Effects of 5-HT1B receptor ligands microinjected into the accumbal shell or core on the cocaine-induced locomotor hyperactivity in rats.

The present study was designed to examine the effect of 5-HT1B receptor ligands microinjected into the subregions of the nucleus accumbens (the shell and the core) on the locomotor hyperactivity induced by cocaine in rats. Male Wistar rats were implanted bilaterally with cannulae into the accumbens shell or core, and then were locally injected with GR 55562 (an antagonist of 5-HT1B receptors) or CP 93129 (an agonist of 5-HT1B receptors). Given alone to any accumbal subregion, GR 55562 (0.1-10 microg/side) or CP 93129 (0.1-10 microg/side) did not change basal locomotor activity. Systemic cocaine (10 mg/kg) significantly increased the locomotor activity of rats. GR 55562 (0.1-10 microg/side), administered intra-accumbens shell prior to cocaine, dose-dependently attenuated the psychostimulant-induced locomotor hyperactivity. Such attenuation was not found in animals which had been injected with GR 55562 into the accumbens core. When injected into the accumbens shell (but not the core) before cocaine, CP 93129 (0.1-10 microg/side) enhanced the locomotor response to cocaine; the maximum effect being observed after 10 microg/side of the agonist. The later enhancement was attenuated after intra-accumbens shell treatment with GR 55562 (1 microg/side). Our findings indicate that cocaine induced hyperlocomotion is modified by 5-HT1B receptor ligands microinjected into the accumbens shell, but not core, this modification consisting in inhibitory and facilitatory effects of the 5-HT1B receptor antagonist (GR 55562) and agonist (CP 93129), respectively. In other words, the present results suggest that the accumbal shell 5-HT1B receptors play a permissive role in the behavioural response to the psychostimulant.

On the role of serotonin2A/2C receptors in the sensitization to cocaine.

Apart from showing involvement of dopamine, recent studies also indicate a role of serotonin (5-HT) in the behavioral effects of cocaine in rodents. In the present study we investigated the role of 5-HT2A/2C receptors in the development or expression of sensitization to cocaine in rats, using ketanserin, an antagonist at these receptors. Since ketanserin also shows a high affinity for alpha1-adrenoceptors, prazosin, a comparative antagonist at those receptors was also examined. Male Wistar rats were treated repeatedly (for 5 days) with cocaine (10 mg/kg) in combination with either vehicle, or ketanserin (1-3 mg/kg) or prazosin (3 mg/kg); afterwards, on day 10, they received a challenge dose of cocaine (10 mg/kg). In another experiment, the animals were given either with vehicle or cocaine (10 mg/kg) for 5 days, and were then challenged with cocaine (10 mg/kg) in combination with vehicle, or ketanserin (1-3 mg/kg) or prazosin (3 mg/kg) on day 10. Acute administration of cocaine increased the locomotor activity in rats; that hyperactivation was inhibited by ketanserin (3 mg/kg), but not by prazosin. In animals treated repeatedly with cocaine, the locomotor hyperactivity induced by a challenge dose of the psychostimulant was ca. 2-3 times higher than that after its first administration. No difference was observed in the response to cocaine challenge in rats treated repeatedly with cocaine, ketanserin+cocaine, or prazosin+cocaine. In animals treated repeatedly with the psychostimulant, the behavioral response to a challenge dose of cocaine was dose-dependently decreased when the drug was combined with ketanserin, but not with prazosin. The above findings indicate a role of 5-HT2A/2C receptors (but not alpha1-adrenoceptors) in the acute locomotor hyperactivity, as well as in the expression (but not development) of cocaine sensitization. Since chronic use of cocaine by humans may lead to psychoses or craving for this drug of abuse, our findings also seem to indicate possible importance of 5-HT2A/2C receptor antagonists in the therapy of cocaine addiction.

Role of 5-hydroxytryptamine1B receptors and 5-hydroxytryptamine uptake inhibition in the cocaine-evoked discriminative stimulus effects in rats.

Mesolimbic dopamine pathways play a critical role in the behavioural effects of cocaine in rodents. Nonetheless, research has also demonstrated involvement of 5-hydroxytryptamine (5-HT; serotonin) transmission in these effects. The present study investigated the ability of selective 5-HT1B receptor ligands and a 5-HT reuptake inhibitor to substitute for or to alter (enhance or antagonise) the discriminative stimulus effects of cocaine. Male Wistar rats were trained to discriminate cocaine (10 mg/kg, i.p.) from saline (i.p.) in a two-choice, water-reinforced fixed ratio (FR) 20 drug discrimination paradigm. In substitution tests, the selective 5-HT1B receptor agonist 3-(1,2,5,6-tetrahydro-4-pyridyl)-5-propoxypyrrolo[3,2-b]pyridine (CP 94253; 2.5-5 mg/kg, i.p.) and the 5-HT reuptake inhibitor fluoxetine (5-10 mg/kg, i.p.) elicited ca. 40 and 0% drug-lever responding, respectively. In combination experiments, CP 94253 (2.5-5 mg/kg) given with submaximal doses of cocaine (0.3-2.5 mg/kg) produced a leftward shift in the cocaine dose-response curve; pretreatment with CP 94253 (5 mg/kg) prior to a dose of cocaine (2.5 mg/kg) which elicited lower than 40% drug-lever responding, caused full substitution. Fluoxetine (5 and 10 mg/kg) given in combination with a submaximal dose of cocaine (2.5 mg/kg) produced a 100% drug-lever responding. Pretreatment with the 5-HT1B receptor antagonists N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-[1,2,4]oxadiazol-3-yl)-1,1'-biphenyl-4 carboxamide (GR 127935; 0.5-5 mg/kg, s.c.) and 3-(3-dimethylamino)-propyl)-4-hydroxy-N-[4-(4-pyridinyl)-phenyl]benzamide (GR 55562; 1 mg/kg, s.c.) failed to modulate the dose-effect curve for cocaine (0.6-5 mg/kg). On the other hand, GR 127935 (5 mg/kg) and GR 55562 (1 mg/kg) significantly attenuated the enhancement of cocaine discrimination evoked by a combination of CP 94253 (5 mg/kg) or fluoxetine (5 mg/kg) and cocaine (2.5 mg/kg). These results indicate that 5-HT1B receptors are not directly involved in the cocaine-induced discriminative stimuli in rats. On the other hand, they indicate that pharmacological stimulation of 5-HT receptors--that also seem to be a target for fluoxetine-mediated increase in 5-HT neurotransmission--can enhance the overall effects of cocaine.

Effect of serotonin (5-HT)1B receptor ligands on cocaine sensitization in rats.

Recent studies have shown that antagonists of serotonin (5-HT)1B receptors attenuate cocaine-induced locomotor hyperactivity, whereas agonists enhance reinforcing and discriminative stimulus effects of the psychostimulant. The present study was designed to determine how 5-HT1B receptor ligands affected the development or the expression phase of sensitization to the cocaine-induced locomotor response in rats. In Experiment 1, rats were treated repeatedly (for 5 days) with cocaine (10 mg/kg) in combination with either saline, GR 127935 (5-HT1B antagonist), CP 94,253 (5-HT1B agonist) or GR 127935 + CP 94,253. On day 10, they received a challenge dose of cocaine (10 mg/kg). In Experiment 2, animals received either saline or cocaine (10 mg/kg) for 5 days, and were then challenged with cocaine (10 mg/kg) in combination with saline, GR 127935, CP 94,253 or GR 127935 + CP 94,253, on day 10. In Experiment 3, rats received either saline, cocaine or CP 94,253 for 5 days; on day 10 they received challenge doses of CP 94,253 or cocaine. In rats treated repeatedly with cocaine, the locomotor hyperactivity induced by a challenge dose of the psychostimulant was about twice as high as that observed after its first administration. The effect evoked by cocaine challenge was further increased in animals treated repeatedly with CP 94,253 + cocaine, but not with GR 127935 + CP 94,253 + cocaine. No difference was observed in the response to cocaine challenge in rats treated repeatedly with cocaine or GR 127935 + cocaine (Experiment 1). In animals treated repeatedly with the psychostimulant, the behavioral response to a challenge dose of cocaine was dose-dependently increased when that drug was combined with CP 94,253, but not with GR 127935 + CP 94,253. No difference was observed in the locomotor response of rats challenged with cocaine or GR 127935 + cocaine (Experiment 2). When rats were treated repeatedly with cocaine, a challenge dose of CP 94,253 produced an about threefold increase in the locomotor effect compared to the animals treated likewise with saline (Experiment 3). Our results indicate that 5-HT1B receptors are involved in neither the development nor the expression of sensitization to cocaine-induced locomotor hyperactivity. On the other hand, they also show that pharmacological activation of 5-HT1B receptors enhances both phases of this phenomenon, and that repeated administration of cocaine leads to an increased functional reactivity of these receptors.

Role of 5-HT(1B) receptors in the sensitization to amphetamine in mice.

The present study was designed to determine how 5-HT(1B) receptor ligands affected the development or the expression phase of sensitization to the amphetamine-induced locomotor response in mice. Mice were treated repeatedly (for 5 days) with amphetamine (2.5 mg/kg) in combination with either vehicle, N-[3-[3-(dimethylamino)ethoxy]-4-methoxyphenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide hydrochloride (SB 216641; an antagonist of 5-HT(1B) receptors), 3-(1,2,5,6-tetrahydro-4-pyridyl)-5-propoxypyrrolo[3,2-b]pyridine (CP 94,253; an agonist of 5-HT(1B) receptors), or SB 216641+CP 94,253; afterwards, on day 10, they received a challenge dose of amphetamine (2.5 mg/kg). In another experiment, mice were given either vehicle or amphetamine (2.5 mg/kg) for 5 days, and were then challenged with amphetamine (2.5 mg/kg) in combination with vehicle, SB 216641, or CP 94,253 on day 10. Locomotor hyperactivity induced by acute administration of amphetamine (day 1) was dose-dependently inhibited by SB 216641 and enhanced by CP 94,253, but not affected by a combination of SB 216641+CP 94,253. The 5-HT(1B) receptor ligands affected similarly the behavioral response to the challenge dose of amphetamine on day 10 (ca. 55-110% more potent than the response to its first administration) when they were combined with the psychostimulant during the development phase (days 1-5) of sensitization. On the other hand, neither SB 216641 nor CP 94,253 administered together with the challenge dose of amphetamine (day 10) affected its behavioral hyperactivity effect in mice treated repeatedly (days 1-5) with the psychostimulant alone. Our results suggest that 5-HT(1B) receptors may play a permissive role in the development, but not expression, of behavioral sensitization, as well as in the acute locomotor response to amphetamine in mice.

Does combined treatment with novel antidepressants and a dopamine D3 receptor agonist reproduce cocaine discrimination in rats?

It is established that dopamine (DA) neurotransmission plays a critical role in the behavioral (e.g. discriminative stimulus) effects of cocaine in rodents. Nonetheless, research has also demonstrated that reciprocal signaling between DA and monoamine neurotransmitters, i.e. serotonin (5-HT) and norepinephrine (NE) has important implication for understanding the actions of cocaine. The present study was focussed on the ability of novel antidepressant drugs (milnacipram, reboxetine and venlafaxine), which affect either NE or both 5-HT and NE reuptake mechanism, to alter (enhance or antagonize) the discriminative stimulus effects of cocaine. Moreover, we investigated if the combined treatment with those drugs and a DA D3 receptor agonist (pramipexole) could reproduce cocaine discrimination. Male Wistar rats were trained to discriminate cocaine (10 mg/kg, ip) from saline (ip) in a two-choice, water-reinforced fixed-ratio 20 drug discrimination paradigm. Given alone, none of antidepressant drugs induced substitution for the cocaine-lever responses. Pramipexole (0.25 mg/kg) produced a partial substitution for cocaine (i.e. 43-52% cocaine-lever responding). In combination experiments, milnacipram (10 mg/kg) or reboxetine (10 mg/kg) given with submaximal doses of cocaine (1.25-5 mg/kg) did not affect the cocaine dose-response curve or its ED50 values. Venlafaxine (10 mg/kg) given in combination with submaximal doses of cocaine (0.6-5 mg/kg) produced significant enhancement of cocaine discrimination with a leftward shift in the cocaine dose-response curve and a decrease in its ED50 value. Pretreatment with either milnacipram (10 mg/kg) or reboxetine (10 mg/kg) failed to modulate the partial substitution evoked by pramipexole (0.25 mg/kg). On the other hand, venlafaxine (10 mg/kg) given in combination with a submaximal dose of pramipexole (0.25 mg/kg), which separately elicited 16 and 42% the cocaine-lever responses, produced significant enhancement of cocaine discrimination (up to 99% of the drug-lever responding). These results indicate that the discriminative stimulus effects of cocaine in rats can be enhanced by venlafaxine or mimicked by the combination with this antidepressant drug and the DA D3 receptor agonist. This finding, together with the recent data reporting the lack of rewarding properties of venlafaxine and the attenuation of morphine dependence and withdrwal signs in rats by the drug, may indicate a possible therapeutic use of this antidepressant in cocaine abuse.

Antidopaminergic effects of 1,2,3,4-tetrahydroisoquinoline and salsolinol.

Immediate behavioral and biochemical effects of single doses of 1,2,3,4-tetrahydroisoquinoline (TIQ, 50 mg/kg) and salsolinol (100 mg/kg), suspected of involvement in etiology of Parkinson's disease, were investigated. Apomorphine (0.25 mg/kg) or haloperidol (1 mg/kg) were administered to TIQ or salsolinol pretreated Wistar rats. In additional experiment the displacement of [3H]apomorphine by TIQ, salsolinol and dopamine receptor agonists and antagonists was tested. Both tetrahydroisoquinolines only slightly affected behavior and dopamine metabolism in naive rats, but very effectively abolished the behavioral and biochemical effects of apomorphine (hyperactivity, depression of striatal HVA level). The behavioral and biochemical effects of haloperidol were unchanged by administration of TIQ nor salsolinol. The tetrahydroisoquinolines displaced [3H]apomorphine from its binding sites with effectiveness comparable to that of dopamine. The results support the hypothesis that endogenous tetrahydroisoquinolines may play an important role in regulation of dopaminergic activity in non-senescent organisms.

Neurochemical changes induced by acute and chronic administration of 1,2,3,4-tetrahydroisoquinoline and salsolinol in dopaminergic structures of rat brain.

The finding that endogenous tetrahydroisoquinolines may be involved in the etiology of Parkinson's disease suggests that their administration may cause changes resembling those observed in parkinsonian brain. We tested, using a high-performance liquid chromatography method, how single and chronic administration of 1,2, 3,4-tetrahydroisoquinoline and salsolinol affects dopamine and serotonin metabolism in the neurons of extrapyramidal and mesolimbic dopaminergic systems. We report that chronic administration of tetrahydroisoquinoline and salsolinol causes a decrease in a dopamine metabolism: the effect of tetrahydroisoquinoline was limited to the striatum, while salsolinol caused also a dramatic decline of dopamine level in the substantia nigra. The effect of both compounds on serotonin metabolism was small or absent. The tetrahydroisoquinolines produced no changes in the nucleus accumbens. The results indicate that tetrahydroisoquinoline and salsolinol specifically affect the nigrostriatal dopamine system, but only when administered chronically, and thus are compatible with the view that endogenous tetrahydroisoquinolines may participate in pathogenesis of Parkinson's disease.