Low doses of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH DPAT) increase ethanol intake

Previous work has reported that the 5-hydroxytryptamine (5-HT)_1A agonist, 8-hydroxy 2-(di-n-propylamino)tetralin (8-OH DPAT), reduces ethanol intake by rats. However, as 8-OH DPAT reduces 5-HT neurotransmission, these findings are inconsistent with the proposed inhibitory role of central 5-HT neurons on ethanol intake. We examined the effect of 8-OH DPAT on ethanol, water and food intake in rats maintained on a limited access schedule using a lower dose range (6–250 µg/kg) and by assessing concomitant changes in behaviour. Low doses of 8-OH DPAT enhanced ethanol intake even when food and water were offered as alternatives. Suppression in ethanol intake was observed at higher doses where elements of the 5-HT syndrome were apparent. Similar observations were made in both fluid and non-fluid deprived water drinking rats, suggesting the latter effect is non-selective. Therefore 8-OH DPAT may both increase or decrease ethanol consumption in the rat depending on the dose used.     

Modification of sexual behavior of Long-Evans male rats by drugs acting on the 5-HT1A receptor

Modulation of the sexual behavior of male rats by the anxiolytic buspirone (S-20499) and its analog gepirone were compared to the effects of 8-OH-DPAT (or DPAT, a selective 5-HT1A reference agonist), and BMY-7378 (a selective 5-HT1A partial agonist). Long-Evans rats were used; modulation of copulatory behavior and alteration of penile reflexes were examined. Modulation of copulatory behavior was assessed by three indices: frequency and length of intromission, and latency of ejaculation. DPAT, at doses of 1-8 mg/kg, reduced these three indices in a time dependent manner such that the effects peaked at 45 min and normalized at 90 min. The dose-effect relationship (assessed 45 min after DPAT injection) is bell-shaped with an ED50 approximately 1 mg/kg on the ascending limb of the curve. The effects of buspirone (2 mg/kg) and gepirone (2 mg/kg) on copulatory behavior were indistinguishable from control. BMY-7378 alone and in combination with these other 5-HT1A agonists reduced copulatory behavior, though not statistically significant. Penile reflexes, including number of erections, cups and flips, were inhibited by these agents: DPAT>buspirone>gepirone (inactive at 2 mg/kg). Furthermore, the latency period to erection was at least doubled by DPAT (2 mg/kg). Buspirone and gepirone, however, reduced the latency period to erection. BMY-7378 inhibited penile reflexes when administered alone and even more in combination with DPAT or buspirone. Two butyrophenone analogs, spiperone (a 5-HT1A and dopamine D2 antagonist) and haloperidol (a D2 antagonist), were also tested for their interaction with DPAT. Both of these drugs (at 0.25 mg/kg, 60 min after administration) reduced all indices of penile reflexes and copulation. Furthermore, in combination with DPAT (2 mg/kg, 45 min), the effects were synergistic such that sexual activity came nearly to a standstill. These opposing effects on putatively brain originated copulatory behavior and spinal mediated penile reflexes indicate that the effects of buspirone and DPAT on sexual behavior in the male rat may be possible at different parts of the central nervous system. If a tentative shared target site by DPAT and buspirone is the 5-HT1A receptor, than the same 5-HT receptor sub-type at different locations (brain, raphe nuclei, spinal cord and autonomic ganglia) may modulate rat sexual behavior in opposing ways.     

Differential roles of hypothalamic serotonin receptor subtypes in the regulation of prolactin secretion in the turkey hen

In the turkey, exogenous serotonin (5-hydroxytryptamine, 5-HT) increases prolactin (PRL) secretion by acting through the dopaminergic (DAergic) system. In the present study, infusion of the 5-HT_2C receptor agonist, (R)(−)-DOI hydrochloride (DOI), into the third ventricle stimulates PRL secretion, whereas the 5-HT_1A receptor agonist, (+/−)-8-OH-DPAT hydrobromide (DPAT), inhibits PRL secretion. Using the immediate-early gene, c-fos, as an indicator of neuronal activity, in situ hybridization histochemistry showed preferential c-fos co-localization within tyrosine hydroxylase immunoreactive neurons (the rate limiting enzyme in DA synthesis) in the areas of the nucleus preopticus medialis (POM) and the nucleus premammillaris (PMM), in response to DPAT and DOI, respectively. To clarify the involvement of 5-HT_1A and 5-HT_2C receptors in PRL regulation, their mRNA expression was determined on hypothalamic tissue sections from birds in different reproductive stages. A significant difference in 5-HT_1A receptor was observed, with the POM of hypoprolactinemic short day and photorefractory birds showing the highest expression. 5-HT_2C receptors mRNA did not change during the reproductive cycle. The data presented support the notion that DA neurons in the PMM and POM mediate the stimulatory and inhibitory effects of 5-HT, respectively, on PRL secretion and the 5-HTergic system can both stimulate and inhibit PRL secretion.     

Dopamine D3 receptors in the rat kidney: role in physiology and pathophysiology

It is well accepted that dopamine receptors play an important role in the regulation of cardiovascular and kidney function. Most of the knowledge on the renal actions of dopamine has been accumulated focussing on the prototypes of the two known dopamine receptor subfamilies, i.e. D₁ and D₂. The dopamine D₃ receptor is a member of the D₂‐like subfamily and has been intensively studied in the neurosciences. Recently, the peripheral actions of this receptor subtype have also raised considerable interest as well because its effects on kidney function appear to be different from that of the other dopamine receptors. This short overview will summarize the data reported and add new results on the role of D₃ receptors in the regulation of renal function as well as their potential pathophysiological implications.     

Effects of serotonergic agonists on firing rates of photically responsive cells in the hamster suprachiasmatic nucleus

Serotonergic neurons from the midbrain raphe nuclei innervate the suprachiasmatic nucleus (SCN) of the hypothalamus, which functions as the dominant pacemaker for mammalian circadian rhythms. We investigated the effects of serotonin (5-HT) on firing rates of light-activated SCN cells in urethane-anesthetized hamsters. Micro-iontophoretic application of 5-HT or 5-HT_1A agonists (8-OH-DPAT and 5-CT) causeda dose-dependent inhibition of spontaneous activity and photic responses in the majority of SCN cells tested. Application of metergoline alone, a non-selective 5-HT antagonist, slightly increased firing rates during darkness and light exposure, suggesting a tonic serotonergic suppression of SCN activity. Metergoline also effectively attenuated suppression induced by the three 5-HT agonists. In addition, the effects of 8-OH-DPAT were blocked by a 5-HT_1A antagonist, SDZ 216-525. However, other putative 5-HT antagonists were weak (propranolol and NAN-190) or ineffective (ketanserin) in blocking the action of 8-OH-DPAT. These results indicate that serotonin has a potent role in reducing photic effects on retinally activated SCN cells in hamsters, and that these effects are mediated by a receptor with properties similar to those of the 5-HT_1A subtype.     

The discriminative stimulus properties of cocaine: effects of microinfusion of cocaine, a 5-HT1A agonist or antagonist, into the ventral tegmental area

 Serotonin (5-HT) afferents may modulate the dopamine mesoaccumbens circuit, which has been shown to be critically involved in the locomotor stimulatory, discriminative stimulus, and rewarding properties of cocaine. In the present study, we investigated the role of 5-HT_1A receptors in the ventral tegmental area (VTA) in mediating the discriminative stimulus effects of cocaine. Male Sprague-Dawley rats were trained to discriminate cocaine (10 mg/kg) from saline in a two-lever, water-reinforced FR 20 task. After acquiring the cocaine-saline discrimination, rats were stereotaxically implanted with bilateral guide cannulae into the VTA or adjacent substantia nigra reticulata (SNR). Intraperitoneal administration of cocaine (0.625–10 mg/kg) produced a dose-related increase in drug-lever responding. Both intra-VTA and intra-SNR infusion of cocaine (12.5–50 μg/0.5 μl/side) engendered primarily saline-like responding. Microinjection of the 5-HT_1A agonist 8-hydroxy-2-(di-N-propylamino) tetralin (DPAT; 0.1–10 μg/0.5 μl/side) or the 5-HT_1A antagonist WAY 100635 (0.01–1.0 μg/0.5 μl/side) into the VTA or SNR did not substitute for the systemic cocaine cue. Further, intra-VTA or intra-SNR DPAT or WAY 100635 in combination with systemic doses of cocaine did not alter (i.e., attenuate or potentiate) the systemic cocaine cue. Overall, these data indicate that 5-HT_1A receptors in the VTA do not mediate or modulate the discriminative stimulus effects of cocaine in the rat. Received: 15 April 1997 / Final version: 21 October 1997     

Dose-dependent effects of buspirone on behavior and cerebral glucose metabolism in rats

In this study we compared the effects of the anxiolytic buspirone on behavior and regional cerebral metabolic rates for glucose (rCMRglc) with those of the reference serotonin (5-HT)_1A agonist 8-hydroxy-2(di-N-propylamino)tetralin (DPAT). Behavioral effects were assessed by scoring the 5-HT syndrome. rCMRglc was measured in 56 brain regions by using the quantitative autoradiographic [¹⁴C]2-deoxyglucose technique, at 10 min after i.p. injection of DPAT (1 mg/kg) or buspirone (0.4, 4 and 40 mg/kg) in awake male Fischer-344 rats. Whereas DPAT produced an intense 5-HT syndrome, buspirone had no behavioral effect. A low dose (0.4 mg/kg) of buspirone reduced rCMRglc in 18 brain areas (32%), more markedly in limbic areas and raphe nuclei. These were the only rCMRglc effects buspirone had in common with the potent 5-HT_1A agonist DPAT and suggest that low dose buspirone activates preferentially 5-HT_1A receptors. Hence, this receptor subtype may mediate buspirone functional effects on the limbic system and, given the role of these brain areas in mood control, possibly buspirone therapeutic actions. High doses (4 and 40 mg/kg) of buspirone produced widespread rCMRglc decreases in 46 (82%) and 44 (79%) of the areas studied and increased rCMRglc in one brain area, the lateral habenula, that was not affected by DPAT or a low dose of buspirone. The topographic distribution and direction of rCMRglc changes by high doses of buspirone differ from those produced by the 5-HT_1A agonist DPAT. Instead these changes resemble the rCMRglc effects of dopaminergic D₂ antagonists like haloperidol and are consistent with some pharmacological and binding properties of buspirone. In summary, this study suggests that buspirone produces dual, dose-dependent rCMRglc effects: (i) at a low dose rCMRglc reductions in limbic areas and raphe nuclei, probably due to preferential activation of 5-HT_1A receptors, and (ii) at higher doses widespread rCMRglc reductions along with a rCMRglc increase in the lateral habenula resulting from dopamine D₂ receptor blockade.     

5-HT precursor loading, but not 5-HT receptor agonists, increases motor function after spinal cord contusion in adult rats

Serotonergic (5-HT) receptors are upregulated following spinal cord transection. Stimulation by administration of serotonergic receptor agonists has been successful in improving hindlimb function. We tested whether this strategy would be successful in incomplete injury models (moderate or severe thoracic contusion) where descending projections are partially spared which should produce less denervation-induced receptor upregulation. Adult rats received midthoracic moderate (MOD: 25 mm drop) or severe (SEV: 50 mm drop) contusion injuries. Distribution of 5-HT and its transporter and expression of 5-HT_2C receptors were evaluated in lumbar spinal cord and motor response to 5-HT receptor activation was assessed using open field locomotion (BBB) score, percent weight supported treadmill stepping (%WS) and evaluation of hindlimb muscle activation (tremor and serotonin syndrome).5-HT immunostaining 3 months post-contusion revealed few 5-HT fibers caudal to the severe contusion, and more spared caudal to the moderate contusion. The distribution of 5-HT transporter paralleled 5-HT staining, but was more greatly reduced. Thus serotonin reuptake may be less efficient in the injured spinal cord. Immunostaining for the 5-HT_2C receptor in the dorsal and ventral horns at L5 showed significant upregulation in SEV, compared to sham or MOD rats.Neither 5-HT_2C nor 5-HT_1A receptor agonists, alone or in combination, nor the serotonin transporter inhibitor d-fenfluramine modified BBB scores or %WS in either group. Despite the increased sensitivity of post-synaptic targets, agonist treatment did not improve function in SEV rats. We conclude that selective 5-HT_2C or 5-HT_1A receptor activation was not effective in improving hindlimb function after incomplete lesions. In contrast, the 5-HT precursor 5-hydroxytryptophan (l-5-HTP), which leads to activation of all classes of 5-HT receptors, increased both %WS and hindlimb activity in the MOD group. While no side effects were observed in normal or MOD rats, SEV rats displayed hindlimb tremors and 33% mortality, indicating hypersensitivity to the precursor.     

The acute and chronic administration of (+/-)-8-hydroxy-2-(Di-n-propylamino)tetralin significantly alters the activity of spontaneously active midbrain dopamine neurons in rats: an in vivo electrophysiological study

This study examined the effect of the acute and chronic systemic administration of (+/-)-8-Hydroxy-2-(Di-n-propylamino)Tetralin(8-OH-DPAT) on the number and firing pattern of spontaneously active dopamine (DA) neurons in the ventral tegmental area (VTA or A10) and substantia nigra pars compacta (SNC or A9) in anesthetized male rats. These parameters were measured using extracellular in vivo electrophysiology. A single s.c. injection of 0.01, 0.1, or 1 mg/kg of 8-OH-DPAT did not significantly alter the number of spontaneously active SNC DA neurons compared to vehicle-treated animals (controls). The acute administration of 0.01 or 0.1 mg/kg of 8-OH-DPAT did not significantly alter, whereas the 1 mg/kg dose significantly decreased the number of spontaneously active VTA DA neurons compared to controls. The acute administration of 8-OH-DPAT significantly increased the percentage of VTA DA neurons firing in a bursting pattern. In contrast, there was a significant decrease in the percentage of SNC DA neurons firing in a bursting pattern following the acute administration of 8-OH-DPAT. The number of spontaneously active SNC DA neurons was not significantly altered by the chronic s.c. administration of 8-OH-DPAT (0.01, 0.1, or 1 mg/kg s.c.) as compared to controls. However, the chronic s.c. administration of all doses of 8-OH-DPAT significantly decreased the number of spontaneously active VTA DA neurons compared to controls. The i.v. administration of (+)-apomorphine (50 microg/kg) did not reverse the 8-OH-DPAT-induced decrease in the number of spontaneously active VTA DA neurons, suggesting that this effect is unlikely due to depolarization blockade. The percentage of VTA DA neurons exhibiting burst firing was significantly increased by 0.01 and 0.1 mg/kg, but significantly decreased by 1 mg/kg of 8-OH-DPAT. Overall, the systemic administration of 8-OH-DPAT preferentially affects the activity of spontaneously active A10 DA neurons in rats.     

The serotonin inhibition of high‐voltage‐activated calcium currents is relieved by action potential‐like depolarizations in dissociated cholinergic nucleus basalis neurons of the guinea‐pig

The aim of the present study was to investigate whether the voltage‐dependent inhibition of calcium currents by serotonin 5‐HT_1A agonists can be alleviated (facilitated) by action potential‐like depolarizations. In dissociated cholinergic basal forebrain neurons using whole‐cell recordings, it is shown that a selective serotonin 5‐HT_1A agonist (8‐OH‐DPAT) predominantly blocks N‐type HVA calcium current, although a minor reduction of P‐type current was also observed. The inhibition may principally occur through G_i‐G_o subtypes of G‐proteins because it was prevented by N‐ethylmaleimide, a substance known to block specifically pertussis‐sensitive G‐proteins. The inhibitory effect of 8‐OH‐DPAT on calcium currents is voltage‐dependent because it was alleviated by long‐lasting depolarizing prepulses. Interestingly, the inhibition could also be reversed by prepulses made‐up of action potential‐like depolarizations that were given at a frequency of 200 Hz. This observation may have important implications during periods of high‐frequency rhythmic bursts, a firing pattern that is prevalent in cholinergic basal forebrain neurons.