Maternal high-fat diet during pregnancy and lactation provokes depressive-like behavior and influences the irisin/brain-derived neurotrophic factor axis and inflammatory factors in male and female offspring in rats.

A balanced maternal diet is necessary for the proper health and development of offspring. Recent clinical and preclinical studies have strongly indicated that maternal exposure to a high-fat diet (HFD) can have an irreversible impact on the structure and function of the offspring's brain and affect the immune system, which may predispose the offspring to brain disorders, including depression. The irisin/brain-derived neurotrophic factor (BDNF) axis is a pathway that influences several neurobehavioral mechanisms involved in the pathogenesis of mental disorders. The aim of the present study was to evaluate the influence of a maternal HFD during pregnancy and lactation on depressive-like behavior, serum irisin concentration and hippocampal levels of irisin, BDNF and inflammatory factors (interleukin-1α, interleukin-6 and tumor necrosis factor-α) in adolescent and adult male and female offspring. The main findings indicate that offspring exposed to a maternal HFD are characterized by an increased immobility time in the forced swimming test at both stages of life. Our results showed that a maternal HFD decreased serum and hippocampal irisin levels in females on postnatal day (PND) 28 and decreased the level of interleukin-1α at postnatal days 28 and 63 in the hippocampus. Interestingly, significant age-dependent changes were observed in irisin, BDNF and interleukin levels. To summarize, our study indicates that a maternal HFD during pregnancy and lactation provokes depressive-like behaviour in the offspring. However, despite the observed changes in the levels of irisin and IL-1α in females, further investigations are required to identify the underlying molecular mechanism associated with depressive-like behavior in the offspring of HFD-fed dams.

The effects of fatty acid amide hydrolase inhibitors on maintenance of cocaine and food self-administration and on reinstatement of cocaine-seeking and food-taking behavior in rats.

Some empirical evidence suggests that the endocannabinoids (eCB) (e.g. anandamide) may play an important role in cocaine addiction. The eCB act as a retrograde messengers activating CB receptors at the presynaptic membrane and are degraded by enzymatic actions of fatty acid amide hydrolase (FAAH). The present study aimed to examine the effect of the FAAH inhibitors, phenylmethylsulphonyl fluoride (PMSF; i.p.) or cyclohexylcarbamic acid 3-carbamoyl biphenyl-3-yl ester (URB597; i.p.) on the cocaine- or food-maintained self-administration as well as on the cocaine-seeking or food-taking behaviors in rats. Male Wistar rats were implanted with a catheter (iv.) and trained to self-administer cocaine (0.5 mg/kg/infusion) on a fixed ratio 5 schedule of reinforcement with a conditioned stimulus (tone+light). After self-administration stabilized, extinction/reinstatement procedures were carried out during which the rats were tested for the response reinstatement induced by cocaine (10 mg/kg, ip) or a cue (light+tone). The food (sweetened milk) self-administration and extinction/reinstatement procedures were conducted in a manner resembling cocaine self-administration. Neither PMSF (30-120 mg/kg) nor URB597 (0.1-3 mg/kg) affected cocaine self-administration. PMSF, 60 mg/kg, significantly reduced cocaine-induced reinstatement and at 120 mg/kg (combined with the challenge dose of cocaine) it evoked behavioral disruption. PMSF (60-120 mg/kg) dose-dependently inhibited cue-induced reinstatement. URB597 (1-3 mg/kg) attenuated both cocaine- and cue-induced drug-seeking behaviors. PMSF (60 mg/kg) decreased food self-administration. Toward reinstatement of food-taking behavior PMSF (60-120 mg/kg) and URB597 (3 mg/kg) showed inhibitory effects. Our results indicate that FAAH inhibitors could be potent modulators of motivational and conditioned aspects of goal-directed behaviors with less prominent effects on consumatory behaviors.

N-oleoyl-dopamine decreases muscle rigidity induced by reserpine in rats.

N-oleoyl-dopamine (OLDA), a product of condensation of oleic acid and dopamine (DA), is a bioactive compound that crosses the blood-brain barrier after systemic administration. The possibility arises that OLDA could have a potential role in treating DA-related disorders, such as Parkinsons disease (PD). In the present study we seek to determine whether OLDA would affect muscle tone and akinesia in two rat models of PD: the reserpine-evoked muscle rigidity and the reserpine- and haloperidol-induced catalepsy. We found that OLDA (20 mg/kg) significantly decreased muscle rigidity induced by reserpine (2.5 mg/kg), measured as an increased mechanical muscle resistance (MMG) in response to a passive extension and flexion of a rat hind limb at the ankle joint. Moreover, OLDA potently decreased the reserpine-enhanced tonic and reflex electromyographic (EMG) activities recorded before and during the movement, respectively. A lower dose of OLDA (10 mg/kg) failed to have appreciable effects. The reference compound L-DOPA (25 mg/kg) also attenuated the reserpine-increased MMG and EMG activities; the effects were, however, observed much later and were less prominent than those characteristic of OLDA. In contrast to the effects on muscle tone, OLDA (20 and 40 mg/kg) did not influence catalepsy induced by either reserpine (1.25 mg/kg) or haloperidol (0.5 mg/kg). In conclusion, the study demonstrates a novel biological action of N-oleoyl-dopamine consisting of lowering the reserpine-induced muscle rigidity. However, the lack of influence on akinesia suggests that the compound has myorelaxant rather than anti-Parkinsonian properties.

Activation of endocannabinoid transmission induces antidepressant-like effects in rats.

Recent reports indicate that endocannabinoid (eCB) system may be involved in depression and in the antidepressant-like activity demonstrated in experimental models. The present study examined the effects of the eCB uptake inhibitor 4-hydroxyphenyl-5Z,8Z,11Z,14Z-eicosatetraenamide (AM404; 0.1-3 mg/kg), the fatty acid amide hydrolase (FAAH) inhibitor cyclohexylcarbamic acid 3-carbamoylbiphenyl-3-yl ester (URB597; 0.03-0.3 mg/kg), the cannabinoid CB(1) receptor agonist (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl) phenyl]-trans-4-(3-hydroxypropyl)-cyclohexanol (CP55,940; 0.03-0.3 mg/kg) and the CB(1) receptor antagonist rimonabant (0.3-3 mg/kg) on immobility time in the forced swim test (FST) in rats. Moreover, the effects of AM404, CP55,940 and URB597 on the antidepressant-like activity of imipramine and citalopram in the FST were also examined. We found that AM404 (0.3-3 mg/kg), CP55,940 (0.1 mg/kg) and URB597 (0.1-0.3 mg/kg) reduced the immobility time of rats, while rimonabant (0.3-3 mg/kg) was inactive in this respect. We also observed that the anti-immobility effects of AM404 (1 mg/kg), CP55,940 (0.1 mg/kg) and URB597 (0.3 mg/kg), but not of imipramine (30 mg/kg), were blocked by rimonabant (3 mg/kg). In another set of experiments we showed that the inactive dose of AM404 (0.1 mg/kg) potentiated the effects of the inactive doses of imipramine (15 mg/kg) or citalopram (30 mg/kg), while CP55,940 (0.03 mg/kg) and URB597 (0.03 mg/kg) enhanced the effect of imipramine only. None of the drugs studied, given alone or in combination, increased the basal locomotor activity of rats. Our results indicate that activation of the eCB system induces antidepressant-like effects in the FST in rats, and that these effects are mediated by CB(1) receptors. Moreover, they also indicate that agents activating eCB transmission enhance the anti-immobility responses to antidepressant drugs.

An endogenous neuroprotectant substance, 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ), prevents the behavioral and neurochemical effects of cocaine reinstatement in drug-dependent rats.

Drug abuse disorder is induced by a variety of substances and results from their interaction with the brain reward system. It is characterized by a high frequency of relapse, usually associated with to craving. In this study we investigated the effects of 1-methyl-1,2,3,4-tetrahydroisoquinoline, an endogenous compound with antidopaminergic and neuroprotective activity, on cocaine-induced reinstatement in cocaine-dependent, self-administering rats. 1-methyl-1,2,3,4-tetrahydroisoquinoline (50 mg/kg i.p.) completely inhibited the expression of reinstatement of cocaine self-administration and accompanying neurochemical changes induced by a single priming cocaine dose (10 mg/kg i.p.). The priming cocaine dose inhibited dopamine metabolism in the structures containing nerve endings (frontal cortex, nucleus accumbens, and striatum) but not in the substantia nigra and ventral tegmental area. A behaviorally active dose of 1-methyl-1,2,3,4-tetrahydroisoquinoline administered 30 min before a priming dose of cocaine significantly increased the dopamine concentration in the limbic structures, and strongly inhibited dopamine metabolism in the substantia nigra and ventral tegmental area. Cocaine also inhibited noradrenaline and serotonin metabolism, and 1-methyl-1,2,3,4-tetrahydroisoquinoline abolished the inhibition in noradrenaline metabolism, while it intensified the inhibition of serotonin metabolism. Our results strongly support the view that 1-methyl-1,2,3,4-tetrahydroisoquinoline, an endogenous compound, has considerable potential as a drug for combating substance abuse disease through the attenuation of craving.

Effects of 1-methyl-1,2,3,4-tetrahydroisoquinoline on the behavioral effects of cocaine in rats.

The efficacy of 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ), a member of endogenous tetrahydroisoquinolines, in cocaine- and food-maintained responding in self-administration procedures under a fixed ratio 5 schedule of reinforcement as well as in cocaine and food seeking behaviors in male Wistar rats was examined. The effects of 1MeTIQ on cocaine discrimination and on basal locomotor activity were also assessed. In rats trained to self-administered either cocaine (0.5 mg/kg/injection) paired with the cue (light+tone) or food under a fixed ratio 5 schedule of reinforcement, 1MeTIQ (25 - 50 mg/kg) dose-dependently decreased the cocaine-maintained responding, but did not alter the food-maintained responding. 1MeTIQ (25 - 50 mg/kg) decreased the cocaine seeking behavior reinstated by a noncontingent presentation of cocaine (10 mg/kg, i.p.), but altered neither behavior reinstated by a discrete cue (tone+light) nor food-induced reinstatement. In rats trained to discriminate cocaine (10 mg/kg) from saline in water-reinforced fixed ratio 20 task, pretreatment with 1MeTIQ resulted in neither substitution nor significant alterations in the cocaine (1.25 - 10 mg/kg)-induced discriminative stimulus effects. 1MeTIQ (25 - 50 mg/kg) did not produce also a significant changes in basal horizontal activity. In conclusion, our present results outline a significance of exogenously applied 1MeTIQ in attenuating drug-evoked relapses to cocaine as well as the direct rewarding properties of cocaine (that model the cocaine-induced "high"), but not cocaine subjective effects. Moreover, a dissociation between effects of 1MeTIQ on cocaine vs. food-maintained responding was demonstrated.

N-oleoyl-dopamine increases locomotor activity in the rat.

N-oleoyl-dopamine (OLDA), a condensation product of oleic acid and dopamine (DA), is a bioactive lipid whose biological functions are not yet fully explored. The compound crosses the blood-brain barrier and might be considered as a carrier of DA into the brain. In this study we sought to determine whether OLDA would influence locomotor behavior and whether the central DA system would be involved in such influence. We addressed this issue by investigating horizontal locomotor activity in male Wistar rats after intraperitoneal administration of OLDA, 5-20 mg/kg, before and after pre-treatment with haloperidol, a D2 receptor antagonist. We found that OLDA caused a prompt stimulation of locomotor activity, with a bell-shaped dose-response. The maximum stimulatory effect was observed after 10 mg/kg of OLDA where the mean distance traveled by rats during a 2-hour test increased to 1213+/-196(SE) cm from the 403+/-89 cm in the vehicle-treated rats (P<0.05). This effect was dose-dependently antagonized by haloperidol (0.1-0.2 mg/kg). The results support the hypothesis that the OLDA-induced hyperlocomotion was mediated by the stimulation of DA systems. Using in vitro assays, we further demonstrated that OLDA is a stable compound that resists hydrolysis over a 2-hour period and thus the integral OLDA compound exerted DA-like effects. We conclude that OLDA is a potential brain modifier of motor behavior, the biological consequences of which remain to be explored.

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.

The effect of amphetamine sensitization on mouse immunoreactivity.

Recent studies indicate a role of the immune system in the behavioral effects of amphetamine in rodents. In the present study we attempted to find a connection between the behavioral changes induced by repeated, intermittent administration of amphetamine and some immunological consequences of sensitization to amphetamine in mice. Male Albino Swiss mice were treated repeatedly (for 5 days) with amphetamine (1 mg/kg, i.p.). On day 9, they received a challenge dose of amphetamine (1 mg/kg). Acute administration of amphetamine increased their locomotor activity by ca. 40%. In animals treated repeatedly with amphetamine, the challenge dose of the psychostimulant induced behavioral sensitization, i.e. the higher locomotor activation as compared with that after its first administration to mice. Immune functions were evaluated by the ability of splenocytes to proliferate and to produce cytokines such as interferon gamma (IFN-gamma), interleukin (IL)-4 and IL-10. Acute amphetamine administration significantly decreased, by ca. 30% and 25%, the proliferation of splenocytes in response to an optimal and a suboptimal dose of concanavalin A (Con A), respectively, and increased their ability to produce IL-4. Chronic intermittent treatment with amphetamine significantly decreased, by ca. 65% and 50%, the proliferative response of T cells to an optimal and a suboptimal dose of Con A, respectively, and diminished by 20% the metabolic activity of splenocytes. The above data showed that both acute and chronic amphetamine administration diminished some aspects of the cell-mediated immunity; nevertheless, immunosuppression was particularly evident in amphetamine-sensitized mice. Our findings seem to indicate possible importance of monitoring and correcting immune changes in the therapy of amphetamine 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.

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.

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.

Serotonin1B receptor ligands in the nucleus accumbens shell do not affect the discriminative stimulus effects of amphetamine in rats.

Enhanced dopamine neurotransmission particularly, in the target area of the mesolimbic system, i.e. the nucleus accumbens (NAc), seems to be critical for the behavioral effects of amphetamine in rodents. Nonetheless, recent findings have also demonstrated a modulatory role of 5-hydroxytryptamine (5-HT; serotonin) in these effects. In the present study, we examined whether 5-HT1B receptors in the NAc shell are engaged in the discriminative stimulus of amphetamine. To this end male Wistar rats were trained to discriminate amphetamine (1 mg/kg, ip) from saline (ip) in a two-lever, water reinforced fixed ratio (FR) 20 task. After acquiring the amphetamine-saline discrimination, rats were stereotaxically implanted with bilateral cannulae aimed at the NAc shell and then infused with selective 5-HT1B receptor ligands. The ability of these drugs to substitute for or to alter (enhance or antagonize) the discriminative stimulus effects of amphetamine was examined. When given systemically, amphetamine (0.125-1 mg/kg) produced a dose-dependent increase in drug-lever responding. In substitution studies, microinjection of the 5-HT1B receptor agonist CP 93129 (1-10 microg/side) or the 5-HTIB receptor antagonist GR 55562 (1-10 microg/side) into the NAc shell did not evoke amphetamine-lever responding. Combination tests of 5-HT1B receptor ligands demonstrated that local injection with fixed doses of CP 93129 (1 or 10 microg/side) or GR 55562 (1 or 10 microg/side) with the submaximal doses of amphetamine (0.125-0.5 mg/kg) did not modify dose-response curves of the psychostimulant, nor did it affect its ED50 value. Our results seem to exclude a role for the NAc shell 5-HT1B receptors in the control of the discriminative stimulus effects of amphetamine. These findings also show that pharmacological stimulation of those receptors does not affect the amphetamine discrimination in rats.

Lack of effect of repeated treatment with a glycineB receptor partial agonist on the amphetamine-induced hyperactivity in rats.

The effect of acute and repeated (once daily, 14 days) administration of a potential antidepressant, the glycineB partial agonist 1-aminocyclopropanecarboxylic acid (ACPC, 100-400 mg/kg, ip), on the hyperactivity induced by amphetamine (0.5 mg/kg, sc) in rats was studied. Neither acute nor repeated treatment with the drug affected the hyperlocomotion induced by amphetamine. The obtained results indicate that ACPC does not resemble antidepressant drugs in this behavioral model.

Effect of adrenalectomy and corticosterone on cocaine-induced sensitization in rats.

Effects of adrenalectomy (ADX) and corticosterone (CORT) on the development and expression of sensitization to the locomotor effect of cocaine (COC) were studied in rats. Sensitization was evoked by 5 daily injections of COC (10 mg/kg) and measured after a challenge dose of the drug (10 mg/kg) after a 5-day withdrawal (on day 10 of the experiment). ADX, performed before the start of COC administration, completely blocked the manifestation of COC-induced sensitization. In contrast, ADX performed on animals already sensitized to COC did not affect the sensitized locomotor activity response to a challenge dose of COC (on day 18). Pretreatment with CORT, 10 mg/kg, but not 5 mg/kg, before each of the 5 daily COC injections facilitated the development of COC sensitization, tested after a 5-day withdrawal. When pretreated with CORT alone (10 mg/kg), the challenge dose of COC administered on day 10 induced cross-sensitization to CORT. CORT (10 mg/kg) injected acutely before COC on day 10, potentiated the expression of COC sensitization. When given alone, on day 10 CORT (5-10 mg/kg) induced an increase in the locomotor activity of rats pretreated daily (5 injections) with COC. No drug treatment induced conditioned locomotion, as measured after saline challenge on day 8. Our results indicate that CORT facilitates the development and expression of COC sensitization, while ADX blocks the initiation of the behavioral phenomenon only. Moreover, there takes place cross-sensitization between CORT and COC, which indicates a close relationship between the drug-related mechanism and behavioral sensitization.

The influence of the benzodiazepine receptor antagonist flumazenil on the anxiolytic-like effects of CGP 37849 and ACPC in rats.

In this paper we examined the effect of flumazenil (Ro 15-1788, 10 mg/kg), a benzodiazepine receptor antagonist, on the anticonflict activity of DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 37849), a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, and 1-aminocyclopropanecarboxylic acid (ACPC), a partial agonist at glycine(B) receptors, in the Vogel conflict drinking test in rats. The effect of flumazenil on the anxiolytic-like (in the plus-maze test) and the anticonvulsant (in the maximal electroshock-induced seizures) activities of CGP 37849 in rats was also studied. Diazepam was used as a reference drug. CGP 37849 (2. 5-5 mg/kg), ACPC (50-200 mg/kg) and diazepam (2.5-5 mg/kg) significantly and dose-dependently increased the number of shocks accepted during experimental sessions in the conflict drinking test. Flumazenil partly but significantly reduced the anticonflict effect of CGP 37849, and it fully blocked the anticonflict effect of ACPC and diazepam. CGP 37849 (2.5-5 mg/kg) and diazepam (2.5-5 mg/kg) were also active in the plus-maze test, as they significantly increased the percentage of the time spent in and entries into the open arms of the plus-maze, both those effects having been antagonized by flumazenil. Flumazenil alone was inactive in both the conflict drinking and the plus-maze tests. In the maximal electroshock-induced seizures, both CGP 37849 (2.5-5 mg/kg) and diazepam (5-10 mg/kg) produced anticonvulsant effects, of which only that of diazepam was antagonized by flumazenil. The results of the present study showing antagonism of flumazenil towards the anxiolytic-like effects of CGP 37849 and ACPC suggest involvement of benzodiazepine receptors in such an activity of the NMDA and glycine(B) receptor ligands, respectively, which may be due to a possible interaction between NMDA and GABA/benzodiazepine systems. The lack of effect of the benzodiazepine antagonist on the anticonvulsant activity of CGP 37849 indicates that involvement of benzodiazepine receptors in the pharmacological action of the NMDA antagonist is not a general phenomenon.

Activation of serotonin (5-HT)1A receptors inhibits amphetamine sensitization in mice.

The effects of serotonin (5-HT)1A drugs on the development and expression of sensitization to the locomotor effect of amphetamine (AMPH) were studied in mice. 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT1A agonist, dose-dependently reduced the expression of AMPH (2.5 mg/kg)-induced sensitization. The latter inhibitory effect of 8-OH-DPAT was reversed by (S)-N-tert-butyl-3-(4-(2-methoxyphenyl)piperazin-1-yl)-2-phenyl propamine (WAY 100135), a 5-HT1A antagonist. WAY 100135 given alone did not affect expression of AMPH sensitization. Combined injections of 8-OH-DPAT, but not WAY 100135, with AMPH (2.5 mg/kg) during the development of sensitization, protected against the expression of sensitization to a challenge dose of AMPH (2.5 mg/kg) 3 days after withdrawal. The above inhibitory effect of 8-OH-DPAT on the development of AMPH sensitization was blocked by pretreatment with WAY 100135. The AMPH-induced conditioned locomotion was unaffected by pretreatment with 8-OH-DPAT. These results indicate that 5-HT1A receptors are not involved in AMPH-induced sensitization per-se, whereas their pharmacological activation leads to the inhibition of both the development and the expression of AMPH-induced sensitization.

Lack of effects of glycineB receptor ligands on the psychostimulant-induced discriminative stimuli in rats.

To examine the role of glycineB receptors in the stimulus effects induced by psychostimulants, separate groups of rats were trained to discriminate amphetamine (AMPH; 1 mg/kg) from saline (SAL), or cocaine (COC; 10 mg/kg) from SAL, using a two-lever operant procedure. Substitution studies showed that neither 1-aminocyclopropanecarboxylic acid (ACPC; 200 mg/kg) nor 7-chloro-4-hydroxy-3-(3-phenoxy)phenyl-(H)quinolone (L-701,324; 3 mg/kg), being a partial agonist or an antagonist at glycineB receptors, respectively, generalized for the training drugs. Combination tests of glycineB ligands demonstrated that injection of a fixed dose of ACPC (200 mg/kg) or L-701,324 (3 mg/kg) together with different doses of AMPH or COC practically did not modify dose-response curves of the psychostimulants, nor did it affect their ED50 values. Our results indicate that glycineB receptors do not play a role in the discriminative effects of AMPH and COC.

Effects of corticosterone and its synthesis blockade on the cocaine-induced discriminative stimulus effects in rats.

Several studies have argued that the hypothalamo-pituitary-adrenal (HPA) axis is of significance to behavioral effects evoked by drugs of abuse (e.g. cocaine). The role of the HPA axis in the subjective effects of cocaine was investigated in rats trained to discriminate cocaine (10 mg/kg, ip, -15 min) from saline (ip, -15 min) in a two-choice, water-reinforced fixed ratio (FR) 20 drug discrimination paradigm. In substitution tests, neither the exposure to a novel environment nor the social defeat stress, applied to rats after a dose of cocaine (2.5 mg/kg) which induced a ca. 42% drug-appropriate responding, influenced cocaine discrimination. Given alone, corticosterone (20 and 40 mg/kg, sc, -60 min) elicited a ca. 7% drug-appropriate responding. Combined injections of corticosterone and cocaine (0.625-5 mg/kg) did not affect the dose-response curve for cocaine. Surgical adrenalectomy did not modify the effects of cocaine; using a cumulative dosing procedure in the drug discrimination paradigm we found, that the dose-response curves for cocaine in adrenalectomized rats and sham-operated controls practically did not differ. Ketoconazole (an inhibitor of adrenocorticosteroid synthesis; 50 mg/kg, ip) given acutely (60 min) did not affect cocaine discrimination. Given subacutely (24, 16 and 1 h before tests), ketoconazole (50 mg/kg) produced a left-ward shift in the dose-response curve for cocaine and decreased its ED50 value. Another inhibitor of corticosterone secretion, metyrapone (50 mg/kg, sc), given acutely (120 min) did not affect the dose-response curve for cocaine. However, repeated injections (24, 16 and 2 h before tests) of metyrapone (50 mg/kg) with different doses of cocaine resulted in a rightward shift in the dose-response curve for cocaine and an increase in its ED50 value. The obtained results seem to exclude any role of the HPA axis in mediating subjective effects of cocaine, since neither corticosterone and stress nor adrenalectomy modified the discriminative stimulus effects of cocaine in rats. The reduction and potentiation of cocaine discrimination following subacute metyrapone and ketoconazole, respectively, may depend on changes in the levels of intermediate neurosteroids "upstream" from corticosterone in its biosynthesis pathway.