Autoreceptor Sensitivity Research Articles

Environmental enrichment enhances the stimulant effect of intravenous amphetamine: Search for a cellular mechanism in the nucleus accumbens

The nucleus accumbens and its related neural circuitry are known to be involved in mediating drug reward. The present brief review provides evidence that manipulation of the stimulus environment may alter the behavioral effects of drugs of abuse by altering accumbal circuitry. In experiments conducted in our laboratory, rats were raised in either an enriched condition (EC) or an impoverished condition (IC) and then were challenged with acute intravenous amphetamine. EC rats were more sensitive than IC rats to the locomotor stimulant effect of amphetamine, as well as to the accumbal dopamine release measured by in vivo microdialysis. No environment-induced difference in [3H]-amphetamine pharmacokinetics was observed. In vitro neurochemical experiments also indicated that accumbal tissue slices isolated from EC and IC rats did not differ in dopamine levels, electrically evoked dopamine release, or dopamine autoreceptor sensitivity. Although the kinetic parameters for [3H]-dopamine uptake into striatal synaptosomes were not different between EC and IC rats, the transport inhibitor GBR 12935 was more potent in inhibiting uptake in EC rats than in IC rats. The latter results suggest that dopamine transporter proteins in the nucleus accumbens may be an important target for future studies aimed at identifying the cellular mechanism responsible for the environmentinduced difference in the behavioral response to amphetamine.

Effect of long-term administration of antidepressant treatments on serotonin release in brain regions involved in obsessive–compulsive disorder

Background: Among all antidepressant treatments, including electroconvulsive shock (ECS) therapy and monoamine oxidase inhibitors (MAOIs), only the selective serotonin (5-HT) reuptake inhibitors (SSRIs) exert a clear therapeutic effect in obsessive–compulsive disorder (OCD). An 8-week, but not a 3-week treatment with the SSRI paroxetine results in an increased electrically evoked [3H]5-HT release and a desensitization of 5-HT autoreceptors in the guinea pig orbitofrontal cortex, a brain region implicated in OCD.Methods: In the present study, the effect of long-term treatment with the SSRI fluoxetine, ECS, and the reversible type A MAOI moclobemide was investigated on evoked [3H]5-HT release from preloaded guinea pig brain slices prepared from the hypothalamus, cingulate cortex, and orbitofrontal cortex.Results: Fluoxetine treatment yielded an enhanced [3H]5-HT release in the three brain areas, but a desensitization of the 5-HT autoreceptor only in the hypothalamus and orbitofrontal cortex. ECS treatment did not result in any alteration of the electrically evoked [3H]5-HT release or of 5-HT autoreceptor sensitivity in any of the brain regions. Moclobemide increased [3H]5-HT release only in the orbitofrontal cortex without any alteration in the 5-HT autoreceptor sensitivity.Conclusions: These findings indicate that only treatments effective in OCD have the capacity to desensitize the terminal 5-HT autoreceptor in the orbitofrontal cortex.

Adaptations in the mesoaccumbens dopamine system resulting from repeated administration of dopamine D 1 and D 2 receptor-selective agonists: relevance to cocaine sensitization

The mesoaccumbens dopamine (DA) system is intricately involved in sensitization to the locomotor stimulant effects of cocaine. Among the adaptations implicated in cocaine sensitization are transient subsensitivity of impulse-regulating DA D2 autoreceptors on ventral tegmental area (VTA) DA neurons leading to hyperactivity of the mesoaccumbens DA pathway, and persistently enhanced DA D1 receptor responses of nucleus accumbens (NAc) neurons. We have tested the hypothesis that both of these adaptations are necessary to produce cocaine sensitization. We injected rats twice daily for 2 weeks with the selective DA D1 class receptor agonist SKF 38393, the DA D2 class receptor agonist quinpirole, or both. We then used single-cell recording procedures to determine possible alterations in VTA DA autoreceptor sensitivity and NAc D1 receptor sensitivity at three withdrawal times: 1 day, 1 week and 1 month. We also tested whether these treatments produced cross-sensitization to cocaine at each withdrawal time. Repeated quinpirole treatment produced a reduction in VTA autoreceptor sensitivity and cross-sensitization to cocaine, but these effects lasted for less than 1 week. Repeated SKF 38393 treatment produced enhanced NAc D1 responses which lasted for 1 week and cross-sensitization to cocaine which was only evident after 1 week of withdrawal. Repeated treatment with the combination of the two agonists transiently down-regulated autoreceptor sensitivity, enhanced and prolonged D1 receptor supersensitivity (lasting 1 month), and produced enduring cross-sensitization to cocaine. These results suggest that neuroadaptations within both the VTA and NAc may be necessary for the induction of enduring cocaine sensitization.

Dopamine Autoreceptors in Rat Nucleus Accumbens Modulate Prepulse Inhibition of Acoustic Startle

Dopamine and 3,4-dihydroxy phenylacetic acid (DOPAC) levels in discrete regions and apomorphine- or (−)-sulpiride–induced changes in electrically evoked dopamine release from nucleus accumbens slices were assessed after testing prepulse inhibition of acoustic startle (PPI) in rats. Dopamine and DOPAC levels in the nucleus accumbens, but not in the striatum, correlated well with PPI ( r = −0.64 for dopamine, r = −0.48 for DOPAC). Evoked dopamine release from the nucleus accumbens did not differ between the high-PPI (more than 60%) and the low-PPI (less than 40%) group. When slices were superfused with 1 μM apomorphine, the S2/S1 ratio in rats showing high PPI was 0.77 ± 0.02 (mean ± SEM, 66% of control), significantly smaller than in the low-PPI group (S2/S1 ratio = 0.97 ± 0.08, 94% of control, p < 0.05). Moreover, (−)-sulpiride–induced increase in evoked dopamine release from the nucleus accumbens in the high-PPI group was inclined to be greater than in the low-PPI group. The results suggest that PPI differences between individuals may reflect the sensitivity of release-modulating dopamine autoreceptors in the nucleus accumbens.

The effect of the selective 5-HT1A agonists alnespirone (S-20499) and 8-OH-DPAT on extracellular 5-hydroxytryptamine in different regions of rat brain.

1. We have examined the effects of the systemic administration of the selective 5-HT1A agonist alnespirone (S-20499) on in vivo 5-hydroxytryptamine (5-HT) release in the dorsal raphe nucleus, the median raphe nucleus and four forebrain areas innervated differentially by both (dorsal striatum, frontal cortex, ventral hippocampus and dorsal hippocampus). 2. Alnespirone (0.1-3 mg kg(-1), s.c.) dose-dependently reduced extracellular 5-HT in the six areas examined. In forebrain, the maximal reductions occurred in striatum and frontal cortex (maximal reduction to 23 and 29% of baseline, respectively). Those in dorsal and ventral hippocampus were more moderate (to ca 65% of baseline). In contrast, the decrease in 5-HT elicited in the median raphe nucleus was more marked than that in the dorsal raphe nucleus (to ca 30 and 60% of baseline, respectively). The selective 5-HT1A antagonist WAY-100635 (0.5 mg kg(-1), s.c.) prevented the decrease in 5-HT induced by alnespirone (0.3 mg kg(-1), s.c.) in frontal cortex. 3. 8-OH-DPAT (0.025, 0.1 and 0.3 mg kg(-1), s.c.) also reduced extracellular 5-HT in a regionally-selective manner (e.g., to 32% of baseline in striatum and to 69% in dorsal hippocampus at 0.1 mg kg(-1), s.c.). In midbrain, 8-OH-DPAT reduced the dialysate 5-HT slightly more in the median than in the dorsal raphe nucleus at all doses examined. 4. Doses of both compounds close to their respective ED50 values (0.3 mg kg(-1) alnespirone, 0.025 mg kg(-1) 8-OH-DPAT) reduced 5-HT to a comparable extent in all regions examined. However, the reductions attained at higher doses were more pronounced for 8-OH-DPAT. 5. These data show that the reduction of 5-HT release elicited by alnespirone and 8-OH-DPAT is more important in forebrain areas innervated by 5-hydroxytryptaminergic neurones of the dorsal raphe nucleus. This regional selectivity seems unlikely to be accounted for by differences in the sensitivity of 5-HT1A autoreceptors controlling 5-HT release, given the dissimilar effects of these two 5-HT1A agonists in regions rich in cell bodies and nerve terminals. This suggests the presence of complex mechanisms of control of 5-HT release by 5-HT1A receptors.

Effects of sleep deprivation on serotonergic neuronal activity in the dorsal raphe nucleus of the freely moving cat

Total sleep deprivation (TSD) for one or more nights produces a rapid antidepressant response in humans. Since most pharmacological treatments for depression increase brain serotonin neurotransmission, the purpose of the present study was to determine whether TSD increases the activity of serotonergic neurons in the dorsal raphe nucleus (DRN) in cats. Cats were prevented from sleeping by the experimenter, who monitored the behavioral state of each animal on a polygraph. Firing rates during quiet waking (QW) and active waking (AW) were obtained throughout a 24-h sleep deprivation period and subsequent 6-h recovery period. During the experiments, unit activity was also recorded during exposure to loud white noise, which elicited strong behavioral arousal. The inhibitory response of serotonergic DRN neurons to systemic administration of the selective 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was determined before and after TSD to assess possible changes in 5-HT1A autoreceptor sensitivity. TSD increased mean firing rates by as much as 18% during both AW and white noise exposure. Maximal effects were observed after 15 h of TSD for AW, and after 18 h for white noise. QW firing rates also tended to be elevated throughout TSD. Firing rates for all conditions during the recovery period were not significantly different from baseline. The neuronal inhibition produced by 8-OH-DPAT was significantly diminished after TSD. Overall, these results indicate that TSD increases the firing rate of serotonergic DRN neurons during AW and arousal. This effect may be attributable to a decrease in the sensitivity of 5-HT1A autoreceptors. These findings are consistent with the hypothesis that TSD exerts its antidepressant action, at least in part, through an activation of brain serotonergic neurons.

Developmental differences in dopamine synthesis inhibition by (+/-)-7-OH-DPAT.

Dopamine synthesis modulation by the D2-family agonist (+/-)-7-OH-DPAT was explored in striatum, accumbens, and prefrontal cortex of 10-40 day old rats using the gamma-butyrolactone (GBL) autoreceptor model. GBL produced an age-dependent increase in dopamine synthesis that was inhibited by (+/-) 7-OH-DPAT (0.1-13.5 mg/kg) at all ages and antagonized by eticlopride in the nucleus accumbens and striatum. The ID50 of (+/-) 7-OH-DPAT increased with age, suggesting decreased autoreceptor sensitivity with maturation. In prefrontal cortex, (+/-) 7-OH-DPAT inhibited synthesis between 10-30 days, with no evidence of autoreceptor function at 40 days. Dopamine synthesis was also inhibited with the D3/D2 agonist quinpirole at 15 days of age in vivo and yielded similar results to those obtained with (+/-) 7-OH-DPAT. Finally, under conditions that result in low D2 receptor affinity, D3 specificity was examined in vitro at 15 days with (+/-) 7-OH-DPAT, which produced comparable (yet more potent) effects to those observed in vivo. These findings illustrate D3 autoreceptor-like activity in ascending dopamine regions and provide further support for transient prefrontal cortex autoreceptor-like function that recedes by puberty.

Stress-induced alterations of somatodendritic 5-HT1A autoreceptor sensitivity in the rat dorsal raphe nucleus--in vitro electrophysiological evidence.

Somatodendritic 5-HT1A autoreceptors play a key role in the control of the electrical and metabolic activity of serotoninergic neurons in the dorsal raphe nucleus. These neurons also possess intracellular glucocorticoid receptors which may be involved in the well established modulation of serotonin (5-hydroxytryptamine, 5-HT) metabolism by corticosterone in stressed animals. The possible mediation by somatodendritic 5-HT1A autoreceptors of such corticosterone-dependent changes in serotoninergic neuron activity was investigated using an in vitro electrophysiological approach. 5-HT1A autoreceptor-mediated inhibition of the firing of serotoninergic neurons was examined in brain stem slices from rats whose serum corticosterone concentrations had been markedly increased (+100-200%) by two different stressful conditions. Immobilization for 30 or 90 min (restraint stress) did not modify the concentration-dependent inhibition of the firing of serotoninergic neurons by the 5-HT1A receptor agonist ipsapirone. In contrast, placing the rats in novel uncontrolled environmental conditions for 16 h significantly reduced the cell response to ipsapirone, indicating a decreased sensitivity of somatodendritic 5-HT1A autoreceptors. Such a change was not observed in adrenalectomized rats subjected to the same stressful conditions. These data show that some forms of stress can reduce the 5-HT1A autoreceptor-dependent inhibitory control of the electrophysiological activity of serotoninergic neurons in the dorsal raphe nucleus. Both the nature and duration of stress seem to be critical factors for triggering the (corticosterone-dependent) mechanism(s) responsible for the functional desensitization of 5-HT1A autoreceptors in stressed rats.

Autoreceptor Antagonists Enhance the Effect of the Reuptake Inhibitor Citalopram on Extracellular 5-HT: this Effect Persists After Repeated Citalopram Treatment

The effect of repeated administration of the reuptake inhibitor citalopram (10 mg/kg s.c., b.i.d. for 14 days) or saline on extracellular 5-hydroxytryptamine (5-HT) and autoreceptor sensitivity was assessed using microdialysis in the frontal cortex (FCx) and dorsal hippocampus (DH) of unanesthetized rats. Acute citalopram (5 mg/kg s.c.) challenge produced significant increases in DH and FCx 5-HT. The nonselective 5-HT1A/1B receptor antagonist (−)-penbutolol (8 mg/kg s.c.), administered 2 hr after citalopram challenge, significantly enhanced 5-HT in FCx and DH of both the chronic citalopram and saline pretreatment groups. Administration of the selective 5-HT1A receptor antagonist WAY 100635 (0.3 mg/kg s.c.) after citalopram challenge significantly enhanced 5-HT in FCx but not DH of both pretreatment groups. This suggests that there may be differences between DH and FCx in regulation of 5-HT release. Nevertheless, these results provide evidence that 5-HT autoreceptors are still active in restraining 5-HT release even after repeated administration of an antidepressant drug. © 1997 Elsevier Science Ltd.

Effects of Food Deprivation on Midbrain 5-HT1A Autoreceptors in Lewis and SHR Rats

Food deprivation stimulates the activity of the hypothalamo-pituitary-adrenal axis and brain serotonin (5-hydroxytryptamine, 5-HT) synthesis. Because midbrain somato-dendritic 5-HT1A autoreceptors may obey homologous and heterologous (e.g. by glucocorticoids) down-regulation, we have analyzed whether 24 hr of fasting affects midbrain 5-HT1A receptor binding and sensitivity in Lewis and SHR rats (i.e. strains that differ in behavioral/neuroendocrine responses to stressors). Fasting affected neither [3H]8-hydroxy-2-(di-N-propylamino)tetralin ([3H]8-OH-DPAT) binding at 5-HT1A autoreceptors nor 8-OH-DPAT-induced inhibition of midbrain 5-HT synthesis (an index of 5-HT1A autoreceptor sensitivity). Because fasting increased 5-HT precursor (tryptophan) levels to similar extents in the midbrains of saline- and 8-OH-DPAT-treated rats, we conclude that food deprivation does not affect 5-HT1A autoreceptors. In turn, our results suggest that the differential effects of 5-HT1A receptor agonists on food intake, in fed and fasted rats may be independent from 5-HT1A autoreceptors. © 1997 Elsevier Science Ltd.

Effects of acute, chronic ethanol and withdrawal on dorsal raphe neurons: electrophysiological studies

The effect of a single intravenous administration of ethanol (0.25–1.0 g/kg) on the spontaneous activity of putative serotonin neurons of the dorsal raphe nucleus was studied in unanesthetized rats. Ethanol produced a slight but progressive decline in neuronal activity in 67% (six of nine) of all neurons tested. The remaining 33% (three of nine) were unresponsive. Upon withdrawal of chronic ethanol treatment (1–5 g/kg every 6 h for six consecutive days, 12 h from last ethanol administration), the mean firing rate of dorsal raphe neurons was found to be significantly reduced, by about 30% ( n=71), as compared with the control group ( n=83), whereas the cells/track index was unaltered. Under these conditions, ethanol administration further reduced firing rate in 67% (four of six) of all the neurons tested. In the remaining 33% (two of six), no response was observed. At 72 h after the last ethanol administration, the mean firing rate of dorsal raphe neurons was found to be within control values ( n=90). Further, to evaluate the functional status of the autoreceptors under control conditions and after withdrawal from chronic ethanol, the selective serotonin-1A receptor agonist 8-hydroxy-(2-di-n-propylamino)tetralin was administered intravenously in cumulative doses (1–16 μg/kg) and dose–response curves were generated for both groups. Autoreceptor sensitivity of dorsal raphe neurons was found to be not statistically different in control and ethanol withdrawn rats ( n=6 for both groups) as indexed by a similar potency displayed by 8-hydroxy-(2-di-n-propylamino)tetralin in reducing the spontaneous activity of dorsal raphe neurons. The results indicate that, in spite of the widespread use of serotonin transmission potentiating agents in the treatment of alcoholism, neither acute nor withdrawal from chronic ethanol administration produces drastic effects on dorsal raphe neurons. However, the inhibition of dorsal raphe neuronal activity after acute ethanol may be due to the reported ability of ethanol to increase serotonin release from terminal areas. This increased serotonin tone could, at the level of recurrent axon collaterals in the dorsal raphe nucleus, reduce the spontaneous activity of the cells. On the other hand, a similar reduction in spontaneous activity after withdrawal from ethanol correlates well with the reduction in serotonin levels observed under these conditions in microdialysis studies.

Regional differences in the effect of the combined treatment of WAY 100635 and fluoxetine: an in vivo microdialysis study

We studied the changes in extracellular serotonin (5-HT) levels in the frontal cortex (FC) and ventral hippocampus (vHi) in conscious rats, induced by the combined administration of a highly selective 5-HT1A receptor antagonist, WAY 100635 (0.1 mg/kg, i.v.), and fluoxetine (1 mg/kg, i.p.), a selective 5-HT reuptake inhibitor (SSRI). In the two brain areas studied, no change in extracellular 5-HT concentrations was observed following fluoxetine administration over the 210 min post-injection period. However, in animals co-administered with [WAY 100635 + fluoxetine], the maximal increase in 5-HT levels in the FC was to 215% of the respective basal value (100%), while no significant change in 5-HT was observed in dialysates from the vHi. Furthermore, the [norfluoxetine]-to-[fluoxetine] ratio in the FC was significantly higher than in the hippocampus as measured in homogenates of animals treated with either fluoxetine alone or a prior administration of WAY 100635. Thus, WAY 100635 made the fluoxetine short-lasting effect apparent in the FC, but not by interfering with pharmacokinetic parameters of fluoxetine. Taken together, our data suggest the possibility, that either 5-HT1A autoreceptor sensitivity or uptake carrier density or higher [metabolite]-to-[parent drug] ratios in the FC than in the hippocampus may be involved in regional specific responses to SSRIs.

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.

Amphetamine-induced changes in nigrostriatal terminal excitability are modified following repeated amphetamine pretreatment

To investigate neural mechanisms associated with behavioral sensitization to amphetamine, we studied the effect of an intrastriatal infusion of amphetamine on nigrostriatal axon terminal electrical excitability in rats following withdrawal from repeated systemic treatment. Rats were injected with amphetamine 2.5 mg/kg s.c. or saline daily for 4 days. Either 24 h or 14 days after the last injection, extracellular recordings were obtained from dopaminergic neurons of the substantia nigra, in a blind design in which the experimenter did not know the pretreatment regime. In order to assess the electrical excitability of the nigrostriatal axonal field, neurons were activated antidromically by stimulating their terminal fields in the striatum. As previously reported, striatal infusion of amphetamine (1 μM/0.3 μl) in control animals resulted in a significant reduction in excitability as indicated by an increase in striatal stimulus current necessary to evoke antidromic activity. In contrast, intrastriatal amphetamine administration to amphetamine-pretreated animals did not decrease excitability. Spontaneous firing rates and patterns of cell discharge did not differ between saline and amphetamine-treated animals. The chronic amphetamine-induced change in the effect of an acute intrastriatal amphetamine infusion on nigrostriatal terminal excitability may be due to enduring alterations in the amphetamine-induced release of dopamine and other striatal neurotransmitters or to changes in the sensitivity of presynaptic hetero and/or autoreceptors on the dopaminergic axons.

Dopamine autoreceptor sensitivity is unchanged in rat nucleus accumbens after chronic haloperidol treatment: an in vivo and in vitro voltammetric study.

Fast cyclic voltammetry was used to assess the effects of chronic oral haloperidol treatment (0.7 mg/kg/day for 21 days) on the sensitivity of dopamine autoreceptors in the rat nucleus accumbens both in vivo and in vitro. Evoked dopamine overflow was significantly reduced after chronic haloperidol treatment, but the sensitivity of dopamine overflow to sulpiride, an antagonist at release-inhibiting dopamine autoreceptors, and quinpirole, an agonist at these receptors, was unchanged. The estimated EC50 values for quinpirole and sulpiride (52 and 60 nM respectively) obtained in vitro and the receptor distribution profiles published in the literature suggest that the autoreceptors involved in this modulation are mainly of the D3 subtype. The finding that the reduced dopamine overflow in the nucleus accumbens observed after chronic treatment with a classical neuroleptic is not due to dopamine autoreceptor supersensitivity may therefore be the first functional evidence for unchanged autoreceptor activity in the nucleus accumbens, supporting biochemical findings of a lack of D3 autoreceptor up-regulation after chronic haloperidol treatment. It lends further support to the assumption that the long-term changes occurring during chronic neuroleptic treatment may not lie at the level of presynaptic dopamine receptor regulation.

Extracellular concentrations of serotonin in the dorsal hippocampus after acute and chronic treatment with citalopram

Citalopram, 1 and 10 mg/kg i.p., that in a previous study using identical treatment and dialysis conditions had little or no effect on dialysate serotonin (5-HT) in the frontal cortex, dose-dependently raised the extracellular concentrations of 5-HT in the dorsal hippocampus, by 70% and 205% respectively at the peak. In animals given 10 mg/kg citalopram twice daily for 14 days, intraperitoneal doses of 1 and 10 mg/kg or infusion of 10 −8−10 −6 M through the hippocampal probe raised dialysate 5-HT in the dorsal hippocampus similarly in animals treated chronically with citalopram or saline. A dose of 100 μg/kg 8-hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT), an agonist at 5-HT 1A receptors, reduced hippocampal extracellular 5-HT concentrations to the same extent in rats repeatedly given saline or citalopram. Half this dose had no such effect in either group. The effect of citalopram and the sensitivity of autoreceptors controlling 5-HT release in the dorsal hippocampus were unaffected by a chronic treatment known to facilitate the drug's effect on dialysate 5-HT and to reduce the sensitivity of 5-HT 1A receptors controlling 5-HT release in the frontal cortex. The effects of acute and chronic treatment with citalopram on dialysate 5-HT in the rat brain thus appear to differ in at least two brain regions: the frontal cortex and the dorsal hippocampus.

Functional Correlates Of 5-HT1A Receptor Activation After Exposure To Repeated Cocaine Administration In Rats

It is well known that acute cocaine treatment has profound effects on serotonin (5-HT) neurons, but the consequences of chronic cocaine administration on 5-HT neurotransmission are not well studied. We used the 5-HT agonist 80H-DPAT as a probe to assess 5-HT1A receptor function in vivo in rats previously exposed to cocaine. Rats were treated with cocaine (15 mg/kg, ip) twice daily for one week. After 42 hr and 8 days of withdrawal, rats were challenged with 80H-DPAT (10-300 μg/kg, sc) or vehicle, and various endpoints were evaluated including: 5-HT synthesis in discrete brain regions, feeding, plasma prolactin, and the 5-HT behavioral syndrome. Prior cocaine exposure did not alter the 80H-DPAT-induced inhibition of 5-HT synthesis in any brain region examined. Although cocaine-treated rats exhibited higher basal rates of feeding, the hyperphagia produced by 80H-DPAT was comparable in cocaine- and saline-treated groups. The plasma prolactin response to 80H-DPAT was significantly blunted in cocaine-treated animals at 42 hr of withdrawal, and this effect was maintained at 8 days. Cocaine exposure did not affect the 5-HT behavioral syndrome elicited by 80H-DPAT. These data indicate that prior cocaine administration does not change 5-HT1A autoreceptor sensitivity (as measured by inhibition of 5-HT synthesis and hyperphagia). However, the attenuated prolactin response to 80H-DPAT suggests that cocaine renders postsynaptic 5-HT1A receptor mechanisms subsensitive in some brain regions. Deficits in 5-HT1A receptor function may underlie feelings of anxiety experienced by cocaine addicts during periods of drug withdrawal.

Lack of circadian variation in the sensitivity of rat terminal 5-HT1B autoreceptors.

The sensitivity of terminal 5-HT1B autoreceptors in the cerebral cortex and hippocampus to both agonist and antagonist was determined at four different time points in the light:dark cycle of the rat to evaluate whether changes in their responsiveness underlie the circadian rhythm in 5-hydroxytryptamine (5-HT) release. No significant circadian differences were evident in the apparent pIC50 values calculated for 5-HT to inhibit K(+)-evoked tritium efflux or in the apparent pA2 values calculated for methiothepin to antagonize the effect of 5-HT, at the different time points, in either brain region. These findings suggest that the sensitivity of terminal 5-HT1B autoreceptors in rat cerebral cortex and hippocampus does not change in a circadian pattern, during the light:dark cycle, and argues against such a change influencing the circadian variation in 5-HT release.

Increase in extracellular serotonin produced by uptake inhibitors is enhanced after chronic treatment with fluoxetine

The effect of prolonged uptake inhibition with fluoxetine (10 mg/kg/day i.p. × 14 days) on extracellular serotonin (5-HT) in the rat diencephalon was monitored using in vivo microdialysis. The increase in extracellular 5-HT after repeated administration of fluoxetine was significantly greater than the increase produced by a single injection of this uptake blocker. This difference may have been due to a decrease in somatodendritic autoreceptor sensitivity, since the response to a low dose of the 5-HT 1A agonist 8-OH-DPAT (25 μg/kg i.v.) was abolished in the chronic rats, while the response to a high dose (100 μg/kg i.v.) was attenuated as compared to animals injected once with fluoxetine.

5-HT1A Receptor Sensitivity in Major Depression

The hypothermic, growth hormone and corticotrophin (ACTH) responses to the 5-HT1A receptor agonist buspirone (30 mg orally) were measured in 20 unmedicated patients with major depression and 20 healthy controls. Compared with the controls, the hypothermic responses of the depressed patients to buspirone were significantly attenuated, particularly in patients with melancholic depression. In contrast, the responses of growth hormone and ACTH to buspirone were unchanged. The data suggest that major depression may be associated with impaired sensitivity of 5-HT1A autoreceptors but that the function of the post-synaptic 5-HT1A receptors that mediate growth hormone and ACTH release is unaltered. Within the limitations that attend the use of buspirone as a 5-HT1A probe, our data suggest that the decrement in serotonin neurotransmission at post-synaptic 5-HT1A receptors in depression is due to decreased serotonin release rather than impaired responsivity of post-synaptic 5-HT1A receptors.