Noradrenergic and serotonergic mediation of spinal analgesia mechanisms

The effects of α-adrenergic and serotonergic receptor agonist administration on spinal analgesia mechanisms (D'Amour-Smith analgesia assay) were examined in the spinal rat from 6 h to 3 weeks following transection. Analgesia (increased response latency)_was observed following administration of the α-adrenergic agonists, clonidine or xylazine at all times after transection. This dose-response-related analgesia was blocked by pretreatment with the α-adrenergic receptor blocker phenoxybenzamine but not by the serotonergic receptor blocker metergoline. Biochemical asay of spinal cord noradrenaline (NA) caudal to the level of transection indicated that the above drugs were effective agonists even when NA levels were not detectable suggesting a mechanism of action via direct Receptor stimulation. Administration of the serotonergic receptor stimulants quipazine or 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) was analgesic only during the first few postoperative days. Specificity of these drugs for the serotonergic receptor is supported by the observations that the drug induced analgesia was blocked by pretreatment with metergoline but not by phenoxybenzamine and that while quipazine or 5-MeODMT administration was only analgesic immediately following transection, α-adrenergic agonists were effective at all times. The implications of the present data for the involvement of descending NA and serotonergic fiber systems in the mediation of narcotic analgesia is discussed. The present data suggest that C.N.S. active α-adrenergic agonists may represent a class of non-narcotic analgesics of future clinical importance.     

Possible serotonergic and dopaminergic mediation of the N-ethyl-3,4-methylenedioxyamphetamine discriminative stimulus.

Eight male rats previously trained to discriminate 2.0 mg/kg N-ethyl-3,4-methylenedioxyamphetamine (MDE) from its vehicle in a two-lever, food motivated task were utilized to characterize the stimulus properties of MDE. The 5-HT receptor agonists 1-(m-trifluoromethylphenyl)piperazine (TFMPP), quipazine and 6-methoxy-1,2,3,4 tetrahydro-beta-carboline were able to generalize to the stimulus produced by MDE. However, the 5-HT receptor agonists m-chlorophenylpiperazine (mCPP), buspirone and norfenfluramine, the dopamine receptor agonist amphetamine, as well as the acetylcholine receptor agonist arecoline did not completely generalize. In addition, the simultaneous administration of norfenfluramine and amphetamine generalized to MDE. Pretreatment with the serotonin receptor antagonists cinanserin and metergoline or the dopamine receptor antagonist haloperidol failed to completely inhibit the discriminative stimulus produced by MDE. Multiple p-chlorophenylalanine (PCPA) pretreatments significantly reduced MDE discrimination, whereas vehicle discrimination was unaffected. Five days following cessation of PCPA pretreatment, MDE discrimination returned to criterion levels and remained at that level. These results suggest that the stimulus produced by MDE involve a complex interaction of various neurotransmitters, with both serotonergic and dopaminergic components.     

The role of telencephalic dopaminergic systems in the mediation of apomorphine-stereotyped behaviour

The electrolytic brain lesion technique was utilised in a systematic evaluation of the role of dopaminergic areas of the rat telencephalon in the mediation of stereotyped behaviour by apomorphine, the effects of the lesions being assessed both during the acute and chronic stages following their induction.After bilateral lesion of the ascending dopaminergic fibres in the lateral hypothalamus rats exhibited hypokinesia and mild catalepsy and, both in the acute and chronic stages following these lesions, the normal dose-dependent stereotypic effect of apomorphine was markedly reduced or abolished. An even greater reduction was observed after pallidectomy although lesion of the caudate-putamen was without effect. Destruction of the ascending dopaminergic fibers to the mesolimbic system caused a reduction in the intensity of apomorphine stereotypy during the acute and chronic stages. A similar reduction was observed after lesion of the tuberculum olfactorium or nucleus accumbens septi, although the effect was less marked following the latter lesions. Stereotypy was also reduced, both during the acute and chronic stages following ablation of the nucleus amygdaloideus centralis, but was not modified by lesion of the stria terminalis.These studies indicate that both extrapyramidal and mesolimbic dopaminergic systems are involved with the mediation of stereotyped behaviour by apomorphine, the degree of involvement of the two systems with the different components of stereotyped behaviour being clearly differentiated. Since lesion of the dopaminergic pathways was virtually as effective in reducing or abolishing the apomorphine effect as lesson of the dopaminergic areas themselves, the possibility that apomorphine may modify pre- as well as post-synaptic mechanisms is considered.     

Tonic immobility in domestic fowl: Possible interaction of serotonergic and dopaminergic mechanisms

Treatment with the dopamine (DA) receptor blocker, haloperidol, enhanced tonic immobility (TI) duration. Fenfluramine, a receptor agonist for serotonin (5-HT), reversed this effect. Tryptophan produced long TI reactions, and is believed to do so due to impaired synaptic transmission of 5-HT following its direct inhibitory effects on 5-HT neurons. DA receptor stimulation by apomorphine prevented the tryptophan potentiation of tonic immobility. The results suggest that serotonergic and dopaminergic systems may interact with respect to tonic immobility.     

Folate induced-hypermotility response after bilateral injection into the nucleus accumbens of the rat. Possible mediation through dopaminergic mechanisms

Folic acid (FA) and certain of its reduced congeners produce excitatory effects when applied to neuronal tissue. Recent evidence has suggested that folates have other biological properties in common with the excitatory amino acids. The purpose of this study was to determine the activity of folate compounds in a system sensitive to excitatory amino acids. Bilateral injection of folic acid into the nucleus accumbens resulted in a marked increase in locomotor activity at doses of 2.5 and 5 micrograms. Larger doses resulted in behavioral responses, such as body tremor and labored breathing, which interfered with the locomotor response. Similarly, 5-formyltetrahydrofolic acid (FTHF) produced a marked hypermotility response after bilateral injection into the nucleus accumbens (2.5-25 micrograms), while dihydrofolic acid, tetrahydrofolic acid, and 5-methyltetrahydrofolic acid were ineffective. Pretreatment with reserpine (10 mg/kg, i.p.) markedly reduced the hypermotility response elicited by folic acid and FTHF as did pretreatment with haloperidol in both peripheral (0.8 mg/kg) and direct (5 micrograms) injection into the nucleus accumbens. In addition, injection of muscimol (30 ng), which depresses hypermotility induced by dopamine and amphetamine, produced a significant decrease in the hypermotility response produced by folic acid. In contrast, pretreatment with phentolamine (5 mg/kg, i.p.) or propranolol (4 mg/kg, i.p.) did not decrease folic acid or FTHF-induced responses. These results suggest that folic acid and FTHF produce an increase in locomotor activity by facilitating dopaminergic neurotransmission in the nucleus accumbens, possibly by inducing the release of dopamine from the nerve terminals. Thus, these folates have effects similar to those of the excitatory amino acids when injected into the nucleus accumbens.     

Influence of dopaminergic and serotonergic neurons on intravenous ethanol self-administration in the rat.

Rats implanted with chronic indwelling intravenous catheters and allowed access to a self-administration apparatus learned to self-inject intravenous ethanol. Ethanol concentrations of 0.5, 1.0, and 2.0%, corresponding to a dose/injection of 1, 2, and 4 mg/kg, respectively, were consistently self-injected. Self-injection was not acquired or maintained with ethanol doses of 0.5 or 8 mg/kg/injection. Saline replacement of ethanol reservoirs led to marked increases in lever-pressing response in animals self-injecting 1, 2, and 4 mg/kg ethanol/injection but not with 0.5 or 8 mg/kg/injection. Neurotoxin-induced lesions of dopamine-(DA) containing neurons in nucleus accumbens septi failed to alter the acquisition or maintenance of ethanol self-injection. Pretreatment with haloperidol (0.05 and 0.1 mg/kg, SC) failed to alter hourly or daily self-injection rates. On the other hand, p-chlorophenylalanine pretreatment increased, while fluoxetine (2.5 and 5.0 mg/kg) administration significantly reduced, self-injected intravenous ethanol. These data suggest that ethanol is self-injected by the rat in a narrow dose range and that 5-hydroxytryptamine (5-HT), but not DA-containing neurons, subserves some function in the reinforcing or aversive affects of ethanol.     

Antagonism of estrogen-induced lordosis by corticosterone in adrenalectomized-ovariectomized female rats and mice

Previous experimentation has established that adrenalectomy can facilitate lordosis in ovariectomized estrogen-primed female rats. Experiment 1 examined the role of adrenal steriods in this effect, the results indicating an attenuation with chronic corticosterone but not with desoxycorticosterone or progesterone administration. Experiment 2 established a dose-response curve for this corticosterone effect. Experiments 3 and 4 indicated that corticosterone administration inhibits lordosis when it precedes estrogen administration. Experiment 5 demonstrated that corticosterone also inhibits estrogen-induced lordosis in mice. These data suggest that corticosterone may modulate estrogen-mediated behavior in rodents.     

Paradoxical GABA excitation of nigral dopaminergic cells: indirect mediation through reticulata inhibitory neurons

Biochemical and electrophysiological and electrophysiological studies suggest that GABA agonists increase the activity of dopaminergic neurons in the zona compacta (ZC) of the substantia nigra despite a known GABAergic input to ZC cells. Using single-unit recording techniques we have investigated this "paradoxical" effect. One population of neurons located in the zona reticulata (ZR) of the substantia nigra was found to be 20 times more sensitive to iontophoretically applied GABA than ZC neurons. GABA introduced by means of microiontophoresis into the ZR caused an increase in ZC cell activity while glutamic acid introduced in the same manner produced an inhibition of ZC cells. The latter effect was blocked by low doses of picrotoxin. Muscimol (i.v.) caused a decrease in ZR cell activity at the same dose that caused a parallel increase in ZC cell firing rate. These data suggest that ZC cells receive an inhibitory GABAergic input from ZR cells that are in turn inhibited by low doses of GABA agonists. Such an anatomical arrangement would account for the "paradoxical" excitatory effect of GABA agonists on ZC neuron activity.     

The effect of verapamil on serotonergic mechanisms in the rat blood platelets

Verapamil in vitro inhibits the uptake and enhances the release of the labeled serotonin from the rat blood platelets. It also inhibits the facilitating action of serotonin on the aggregation response of platelets stimulated by ADP. The obtained results indicate that verapamil significantly influences serotonergic mechanisms in the blood platelets, at least in the rat.     

Chronic lead exposure alters dopaminergic mechanisms in rat pituitary

The effect of chronic lead treatment on pituitary dopamine (DA) D2 receptors was studied by measuring (-)sulpiride-displaceable [3H]spiroperidol-binding and DA-inhibited adenylate cyclase. Receptor number was reduced in lead-exposed animals and bromocriptine was less able to inhibit cyclase activity in pituitary homogenates. In addition, the capacity of DA to inhibit the VIP-stimulated cAMP formation was decreased.     

Evidence for the involvement of central 5-HT1A receptors in the mediation of lordosis behavior in the female rat

5-Hydroxy-L-tryptophan (5-HTP), 25 mg kg^-1 IP, in combination with the peripheral 5-HTP decarboxylase inhibitor benserazide, 25 mg kg^-1 IP, and the selective inhibitor of neuronal 5-hydroxytryptamine (5-HT) re-uptake, zimeldine, 10 mg kg^-1 IP, suppressed lordosis in ovariectomized female rats, treated with estradiol benzoate (EB) or with EB plus progesterone (P). The suppression of lordosis produced by 5-HTP was antagonized by the -receptor blocker (-)pindolol, which also is a selective 5-HT₁ receptor antagonist, but not by the 5-HT₂ receptor antagonists metitepine or pirenperone, nor by the -receptor blocker betaxolol. The EB-or EB plus P-activated lordosis was also suppressed by administration of the selective 5-HT_1a receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Together, these observations indicate an important role of central 5-HT_1a receptors in the mediation of lordosis behavior in the female rat.     

Involvement of serotonergic and dopaminergic mechanisms in hyperthermia induced by a serotonin-releasing drug, p-chloroamphetamine in mice.

Serotonergic and dopaminergic involvement in hyperthermia induced by a serotonin (5-hydroxytryptamine, 5-HT)-releasing drug, p-chloroamphetamine, was investigated in mice. Neither the 5-HT transporter inhibitor fluoxetine nor the 5-HT depleter p-chlorophenylalanine affected p-chloroamphetamine-induced hyperthermia. The dopamine depleter -methyl-p-tyrosine significantly reduced p-chloroamphetamine-induced hyperthermia. The dopamine D₁ receptor antagonist 7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH 23390) antagonized p-chloroamphetamine-induced hyperthermia, although the dopamine D₂ receptor antagonist sulpiride was without effect. These results indicate that p-chloroamphetamine-induced hyperthermia in mice is mediated by dopamine release followed by activation of the dopamine D₁ receptor.     

Specific asymmetric behaviour induced by the direct chemical stimulation of neostriatal dopaminergic mechanisms

Summary The role of neostriatal dopamine in the control of motor function was investigated by assessment of the asymmetric motor behaviour resulting from the unilateral intracaudate administration of pharmacological and neurochemical substances. The unilateral intracaudate administration of 100 g dopamine to saline pretreated rats induced a mild contralateral asymmetry but lower doses of dopamine were ineffective. Dopamine was similarly active by intrapallidal injection but no asymmetries were observed following injections into the thalamus, nucleus lateralis septi, cerebral cortex or area preoptica. Pretreatment with haloperidol, nialamide or a combination of these two agents increased the sensitivity of caudate tissue to the dopamine effect. This enhancement was shown to be specific for the neuroleptic agents (haloperidol, clothiapine and oxypertine were effective whilst aceperone and phenoxybenzamine were relatively ineffective) and the contralateral behaviour specific for dopamine (noradrenaline, RS 86, procaine, chlorpromazine, trifluphenazine, amitriptyline and protripytline were ineffective) although a contralateral asymmetry was observed following unilateral intracaudate atropine or 5-hydroxytryptamine but these could be differentiated from the dopamine effect. The action of dopamine was mimicked by dopamine agonists and abolished by ablation of the substantia nigra.     

Dopaminergic and serotonergic mediation of the discriminable effects of Ergot alkaloids

The involvement of dopamine (DA) and serotonin (5-HT) neuronal systems in the discriminative stimulus effects of various ergot derivatives was assessed by administering four ergots to 36 rats which had been trained to discriminate either apomorphine (APO) or d-lysergic acid diethylamide (LSD) from saline. Lergotrile, lisuride and LSD substituted for APO (0.25 mg/kg) while bromocriptine and ergonovine (ergometrine) did not; only lisuride mimicked LSD (0.08 mg/kg). Antagonism tests showed that the DA antagonist haloperidol but not the 5-HT antagonist BC-105 (pizotifen) blocked the APO cue; both the LSD cue and the substitution of LSD for APO were blocked by BC-105 but not by haloperidol. It was concluded that DA receptor activation plays a prominent role in the discriminative stimulus effects of lergotrile and lisuride as well as APO and a secondary role in the LSD cue; 5-HT seems to be of major importance in the mediation of the effects of LSD and, to a lesser extent, lisuride. The functions of the two monoamines in the discriminable effects of bromocriptine and, particularly, ergonovine are less clear.     

Role of central dopaminergic mechanisms in piribedil and clonidine induced hypothermia in the rat

The colonic temperature of rats maintained at different ambient temperatures (6, 20 and 30°C) was measured following intraperitoneal injection of piribedil and clonidine. Piribedil caused a dose-dependent fall in temperature, most prominent at 6°C, which was attenuated by pretreatment with pimozide but not with phenoxybenzamine or propranolol.Intraperitoneal clonidine also produced dose-dependent hypothermia but this was not related to ambient temperature, since hypothermia was as great at 20°C as at 6°C. The clonidine induced fall was abolished by phenoxybenzamine but not by pimozide pretreatment.Selective depletion of brain dopamine, achieved by intracisternal 6-hydroxydopamine following intraperitoneal desmethylimipramine, significantly enhanced the hypothermic effect of piribedil at 6°C. By contrast the effect of clonidine was unchanged.It is suggested that the hypothermia induced by piribedil is due to stimulation of central dopaminergic receptors, while the effect of clonidine is probably mediated via adrenergic mechanisms.     

Effects of N-ethyl-3,4-methylenedioxyamphetamine (MDE) on central serotonergic and dopaminergic systems of the rat

The influence of N-ethyl-3,4-methylenedioxyamphetamine (MDE) on the central serotonergic and dopaminergic systems of the rat after a single or multiple injections was studied. MDE (10 mg/kg) produced a significant decrease in the concentration of 5-hydroxytryptamine (5-HT) 1 hr later in the frontal cortex and the hippocampus without affecting the concentration of 5-hydroxyindoleacetic acid (5-HIAA) or tryptophan hydroxylase (TPH) activity. Hypothalamic and neostriatal concentrations of 5-HT, 5-HIAA, dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) remained unaffected, as well as the neostriatal TPH and tyrosine hydroxylase (TH) activities. However, 3 hr after the MDE injection, the serotonergic variables including TPH activity were decreased in most of the brain areas examined. The dopaminergic system remained unaffected, except for a significant reduction in neostriatal DOPAC concentrations. The changes in transmitter concentrations after a single injection were dose dependent; the maximum depletion in TPH activity was reached with a 10 mg/kg dose. The administration of multiple doses of MDE caused greater decreases in TPH activity and 5-HT concentrations 3 hr after the treatment than did a single injection; in addition, a partial recovery from multiple administrations occurred by 18 hr. The effects of MDE on DA and its metabolites were transient, and neostriatal TH activity was not altered. This study demonstrates that MDE primarily affects the central serotonergic system, as reported for its congeners 3,4-methylenedioxyamphetamine and 3,4-methylenedioxymethamphetamine. It does, however, produce less neurotoxicity as judged by its lower potency on the dopaminergic and the serotonergic systems as well as the recovery occurring in these systems.     

The effect of ethanol on some serotonergic mechanisms in rat blood platelets

Under in vitro conditions ethanol inhibits the uptake and enhances release of [14C]-5HT from rat blood platelets. Similar results were obtained in blood platelets isolated from the blood rats receiving 2 g/kg ethanol. Ethanol decreased also the 5-HT content in the blood platelets. It inhibited the aggregation of blood platelets but did not change the potentiating action of 5-HT on ADP-induced aggregation. The results indicate that ethanol by its action on the transport mechanisms in blood platelets may elevate the level of free 5-HT in the blood plasma, in this manner potentiating the action of the amine in the circulatory system.     

Interactions between serotonergic and dopaminergic systems in rat brain demonstrated by small unilateral lesions of the raphe nuclei

Unilateral lesions in the dorsal raphe (DR) resulted in decreased concentrations of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid and increases in homovanillic acid and 3,4-dihydroxyphenylacetic acid in the ipsilateral substantia nigra (SN). Unilateral lesions in the median raphe (MR) caused similar biochemical changes in the corpus striatim (CS). Apomorphine and amphetamine caused turning behaviour in the lesiond animals which was ipsiversive after DR lesions but contraversive after MR damage. The animals turned in the opposite direction to that induced by these drugs after treatment with 5-methoxy-N,N-dimethyltryptamine and in the same direction after treatment with phenelzine plus L-tryptophan. All the drug-induced turning behaviour was blocked by haloperidol. The turning induced by 5-methoxy-N,N-dimethyltryptamine and in the same direction after treatment with phenelzine plus L-tryptophan. All the drug-induced turning behaviour was blocked by haloperidol. The turning induced by 5-methoxy-N,N-dimethyltryptamine was blocked by methysergide. This work suggested that the DR and MR nuclei send projections differentially to SN and CS respectively. These projections may exert a tonically active inhibition of dopamine metabolism in their respective terminal areas.     

Double dissociation of serotonergic and dopaminergic mechanisms on attentional performance using a rodent five-choice reaction time task

Abstract Rationale. Converging evidence suggests that dopaminergic and serotonergic mechanisms affect distinct aspects of cognitive performance. Experiments using the rodent five-choice reaction time task have established a critical role for dopaminergic mechanisms in the rat medial prefrontal cortex (mPFC), but have yielded only incomplete evidence regarding the specific functions of serotonin receptors. Objectives. To contrast the effects of systemic or intra-mPFC administration of dopamine or serotonin agents on performance of the five-choice reaction time task. Methods. Two groups of rats trained on the five-choice reaction time task received systemic administration of either the dopamine D₁ receptor partial agonist SKF 38393 (0, 1, 3 or 10 mg/kg IP) or the serotonin 5-HT_2A/C receptor antagonist ketanserin (0, 0.3, 0.6 or 1 mg/kg SC) prior to testing; a further group was implanted with chronic guide cannulae and received ketanserin (0, 0.025, 0.1 or 0.4 μg/side) infused into the mPFC prior to testing. Results. SKF 38393 affected aspects of accuracy and vigour of responding, while regardless of the route of administration ketanserin reduced premature responding without any effect on choice accuracy. Conclusions. Together with our previous findings of increased choice accuracy following intra-mPFC SKF 38393 (Granon et al. 2000), the present results support the notion that the functions of dopamine and serotonin receptors in the mPFC relate to two distinct domains of executive control. Dopamine D₁ receptors are critical to optimise response selection in skilled non-automatic tasks, while serotonin 5-HT_2A receptors regulate the execution of primed responses. Electronic Publication