-HT1B receptor involving changes in 5-HT uptake capacity occurred in vivo. As steady-state brain concentrations of paroxetine at day 14 were similar in both genotypes, it is unlikely that differences in the effects of a paroxetine challenge on hippocampal [5-HT]ext are due to alterations of the drug's pharmacokinetic properties in mutants. These data suggest that there are differences between the ventral hippocampus and medial prefrontal cortex in activation of terminal 5-HT1B autoreceptors and their role in regulating dialysate 5-HT levels. These presynaptic receptors retain their capacity to limit 5-HT release mainly in the ventral hippocampus following chronic paroxetine treatment in mice.

Evidence that chronic administration of paroxetine or fluoxetine enhances 5-HT 2 receptor function in the brain of the guinea pig

The effects of chronic treatment with antidepressants on 5-HT-stimulated hydrolysis of phosphoinositide (PI) in the cerebral cortex of the guinea pig were examined. The pharmacological profile of the response was consistent with it being mediated by a 5-HT 2 receptor. Chronic (but not acute) treatment with the selective 5-HT uptake inhibitors, paroxetine and fluoxetine (10 mg/kg, p.o., for 21 days), resulted in a significant increase in the maximum response to 5-HT without altering the EC 50. There were no significant alterations in the density or affinity of 5-HT 2 receptors, labelled with [ 3H]ketanserin. In contrast, treatment with the tricyclic antidepressant, amitriptyline (10 mg/kg, p.o., for 21 days), did not produce a significant change in 5-HT-stimulated hydrolysis of PI or in the number and affinity of 5-HT 2 receptors. The findings are discussed in relation to the possible neurochemical targets for antidepressant drugs and species differences in the responses to these agents.

Effects of paroxetine on 5-HT-induced head twitches and phosphatidylinositol hydrolysis in mice.

Head-twitch response and phosphatidylinositol (PIP) hydrolysis in cortex and spinal cord were measured after single or chronic (21 days) administration of paroxetine to normal mice or to mice neonatally treated with 5,7-dihydroxytryptamine, a serotonergic neurotoxin. In normal animals, a down-regulation of 5-HT-receptor numbers after chronic paroxetine was suggested by the attenuation of head-twitch responses compared with a single dose. There was a concomitant decrease in PIP hydrolysis. In DHT-treated animals, although changes in behavioural responses were comparable to those in normals, PIP hydrolysis in cortex and spinal cord after chronic paroxetine increased significantly. These results demonstrate that head-twitch responses and PIP hydrolysis may not be mediated by the same receptor and that the effects of chronic administration of paroxetine depend on the functional state of the serotonergic pathways.