Effect of CNS-active drugs on TRH-induced prolactin release

The effects of several central acting drugs upon thyrotropin-releasing hormone (TRH)-induced increases in prolactin (PRL) release were compared in estrogen-primed male rats. Administration of the serotonin antagonist, p-chlorophenylalanine, or the opiate antagonist, naltrexone, did not alter TRH-induced release of PRL. Pre-treatment with either the dopamine agonist, piribedil, or the cholinergic agonist, pilocarpine, resulted in significantly reduced TRH-induced PRL release. Pilocarpine did not inhibit the TRH-induced increase in PRL release when rats were first pre-treated with the dopamine receptor blocker, haloperidol. These results indicate that the dopaminergic and cholinergic systems can modify TRH-induced release of PRL in vivo.     

Effects of dopaminergic system activation on feeding behavior and growth performance of the sea bass (Dicentrarchus labrax): A self-feeding approach

Dopamine is synthesized from l-dopa and subsequently processed into norepinephrine and epinephrine. Any excess neurotransmitter can be taken up again by the neurons to be broken down enzymatically into DOPAC. The effect of dopamine on mammalian food intake is controversial. Mice unable to synthesize central dopamine die of starvation. However, studies have also shown that central injection of dopamine inhibits food intake. The effect of dopaminergic system in the fish feeding behavior has been scarcely explored. We report that the inclusion of l-dopa in the diets results in the activation of sea bass central dopaminergic system but also in the significant increase of the hypothalamic serotonin levels. Dietary l-dopa induces a decrease of food intake and feed conversion efficiency that drives a decline of all growth parameters tested. No behavioral effects were observed after l-dopa treatment. l-dopa treatment stimulated central expression of NPY and CRF. It suggests that CRF might mediate l-dopa effects on food intake but also that CRF neurons lie downstream of NPY neurons in the hierarchical forebrain system, thus controlling energy balance. Unexpectedly, dietary administration of haloperidol, a D₂-receptor antagonist, cannot block dopamine effects but also induces a decline of the food intake. This decrease seems to be a side effect of haloperidol treatment since fish exhibited a decreased locomotor activity. We conclude that oral l-dopa inhibits sea bass food intake and growth. Mechanism could also involve an increase of hypothalamic serotoninergic tone.     

Effect of an imidazobenzodiazepine (RO 15-1788) on aggressive behavior in mice

Imidazobenzodiazepine (Ro 15-1788, 5 mg/kg) similarly to a lose dose of apomorphine (0.1 mg/kg) decreased the intensity of footshock aggression in male rats. Ro 15-1788 significantly potentiated the antiaggressive action of apomorphine. Pirenperone (0.01 mg/kg) potentiated the effect of both drugs, whereas haloperidol (0.01 mg/kg) had an opposite action. After long-term treatment with apomorphine and Ro 15-1788 the tolerance to their antiaggressive action developed. This change was in agreement with increased serotonin metabolism in the forebrain. Unlike the action on aggressive behavior, Ro 15-1788 similarly to haloperidol (0.05 mg/kg) decreased the motor depressant effect of apomorphine (0.01 mg/kg) in mice. This effect correlated with the lowered serotonin metabolism after Ro 15-1788 administration. Unlike apomorphine, Ro 15-1788 reversed catalepsy induced by haloperidol (0.25 mg/kg). Administration of pirenperone (0.03 mg/kg) and destruction of serotoninergic terminals by p-chloroamphetamine (2 X 15 mg/kg) significantly potentiated the sedative action of apomorphine. It appears that different action of Ro 15-1788 on behavioral effects of apomorphine is related to different influence of Ro-1788 on serotoninergic processes in the striatum and limbic structures.     

Biochemical Evidence for Alteration of Neostriatal Dopaminergic Function by 5,7-Dihydroxytryptamine

Unilateral injection of 5,7-dihydroxytryptamine (DHT) into the rat neostriatum markedly reduced not only striatal tryptophan hydroxylase (TPH) activity but also striatal tyrosine hydroxylase (TH) activity and dopamine (DA) concentration measured 10--15 days later. The decrease in striatal TH activity was dose related over the range of 8--32 micrograms of DHT; a dose of 16 micrograms reduced striatal TH activity to 40--50% of control, DA concentration to 38% of control, and TPH activity to 5--20% of control. Intrastriatal injection of 16 micrograms of DHT reduced TH activity in the ipsilateral substantia nigra to 51% of control. Pretreatment with amfonelic acid, a potent DA uptake inhibitor, significantly reduced the effect of DHT on striatal and nigral TH activity and striatal DA concentration without affecting the DHT-induced decrease in striatal TPH activity. Desmethylimipramine (5 and 25 mg/kg) had no effect on the DHT-induced decrease in striatal TH activity. Striatal choline acetyltransferase and glutamic acid decarboxylase activities were not decreased by 16 micrograms of DHT. The results indicate that DHT can alter dopaminergic function in the rat neostriatum through a direct effect of the drug on DA neurons.     

Effects of dopaminergic and serotonergic drugs on ethanol-induced hypothermia

The effects of dopaminergic and serotonergic drugs on ethanol-induced hypothermia were studied in the rat. Pretreatment with haloperidol attenuated the hypothermia in a dose-dependent manner. Apomorphine produced a dose-dependent effect on the hypothermia. At a dose of 2.0 mg/kg, apomorphine potentiated ethanol-induced hypothermia, whereas at 0.1 mg/kg, it produced a delayed attenuation effect between 30 min and 45 min after its injection. The former effect was blocked by haloperidol, whereas the latter was not affected by haloperidol, but blocked by pretreatment with parachlorophenylalanine. It is concluded that both dopamine and serotonin exert modulatory effects on ethanol-induced hypothermia.     

Increase of the number of bone marrow T-suppressor cells under inhibition of immunogenesis during changes of the activity of the neuromediator system

Increase of serotoninergic system activity and blockade of dopaminergic system activity led to the change of T- and B-lymphocyte distribution in immunocompetent organs of non-immunized animals. Increase of suppressor cel number with Lyt2.2 phenotype was found in bone marrow of C57Bl/6 mice under activation of serotoninergic system (blockade of serotonin reuptake by sertraline) as well as under blockade of dopaminergic system by administration of dopamine autoreceptor agonist--3-PPP. Role of bone marrow in neuro-immunomodulation is discussed.     

The effect of chronic L-DOPA administration on supersensitive pre- and postsynaptic dopaminergic receptors in rat brain

Chronic administration of haloperidol induced supersensitivity of the pre- and postsynaptic dopaminergic receptors in rat brain. The response of the presynaptic receptors was determined by an enhanced inhibitory effect of apomorphine on dopamine synthesis after gamma-butyrolactone injection. This change in the receptor function was detected both in the nigrostriatal and mesolimbic pathways. Haloperidol also increased the ³H-spiperone binding sites in striatal membranes, indicating supersensitivity of the postsynaptic receptors. Subsequent prolonged treatment with high doses of L-DOPA/carbidopa resulted in a decrease in ³H-spiperone binding sites, but had no effect on the supersensitive presynaptic receptors. It is suggested that tardive dyskinesia may be a state of both pre- and postsynaptic dopamine receptor supersensitivity and that chronic L-DOPA treatment may have a differential effect on these sites.     

Central dopaminergic regulation of adrenomedullary ornithine decarboxylase activity

The administration of the two dopamine receptor agonists apomorphine (APM) and piribedil (PBD) to rats leads to an increase in ornithine decarboxylase (ODC) activity in the adrenal medulla. In this work, we have tried to elucidate the neural pathways involved in the regulation of this enzyme. The treatments used are: unilateral splanchnicotomy, spinal cord section, intraventricular injection of the neurotoxin 6-hydroxydopamine and section of the brain at various levels. Unilateral splanchnicotomy reduces very significantly the induction of ODC produced by either APM or PBD. Spinal cord section at either of two different levels (T₅ or T₂) also lowers the response to APM. Intracerebroventricular injection of 6-hydroxydopamine, on the other hand, elevates the mean response to APM, although not to a statistically significant extent. Section of the mesencephalon well below the periaqueductal gray does not alter the response of adrenomedullary ODC to APM. Transection of the diencephalon almost prevents it whereas hypothalamic deafferentation and incomplete diencephalic transection potentiate the effect of this drug. These observations strongly suggest that adrenomedullary ODC activity is predominantly regulated by a central system, originating mainly in the diencephalon-telencephalon and including a facilitatory dopaminergic component.     

Interaction between opiates and hypothalamic dopamine on prolactin release.

Opiate stimulation of prolactin (PRL) release appears to involve a hypothalamic mechanism(s). The present study utilized both central acting drugs and direct measurement of hypothalamic dopamine (DA) to investigate this problem. Administration of L-dopa, the precursor of DA; piribedil, a DA agonist; or amineptine, a DA reuptake inhibitor, each decreased serum PRL concentrations. Morphine sulfate (MS) and haloperidol (HAL) significantly increased serum PRL levels. L-dopa and piribedil reversed the stimulatory effect of MS on serum PRL concentrations by increasing dopamine activity. MS blocked the inhibitory effects of amineptine on serum PRL release, possibly by decreasing the concentration of DA available for reuptake. Injection of subeffective doses of HAL concurrently with a subeffective dose of MS increased serum PRL concentrations, by an additive inhibitory action on dopaminergic activity. β-endorphin, an endogenous opioid peptide, decreased the rate of DA turnover in the median eminence, and increased serum PRL levels approximately 10 - fold. These observations indicate that opiates stimulate PRL release by decreasing DA activity in the median eminence.     

Effect of monoamine receptor agonists and antagonists on cyclic AMP accumulation in human cerebral cortex slices.

In human cerebral cortex slices noradrenaline, isoproterenol (a beta-adrenergic agonist), dopamine, apomorphine (a dopaminergic agonist), and serotonin stimulated cyclic AMP formation: noradrenaline greater than or equal to isoproterenol greater than dopamine = apomorphine = serotonin. Clonidine (and alpha-adrenergic agonist) was ineffective in stimulating cyclic AMP formation in temporal cortex slices. The stimulatory effect of noradrenaline and isoproterenol was blocked by propranolol (a beta-adrenergic blocker) but not by phentolamine (an alpha-adrenergic blocker). Pimozide (a selective dopaminergic antagonist) inhibited the increase of cyclic AMP formation induced by dopamine or apomorphine but not that induced by noradrenaline, isoproterenol, or serotonin. Neither propranolol or phentolamine had any effect on dopamine- or serotonin-stimulated cyclic AMP formation. Chlorpromazine blocked the increase of cyclic AMP formation induced by noradrenaline, dopamine or serotonin, while cyproheptadine, a putative central serotonergic antagonist, was ineffective. These observations suggest that there may be at least two monoamine-sensitive adenylate cyclases in human cerebral cortex which have the characteristics of a beta-adrenergic and a dopaminergic receptor, respectively, and also possibly a serotonergic receptor.     

Caffeine-induced locomotor activity: Possible involvement of GABAergic-dopaminergic-adenosinergic interaction

Caffeine (10–40 mg/kg, p.o.) enhanced locomotor activity (LA). Administration of GABA antagonist, bicuculline (0.5–1.0 mg/kg, i.p.), potentiated this caffeine-induced increase of LA, as well as LA of control rats. Treatment with the GABA agonist, muscimol (0.25–1 mg/kg, i.p.) or dopaminergic antagonist, haloperidol (0.25–1 mg/kg, i.p.) or muscarinic receptor blocker, atropine (3.75–5 mg/kg, i.p.), or inhibitor of acetylcholine esterase physostigmine (0.05–0.30 mg/kg, i.p.) or nicotine (0.5–1.5 mg/kg, i.p.) an nicotinic receptor agonist all decreased the LA of both caffeinetreated and control rats. Haloperidol-induced reduction in caffeine-induced increase in LA was found to be withdrawn with higher dose of caffeine. The dopamine agonist L-Dopa (75–150 mg/kg, p.o.) along with carbidopa (10 mg/kg, p.o.) increased the LA in control rats and potentiated the LA of caffeine treated rats. The haloperidol attenuated the bicuculline-induced increase in LA and atropine or physostigmine attenuated the bicuculline or L-Dopa+carbidopa-induced increase in LA in both caffeine treated and control rats when those drugs were administered concomitantly with bicuculline or L-Dopa+carbidopa. These results suggest that (a) the GABAergic system has direct role in the regulation of LA, and (b) caffeine potentiates LA by antagonism of the adenosine receptor and activation of the dopaminergic system which, in turn, reduces GABAergic activity through the reduction of cholinergic system.     

Stimulatory role of dopamine on fibroblast growth factor-2 expression in rat striatum

We have previously shown that systemic injection of (-)nicotine produces a selective up-regulation of fibroblast growth factor (FGF)-2 mRNA levels in rat striatum. Because (-)nicotine can increase striatal release of dopamine and glutamate, in the present study we have investigated the contribution of these neurotransmitters in the modulation of FGF-2 expression. We found that coinjection of dopaminergic D1 (SCH23390) or D2 (haloperidol) receptor antagonists prevents nicotine-induced elevation of FGF-2 expression. However, injection of the NMDA receptor antagonist MK-801 produced a significant increment of FGF-2 mRNA and protein levels in rat striatum similar to the effect produced by (-)nicotine alone. Interestingly this effect of MK-801 could also be prevented by D1 or D2 receptor antagonists, suggesting that an elevation of dopamine levels may be required for the regulation of the trophic molecule. Accordingly we found that the non-selective dopaminergic agonist apomorphine can similarly increase striatal FGF-2 mRNA levels. Despite the observation that both D1 and D2 receptors appear to contribute to the modulation of FGF-2 expression, only a direct activation of D2 receptors, through quinpirole administration, was able to mimic the effect of apomorphine. On the basis of FGF-2 neurotrophic activity, these results suggest that direct or indirect activation of dopaminergic system can be neuroprotective and might reduce cell vulnerability in degenerative disorders.     

Effects of Dopaminergic Drugs on Cerebellar Prostaglandin Concentrations

Abstract: Previous data indicate that the injection of dopaminergic drugs induces changes in cerebellar 3',5'-guanosine monophosphate (cGMP) content. Accordingly, we have investigated the effects of haloperidol, sulpiride, or apomorphine on cerebellar prostaglandin (PG) concentration, a parameter related to cGMP content. Results obtained show that dopamine receptor blocking agents, such as haloperidol and sulpiride, significantly decrease cerebellar PGE₂ and PGF_2α concentrations, while opposite changes are induced by apomorphine, a dopamine receptor agonist.     

Age related alterations of motor behavior and release of dopaminergic supersensitivity in rats

Rats aged greater than or equal to 18 months show, aside from clearly diminished motor parameters (exploratory behavior, resting activity, nocturnal activity profile, rotation behavior), after intracerebral dopamine injection a considerably lower apomorphine hypermotility than young animals. The characteristic alteration of activity occurring in young rats during and following chronic administration of haloperidol (1 mg/kg . day, s.c. for 21 days) as an expression of developing dopaminergic supersensitivity does not appear in older animals. Repeated application of amphetamine (2 X 2 mg/kg daily) caused a significant increase in hypermotility. The results are interpreted as the consequence of a age-related reduction of the activity of central-dopaminergic transmission systems and are discussed with regard to possible differences in the realization of agonist- or antagonist-induced supersensitivity.     

Catecholaminergic mechanisms of reinforcement: Direct assessment by drug self-administration

Reinforcing qualities in rats were shown by i.v. doses of two dopaminergic agonists, apomorphine and piribedil, and one noradrenergic agonist, clonidine, both in tests for primary reinforcement as seen in self-administration behavior and for conditioned reinforcement. Pretreatment with a dopaminergic blocker (haloperidol) interfered with the reinforcing effectiveness of apomorphine whereas an inhibitor of norepinephrine biosynthesis (U-14, 624) did not. Haloperidol also inhibited piribedil-based reinforcement. Pretreatment with an α-adrenergic blocking agent (phenoxybenzamine) inhibited the reinforcing effect of clonidine. These studies indicate that activation of either central dopaminergic or noradrenergic receptors can result in positive reinforcing effects.     

Taftsin correction of pharmacologically induced behavioral disorders in white rats

Tetrapeptide tuftsin in doses adapted to its physiological blood concentrations partially normalized locomotor activity and orientation behaviour of rats altered by drugs affecting aminergic brain systems. At the same time tuftsin had no effect when applied after the treatment by dopaminergic drugs (DTC, haloperidol, apomorphine). It can be concluded that the central effect observed in the first minutes after tuftsin administration is mediated through dopaminergic system. Elimination of some drug-induced behavioural disturbances by tuftsin opens new prospects for its therapeutic application.     

A comparative study of the locomotor activity effects of apomorphine and the "atypical dopamine agonists" (piribedil and S3608)

Apomorphine and the "atypical dopamine agonists" (piribedil and S3608) dose dependently increase locomotor activity (LA) in rats. The LA effects of all 3 drugs are readily attenuated by pretreatment with pimozide or sulpiride. Reserpine pretreatment or bilateral 6-hydroxydopamine lesions of the nucleus accumbens (NAS) potentiates apomorphine-induced LA but attenuates piribedil- and S3608-induced LA. The latter suggests an indirect mode of action for piribedil and for S3608. However, piribedil and S3608 at concentrations up to 10(-4)M do not cause release or inhibition of 3H-dopamine uptake in synaptosomes prepared from the rat NAS. Sulpiride antagonism of apomorphine-induced LA is surmountable by increasing the dose of apomorphine. Antagonism of piribedil- or S3608-induced LA by sulpiride is not surmountable by increasing the dose of either of the "atypical dopamine agonists". Furthermore, pretreatment with either piribedil or S3608 substantially increases the peak LA inducible by apomorphine. The effects of simultaneous injections of piribedil and S3608 are, however, not additive. These findings suggest that the LA stimulant effects of piribedil and S3608 are mediated via receptors or systems which differ from the receptors involved in the mediation of apomorphine-induced LA.     

The effect of chronic levodopa on haloperidol induced behavioral supersensitivity in the guinea pig

The effect of chronic levodopa-carbidopa administration (200 mg/kg for 21 days) on guinea pigs rendered behaviorally supersensitive by the prior administration of haloperidol (.5 mg/kg for 21 days) was examined. Animals who showed an increased behavioral response to apomorphine after chronic haloperidol administration were treated with levodopa-carbidopa and then apomorphine - induced stereotypy was reexamined. Although the chronic levodopa control groups and the chronic haloperidol control remained supersensitive to the behavioral effect of apomorphine, the haloperidol-levodopa group's behavioral response to apomorphine returned to normal. Both chronic dopaminergic antagonist and agonist administration have been demonstrated to induce heightened apomorphine-induced stereotypy and this has been interpreted as a reflection of altered striatal dopamine receptor site sensitivity. The finding that the serial administration of a chronic dopaminergic antagonist followed by a chronic dopaminergic agonist results in a return to normal of a striatal dopamine receptor-dependent behavior suggests that these chronic treatments affect dopamine receptor sites by different mechanisms of action. Since neuroleptic induced dopaminergic supersensitivity in animals is an accepted model of tardive dyskinesia, levodopa may also reverse dopaminergic supersensitivity in patients and might be a potential therapeutic agent in tardive dyskinesia.     

Dopamine-synthesis and tyrosine-hydroxylase are regulated by independent DA-receptor mediated mechanisms.

Intrastriatal injection of kainic acid, which destroys striatal post-synaptic structures, prevents the increase in TH cofactor affinity but not the in vivo stimulation of DA-synthesis produced by haloperidol. Destruction of cortico-striatal input by decortication fails to prevent the effect of haloperidol and of apomorphine on striatal DA-metabolism. The results are taken to indicate that post-synaptic DA-receptors control stable conformational changes of TH molecule while pre-synaptic DA-receptors control DA-synthesis in a manner independent of changes in TH activity persisting in vitro. No evidence could be obtained that pre-synaptic DA-receptors located on cortico-striatal axons play a major role in the control of DA-metabolism in vivo.     

Compensatory regulation of dopamine after ablation of the tyrosine hydroxylase gene in the nigrostriatal projection

The tyrosine hydroxylase (TH; EC 1.14.16.2) is a rate-limiting enzyme in the dopamine synthesis and important for the central dopaminergic system, which controls voluntary movements and reward-dependent behaviors. Here, to further explore the regulatory mechanism of dopamine levels by TH in adult mouse brains, we employed a genetic method to inactivate the Th gene in the nigrostriatal projection using the Cre-loxP system. Stereotaxic injection of adeno-associated virus expressing Cre recombinase (AAV-Cre) into the substantia nigra pars compacta (SNc), where dopaminergic cell bodies locate, specifically inactivated the Th gene. Whereas the number of TH-expressing cells decreased to less than 40% in the SNc 2 weeks after the AAV-Cre injection, the striatal TH protein level decreased to 75%, 50%, and 39% at 2, 4, and 8 weeks, respectively, after the injection. Thus, unexpectedly, the reduction of TH protein in the striatum, where SNc dopaminergic axons innervate densely, was slower than in the SNc. Moreover, despite the essential requirement of TH for dopamine synthesis, the striatal dopamine contents were only moderately decreased, to 70% even 8 weeks after AAV-Cre injection. Concurrently, in vivo synthesis activity of l-dihydroxyphenylalanine, the dopamine precursor, per TH protein level was augmented, suggesting up-regulation of dopamine synthesis activity in the intact nigrostriatal axons. Collectively, our conditional Th gene targeting method demonstrates two regulatory mechanisms of TH in axon terminals for dopamine homeostasis in vivo: local regulation of TH protein amount independent of soma and trans-axonal regulation of apparent L-dihydroxyphenylalanine synthesis activity per TH protein.