NLX-112, a highly selective 5-HT1A receptor agonist: Effects on body temperature and plasma corticosterone levels in rats.

NLX-112 (a.k.a. F13640 or befiradol), exhibits nanomolar affinity, exceptional selectivity and high agonist efficacy at 5-hydroxytryptamine 5-HT1A receptors. It possesses marked activity in a variety of animal models of depression, pain and L-DOPA-induced dyskinesia. However, its influence on translational biomarkers of central 5-HT1A receptor activation has not been previously described. Here, we report on the activity, in rats, of NLX-112 to increase plasma corticosterone levels and produce hypothermia, two responses which are also elicited by 5-HT1A receptor agonists in humans. NLX-112 elicited dose-dependent hypothermia (minimal effective dose, MED: 0.31mg/kg p.o.) and also increased plasma corticosterone both by oral and intraperitoneal routes (MED: 0.63mg/kg in both cases). The increase in corticosterone induced by NLX-112 (0.63mg/kg p.o.) was abolished by co-administration of the selective 5-HT1A receptor antagonist, WAY100635. Additionally, NLX-112 also dose-dependently induced flat body posture, forepaw treading and lower lip retraction (MEDs 0.31-0.63mg/kg p.o.). The doses of NLX-112 which induce hypothermia or corticosterone release were similar to those inducing serotonergic behaviors but greater than those reported previously in models of therapeutic-like activity (range 0.04 to 0.16mg/kg). Overall, the present study provides information for clinical dose estimations of NLX-112 and suggests that therapeutic effects may occur at doses below those at which biomarker responses are observed.

F15063, a compound with D2/D3 antagonist, 5-HT 1A agonist and D4 partial agonist properties. III. Activity in models of cognition and negative symptoms.

BACKGROUND AND PURPOSE: The D(2)/D(3) receptor antagonist, D(4) receptor partial agonist, and high efficacy 5-HT(1A) receptor agonist F15063 was shown to be highly efficacious and potent in rodent models of activity against positive symptoms of schizophrenia. However F15063 induced neither catalepsy nor the 'serotonin syndrome'. Here, we evaluated its profile in rat models predictive of efficacy against negative symptoms/cognitive deficits of schizophrenia. EXPERIMENTAL APPROACH: F15063, given i.p., was assessed in models of behavioural deficits induced by interference with the NMDA/glutamatergic (phencyclidine: PCP) or cholinergic (scopolamine) systems. KEY RESULTS: Through 5-HT(1A) activation, F15063 partially alleviated (MED: 0.04 mg kg(-1)) PCP-induced social interaction deficit between two adult rats, without effect by itself, underlining its potential to combat negative symptoms. At doses above 0.16 mg kg(-1), F15063 reduced interaction by itself. F15063 (0.16 mg kg(-1)) selectively re-established PCP-impaired 'cognitive flexibility' in a reversal learning task, suggesting potential against adaptability deficits. F15063 (0.04-0.63 mg kg(-1)) also reversed scopolamine-induced amnesia in a juvenile-adult rat social recognition test, indicative of a pro-cholinergic influence. Activity in this latter test is consistent with its D(4) partial agonism, as it was blocked by the D(4) antagonist L745,870. Finally, F15063 up to 40 mg kg(-1) did not disrupt basal prepulse inhibition of startle reflex in rats, a marker of sensorimotor gating. CONCLUSIONS AND IMPLICATIONS: The balance of D(2)/D(3), D(4) and 5-HT(1A) receptor interactions of F15063 yields a promising profile of activity in models of cognitive deficits and negative symptoms of schizophrenia.

F15063, a compound with D2/D3 antagonist, 5-HT 1A agonist and D4 partial agonist properties. II. Activity in models of positive symptoms of schizophrenia.

BACKGROUND AND PURPOSE: F15063 is a high affinity D(2)/D(3) antagonist, D(4) partial agonist, and high efficacy 5-HT(1A) agonist, with little affinity (40-fold lower than for D(2) receptors) at other central targets. Here, the profile of F15063 was evaluated in models of positive symptoms of schizophrenia and motor side-effects. EXPERIMENTAL APPROACH: Rodent behavioural tests were based on reversal of hyperactivity induced by psychostimulants and on measures of induction of catalepsy and 'serotonin syndrome'. KEY RESULTS: F15063 potently (ED(50)s: 0.23 to 1.10 mg kg(-1) i.p.) reversed methylphenidate-induced stereotyped behaviors, blocked d-amphetamine and ketamine hyperlocomotion, attenuated apomorphine-induced prepulse inhibition (PPI) deficits, and was active in the conditioned avoidance test. In mice, it reversed apomorphine-induced climbing (ED(50)=0.30 mg kg(-1) i.p.). F15063, owing to its 5-HT(1A) agonism, did not produce (ED(50)>40 mg kg(-1) i.p.) catalepsy in rats and mice, a behavior predictive of occurrence of extra-pyramidal syndrome (EPS) in man. This absence of cataleptogenic activity was maintained upon sub-chronic treatment of rats for 5 days at 40 mg kg(-1) p.o. Furthermore, F15063 did not induce the 'serotonin syndrome' in rats (flat body posture and forepaw treading: ED(50) >32 mg kg(-1) i.p.). CONCLUSIONS AND IMPLICATIONS: F15063 conformed to the profile of an atypical antipsychotic, with potent actions in models of hyperdopaminergic activity but without inducing catalepsy. These data suggest that F15063 may display potent antipsychotic actions with low EPS liability. This profile is complemented by a favourable profile in rodent models of negative symptoms and cognitive deficits of schizophrenia (companion paper).

Evaluation of pindolol dosage in hypertension by automatic indirect BP monitoring.

Pindolol, a nonselective beta-adrenergic blocking drug, lowered systolic and diastolic BP equally well during once-daily and twice-daily dosage. Side effects were few. Absence of supine bradycardia distinguished this drug from other beta-adrenergic blockers and likely was attributable to the agent's intrinsic sympathomimetic activity. Blood pressure variability was less during therapy. Automatic indirect BP monitoring reliably confirmed office and home BP recordings and indicated good control throughout waking and sleeping periods.

NLX-112, a novel 5-HT1A receptor agonist for the treatment of L-DOPA-induced dyskinesia: Behavioral and neurochemical profile in rat.

L-DOPA is the gold-standard treatment for Parkinson's disease (PD), but induces troublesome dyskinesia after prolonged treatment. This is associated with the 'false neurotransmitter' conversion of L-DOPA to dopamine by serotonin neurons projecting from the raphe to the dorsal striatum. Reducing their activity by targeting pre-synaptic 5-HT1A receptors should thus be an attractive therapeutic strategy, but previous 5-HT1A agonists have yielded disappointing results. Here, we describe the activity of a novel, highly selective and potent 5-HT1A agonist, NLX-112 (also known as befiradol or F13640) in rat models relevant to PD and its associated affective disorders. NLX-112 (0.16 mg/kg, i.p.) potently and completely reversed haloperidol-induced catalepsy in intact rats and abolished L-DOPA-induced Abnormal Involuntary Movements (AIMs) in hemiparkinsonian rats, an effect that was reversed by the selective 5-HT1A antagonist, WAY100635. In microdialysis experiments, NLX-112 profoundly decreased striatal 5-HT extracellular levels, indicative of inhibition of serotonergic function. NLX-112 also blunted the L-DOPA-induced surge in dopamine levels on the lesioned side of the brain, an action that likely underlies its anti-dyskinetic effects. NLX-112 (0.16 mg/kg, i.p.) robustly induced rotations in hemiparkinsonian rats, suggesting that it has a motor facilitatory effect. Rotations were abolished by WAY100635 and were ipsilateral to the lesioned side, suggesting a predominant stimulation of the dopamine system on the non-lesioned side of the brain. NLX-112 also efficaciously reduced immobility time in the forced swim test (75% reduction at 0.16 mg/kg, i.p.) and eliminated stress-induced ultrasonic vocalization at 0.08 mg/kg, i.p., effects consistent with potential antidepressant- and anxiolytic-like properties. In other tests, NLX-112 (0.01-0.16 mg/kg, i.p.) did not impair the ability of L-DOPA to rescue forepaw akinesia in the cylinder test but decreased rotarod performance, probably due to induction of flat body posture and forepaw treading which are typical of 5-HT1A agonists upon acute administration. However, upon repeated administration of NLX-112 (0.63 mg/kg, i.p., twice a day), flat body posture and forepaw treading subsided within 4 days of treatment. Taken together, these observations suggest that NLX-112 could exhibit a novel therapeutic profile, combining robust anti-dyskinetic properties without impairing the therapeutic properties of L-DOPA, and with additional beneficial effects on non-motor (affective) symptoms.

Novel derivatives of 2-pyridinemethylamine as selective, potent, and orally active agonists at 5-HT1A receptors.

The aim of this work was to improve the oral bioavailability of a recently discovered, novel structural class of 5-HT1A receptor agonists: aryl-{[4-(6-R-pyridin-2-ylmethyl)-amino]-methyl}-piperidin-1 -yl-metha none. Incorporation of a fluorine atom in the beta-position to the amino function in the side chain led to analogues that exhibited, in general, enhanced and long-lasting 5-HT1A agonist activity in rats after oral administration. Location of the fluorine atom at the C-4 position of the piperidine ring was the most favorable, and among the various substituents tested, the ability of the fluorine was unique in improving the oral activity of this family of ligands. Thus, the derivatives 39, 46, and 61 bound with higher affinity and selectivity to 5-HT1A receptors (versus dopaminergic D2 and adrenergic alpha1 receptors) and displayed more potent 5-HT1A agonist activity in vitro and in vivo than their C-4 desfluoro analogues. To examine the relationship between the conformation of the pharmacophore and the level of agonistic activity of this type of ligand, we synthesized a series of 3-chloro-4-fluorophenyl-(4-fluoro-4{[(5-(H or CH3)-6-R-pyridin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl-+ ++methanone derivatives and found that the combination of a 5-methyl and a 6-methylamino substituent on the pyridine ring synergistically affected their 5-HT1A agonist properties. Thus, the 3-chloro-4-fluorophenyl-(4-fluoro-4{[(5-methyl-6-methylamino-pyridin- 2-ylmethyl)-amino]-methyl}-piperidin-1-yl-methanone 40 behaved as a more potent 5-HT1A receptor agonist in vitro and in vivo than its 5-unsubstituted analogue 38. The antidepressant potential of the lead compounds 40, 45, and 54 was examined by means of the forced swimming test (FST) in rats. The results indicated that, after a single oral administration, these compounds inhibited immobility in the FST more potently and more extensively than the clinically used antidepressant imipramine. Thus, 40, 45, and 54 are potent, orally active 5-HT1A receptor agonists with marked antidepressant potential.

Evaluation of the Del Mar Avionics automatic ambulatory blood pressure-recording device.

We have the opportunity to evaluate a portable ambulatory device for the recording of sequential indirect arterial blood pressure and continuous electrocardiogram (Del Mar Avionics automatic ambulatory blood pressure recording device). With careful attention to technique, only 11% of systolic and 5% of diastolic blood pressure readings differed by more than 10 mm Hg as compared with a trained technician's observations simultaneously in the same arm. The device has been useful in the evaluation of borderline (labile) hypertension, hypertensive drug therapy programs, and various episodic cardiovascular phenomena--for example, vasodepressor syncope and pheochromocytoma crises.

Pindolol--a new beta-adrenergic blocking agent with intrinsic sympathomimetic activity in the management of mild and moderate hypertension.

Pindolol, a well-tolerated noncardioselective beta-adrenergic blocking drug, effectively reduced blood pressure in patients with mild to moderate hypertension without causing orthostatic hypotension. In common with other beta-adrenergic blocking agents, pindolol blocked the normal increase in the standing pulse rate. The drug, however, did not decrease the supine pulse rate, a feature that can be interpreted as evidence of the postulated intrinsic sympathomimetic activity of pindolol.

Discriminative stimulus properties of cocaine: enhancement by beta-adrenergic receptor antagonists.

Although many of the behavioral effects of cocaine are widely believed to be mediated by blockade of dopamine transporters, recent studies suggest that norepinephrine (NE) may play a modulatory role. In this study, selective and nonselective beta-adrenergic receptor antagonists were administered alone or in combination with cocaine (2.5 mg/kg, i.p.) to rats trained to discriminate a low dose (2.5 mg/kg) from a high dose of cocaine (10 mg/kg) in a two-lever, FR10 drug discrimination procedure. The central beta 2/beta 1-adrenergic antagonists (-)-propranolol and tertatolol, and the beta 2-adrenergic antagonist, ICI 118,551, produced high-dose appropriate responding in a dose-related manner when administered (i.p.) in combination with the low training dose of cocaine. In contrast, neither the peripheral beta 2/beta 1-adrenergic antagonist, nadolol, nor the central beta 1-adrenergic antagonist, beta-xolol enhanced the behavioral effects of the low dose of cocaine in a manner comparable with that produced by compounds with central beta 2-adrenergic antagonist properties. Also in contrast to findings obtained using beta-adrenergic antagonists, neither the alpha 1-adrenergic agonist cirazoline, nor the alpha 2-adrenergic ligands (+/-)-efaroxan and UK-14304 enhanced the behavioral effects of the low dose of cocaine. Overall, these results suggest that central beta 2-adrenergic receptors may play a modulatory role in the discriminative stimulus effects of cocaine.

Effects of benzodiazepine agonists on punished responding in pigeons and their relationship with clinical doses in humans.

Anxiolytic drugs generally produce anticonflict effects in both pigeons and rats, although relatively few anxiolytics have been examined in the pigeon and the procedure has not been as completely validated as the rat model. In this study, we examined the antipunishment effects of a variety of benzodiazepine agonists in pigeons and compared the relationship between their potencies to engender anxiolytic-like effects and their clinical doses in humans. In pigeons whose responding was maintained under a multiple FR30food:FR30food+shock schedule, the benzodiazepine agonists diazepam, flunitrazepam, alprazolam, chlordiazepoxide, lorazepam, flurazepam, bromazepam, medazepam, and clorazepate produced dose-related increases in punished responding, and, with the exception of medazepam, decreased unpunished responding at higher doses. Potencies calculated from the percentage of pigeons showing significant increases in punished responding ranged from 0.081 to 11 mg/kg, and these potencies were invariably lower than those for decreases in unpunished responding by factors ranging from 2.2 to more than 14. The comparison of relative potencies of benzodiazepine receptor agonists in pigeons and humans revealed a high positive correlation (0.90, P<0.005), thus demonstrating the predictive validity of this preclinical animal model for anxiolytic benzodiazepines. The results agree with previous findings of robust anticonflict effects of benzodiazepine receptor agonists and extend further the pharmacological characterization to compounds that have not been examined previously in pigeons.

Effects of different classes of partial benzodiazepine agonists on punished and unpunished responding in pigeons.

RATIONALE: Although all of the benzodiazepines in use for the treatment of anxiety are presumably full agonists, it is conceivable that partial benzodiazepine agonists may also be clinically effective on the basis of their effects in preclinical models of anxiety. OBJECTIVES: To compare the anxiolytic-like effects of different pharmacological/chemical classes of partial benzodiazepine agonists in the pigeon conflict procedure. METHODS: Anticonflict effects in pigeons whose responding was maintained under a multiple FR30 food:FR30 food+shock schedule were characterized by 1) the magnitude of punished responding or 2) the percentage of pigeons (n=5-7/dose) showing significant increases in punished responding. RESULTS: The partial allosteric modulators bretazenil and imidazenil produced anticonflict effects comparable with or superior to those observed following administration of the relatively full agonist midazolam. In contrast, neither the beta-carbolines CGS 9896, ZK 95962 and ZK 91296, nor the imidazopyridines, alpidem and zolpidem, produced anticonflict effects comparable to either bretazenil and imidazenil or the relatively full benzodiazepine agonist, midazolam, at the doses examined in this study. CONCLUSIONS: Although the beta-carboline ZK 95962 produced some anticonflict effects, none of the other compounds had anxiolytic-like effects like those observed with midazolam, bretazenil or imidazenil. However, because bretazenil and imidazenil produced robust anticonflict activity, the results indicate that partial allosteric modulators could have anxiolytic effects similar to those produced by higher efficacy compounds. Altogether, the results indicate that partial benzodiazepine agonists differ in their ability to produce robust anticonflict effects in the pigeon.

Evidence for cocaine dependence in monkeys following a prolonged period of exposure.

The behavioral consequences of prolonged continuous exposure to cocaine were examined in rhesus monkeys. Operant behavior was sampled for 0.5 h every 6 h, and cocaine was continuously infused through an intravenous catheter. Cocaine (4.0-32 mg/kg/day) initially caused reductions in the rate of responding for food and tolerance developed to this effect. When the infusion of cocaine was terminated following a period of exposure during which cocaine dose was escalated to 32 mg/kg/day, there was a marked suppression of operant behavior, lasting as long as 72 h, as well as observable changes in behavior (e.g., hyporesponsiveness). This is the first demonstration of behavioral disruptions following discontinuation of cocaine exposure and suggests that the preparation will be a useful animal model for further examining the possibility that exposure to cocaine can induce dependence.

Effects of bromocriptine and desipramine on behavior maintained by cocaine or food presentation in rhesus monkeys.

This experiment tested whether bromocriptine or desmethylimipramine (DMI), both agents used clinically to treat cocaine abuse, could specifically alter behavior maintained by cocaine injections. Rhesus monkeys were trained to press a lever in daily experimental sessions under a three-component multiple schedule of reinforcement. In the first and third components, food was available under a fixed-ratio (FR) 30 schedule. In the second component cocaine (0.025 or 0.050 mg/kg/injection, IV) was available under a FR 30 schedule. Monkeys received continuous (24 h/day) IV infusions of several doses of bromocriptine or DMI. Bromocriptine (0.8-6.4 mg/kg/day) was infused for at least the same number of sessions as was required for responding to decline to low levels when the monkeys were allowed to self-administer saline. DMI (0.8-12.8 mg/kg/day) was infused for a minimum of 3 weeks. In some instances, low doses of bromocriptine decreased responding maintained by cocaine without reducing food-maintained responding, while higher doses of bromocriptine decreased responding maintained by either food or cocaine. However, bromocriptine doses that reduced cocaine intake also caused overt stimulation of locomotor activity. In contrast, DMI, at doses as much as 10 times higher than those used clinically to treat cocaine abuse did not affect responding maintained by cocaine or food. These results indicate that bromocriptine can selectively reduce behavior maintained by cocaine, although apparently by a mechanism other than blockade of reinforcing effects. On the other hand, DMI did not alter the reinforcing effects of either cocaine or food under these conditions.

Modification of quasi-morphine withdrawal with serotonin agonists and antagonists: evidence for a role of serotonin in the expression of opiate withdrawal.

Methylxanthines produce a quasi-morphine withdrawal syndrome (QMWS) in opiate naive rats. Additionally, methylxanthine-induced suppression of conditioned behavior in rats is reversed by the alpha 2 adrenergic agonist clonidine which also attenuates true opiate withdrawal and the QMWS. Therefore, the operant behavioral effects of 3-isobutyl-1-methylxanthine (IBMX) provide a model with which to study mechanisms involved in the expression of opiate withdrawal. In order to examine the role of serotonin (5-HT) in the rate-decreasing effects of IBMX on operant behavior, the 5-HT precursor 5-hydroxytryptophan, and 5-HT reuptake blocker fluoxetine were administered in combination with IBMX to rats performing a fixed-ratio 30 operant for food reinforcement. Both drugs failed to reverse the behavioral suppression caused by relatively low doses of IBMX, suggesting that elevated 5-HT neurotransmission contributes to, rather than attenuates, the QMWS. The relatively selective 5-HT2 antagonists mianserin and pirenperone blocked the IBMX-induced suppression, whereas the classic 5-HT antagonist methysergide had no effect. The results indicate that the operant behavioral effects of IBMX and possibly the QMWS may be mediated by serotonergic mechanisms.

Effects of dopamine antagonists in a two-way active avoidance procedure in rats: interactions with 8-OH-DPAT, ritanserin, and prazosin.

Using a conditioned avoidance procedure in rats, the present study examined the ability of 8-OH-DPAT, ritanserin, and prazosin to alter the effects of the dopamine antagonists, raclopride and haloperidol, on avoidance- and on escape responding. The 5-HT1A agonist 8-OH-DPAT (0.16 mg/kg) significantly enhanced the inhibitory effects of both raclopride and haloperidol on the conditioned avoidance response and produced a small enhancement of the effects of haloperidol on escape failures. the alpha 1-adrenoceptor antagonist prazosin (0.63 mg/kg) significantly enhanced the effects of raclopride on the conditioned avoidance response, but enhanced the effects of only a single dose of haloperidol; prazosin did not alter the effects of either dopamine antagonist on escape failures. The 5-HT2 antagonist ritanserin (0.16 mg/kg) failed significantly to alter the effects of the dopamine antagonists examined here. These findings suggest that blockade of 5-HT2 receptors may not enhance the antipsychotic efficacy of D2-like antagonists. Further, they confirm previous findings with respect to interactions between 5-HT1A agonists and neuroleptics, and support the hypothesis that combined 5-HT1A agonist/D2-like antagonist properties may be of clinical importance.

Interactions between neuroleptics and 5-HT(1A) ligands in preclinical behavioral models for antipsychotic and extrapyramidal effects.

RATIONALE: Combining neuroleptics with 5-HT1A ligands is thought to improve the preclinical profile of neuroleptics and may be of interest in the development of new compounds that have greater therapeutic potential and/or are better tolerated. OBJECTIVE: To examine 1) the ability of 5-HT1A ligands to alter the effects of neuroleptics in preclinical models for antipsychotic potential (hindlimb retraction time in the paw test) and extrapyramidal side-effects (forelimb retraction time in the paw test; catalepsy tests), 2) the role of intrinsic activity at 5-HT1A receptors in the modulatory effects of 5-HT1A ligands, and 3) the generality of the interactions across neuroleptics. METHODS: The effects of different doses of 5-HT1A ligands with intrinsic activity ranging from high (e.g., 8-OH-DPAT) to low (e.g., WAY 100135) administered together with a fixed, high dose of the neuroleptics haloperidol, risperidone, and tropapride were examined in the paw test and on catalepsy. RESULTS: Firstly, the 5-HT1A agonists 8-OH-DPAT and ipsapirone attenuated the extrapyramidal-like effects of haloperidol and risperidone more than their therapeutic-like effects; this was not observed for tropapride, where all of its effects were markedly attenuated. Secondly, neither the weak 5-HT1A agonist WAY 100135 nor the silent antagonist WAY 100635 attenuated the effects of neuroleptics. Thirdly, neuroleptics apparently differed in their sensitivity to interactions with 5-HT1A agonists inasmuch as 8-OH-DPAT and ipsapirone attenuated the effects of tropapride on hindlimb retraction times more than those of haloperidol or risperidone. CONCLUSIONS: The present data suggest that 5-HT1A agonists with intermediate or high, but not low, intrinsic activity may abolish the extrapyramidal effects of neuroleptics. Together with results of previous studies, it appears that 5-HT1A agonists alter the antipsychotic-like effects of neuroleptics, although this may depend on the neuroleptic studied.

Repeated administration of cocaethylene induces context-dependent sensitization to its locomotor effects.

The cocaine analog, cocaethylene, has recently been identified as an active metabolite in humans consuming ethanol and cocaine. Since this compound exhibits affinity for the dopamine transporter that is more selective than that of cocaine, it is conceivable that its behavioral properties may be distinguishable from those of cocaine (cf. Elsworth et al. 1993). To investigate further the behavioral effects of cocaethylene, its ability to induce sensitization to locomotor activity in C57BL/6 mice was determined and compared with that of cocaine. In the first part of the study, mice were treated repeatedly with cocaethylene in the test environment and were then challenged with several different doses of the same drug. Repeated administration of 10, 20 or 40 mg/kg cocaethylene (IP) for 3 consecutive days produced leftward and upward shifts of the cocaethylene (2.5-56.6 mg/kg, IP) dose-effect curve on day 4. In the second part of the study, mice were treated with 20 mg/kg cocaethylene for 3 days, but were immediately placed back in their home cage following the injection: repeated administration of cocaethylene for 3 consecutive days did not significantly affect the dose-effect curve of cocaethylene (2.5-40 mg/kg, IP) on day 4. In the same paradigm, repeated administration of 20 mg/kg cocaine for 3 consecutive days produced a significant leftward shift of the cocaine (2.5-56.6 mg/kg, IP) dose-effect curve on day 4. These results confirm that cocaethylene shares a number of properties with cocaine, but also suggest that the drugs are not identical.

Pharmacological characterization of the discriminative stimulus properties of the phencyclidine analog, N-[1-(2-benzo(b)thiophenyl)-cyclohexyl]piperidine.

RATIONALE: Although both cocaine and the phencyclidine analog, BTCP, have dopamine (DA) re-uptake blocking properties, under some conditions their behavioral effects can be differentiated. Therefore, we examined whether the discriminative stimulus (DS) effects of BTCP are different from those of cocaine. OBJECTIVES: To compare the effects of monoamine re-uptake blockers, varying in their in vitro potencies as inhibitors of DA, norepinephrine (NE), or serotonin re-uptake, in different groups of rats trained to discriminate either BTCP or cocaine from saline. Additionally, drugs from other pharmacological classes were tested in both groups. METHODS: Rats were trained to discriminate either BTCP (5 mg/kg, i.p.) or cocaine (10 mg/kg, i.p.) from saline under a two-lever FR10 drug discrimination procedure. RESULTS: BTCP and cocaine cross-substituted in BTCP- and cocaine-trained rats. The DA re-uptake blockers, mazindol, indatraline, methylphenidate, GBR12909, and GBR12935, occasioned dose-related drug-lever (DL) selection both in cocaine- and in BTCP-trained rats, with potencies that were significantly correlated. In contrast, the NE re-uptake blockers, nisoxetine, desipramine, and nortriptyline, produced higher levels of DL selection in BTCP-trained rats than in cocaine-trained rats, a profile like that reported in low-dose cocaine-trained rats. Drugs from other classes acted similarly in both discriminations. Further, the alpha1-adrenergic antagonist prazosin dose dependently blocked the DS effects of the training dose of BTCP, but not of cocaine. CONCLUSIONS: The results suggest that the DS effects of BTCP are similar to cocaine, and resemble those of a low training dose of cocaine.

Does crossing over repeated treatment with the dopamine reuptake inhibitors cocaine and BTCP modify their effects on cocaine-induced locomotion?

Because the dopamine reuptake inhibitors cocaine and BTCP produce different behavioral effects after repeated administration, we studied whether they could alter each other's effects by examining the effects of crossing over repeated treatment with cocaine and BTCP on cocaine-induced locomotion. Male C57BL/6 mice were treated repeatedly with cocaine or BTCP during a first phase (days 1-3) and 3 days later, treated repeatedly with the same or the other compound during a second phase (days 7-9), after which they were administered one of several doses of cocaine on the next day. Locomotor activity was assessed after every daily treatment. The results show that 1) cocaine induced sensitization to its locomotor effects, 2) cocaine-induced sensitization was not altered by subsequent repeated treatment with BTCP, 3) initial repeated treatment with BTCP induced apparent cross-tolerance to cocaine, and 4) the initial effects of repeated BTCP were not markedly altered by subsequent repeated treatment with cocaine. The results indicate that the initial effects produced by repeated cocaine or BTCP are enduring and relatively difficult to alter by crossing over repeated treatment with the other compound. Thus, sensitization to the locomotor effects of cocaine in mice appeared to be attenuated by prior repeated treatment with BTCP but not reversed when followed by repeated treatment with BTCP.

Parametric analysis of cocaine self-administration under a progressive-ratio schedule in rhesus monkeys.

The present study was designed to investigate parameters and quantitative analysis of cocaine self-administration under a progressive-ratio (PR) schedule of reinforcement, with the goal of enhancing the resolution of PR schedules for measuring reinforcing efficacy. Six rhesus monkeys were prepared with chronic intravenous catheters and trained to self-administer cocaine under a PR schedule. The schedule consisted of five components, each made up of four trials (i.e., 20 trials total). Each trial within a component had the same response requirement. Three initial response requirements were tested: fixed-ration (FR) 60, FR 120 and FR 240. The response requirements doubled in successive components to a maximum of FR 960, FR 1920 or R 3840, respectively, in the fifth component. A trial ended with an injection or the expiration of a 12- or 24-min limited hold (LH). The inter-trial interval (ITI) was 15 or 30 min. Four dependent measures were assessed: break point (last FR completed), injections/session, responses/session and response rate (responses/s). For the three initial FRs, the break point, number of injections/session, responses/session and rate increased with dose of cocaine (0.013-0.1 mg/kg per injection) at both ITI/LH values. At the ITI15/LH12, responding decreased at higher doses, i.e., the dose-response functions were biphasic. In contrast, at the ITI30/LH24, responding reached an asymptote at higher doses. In general, cocaine maintained significantly higher break points, injections/session, responses/session and rate at ITI30/LH24 than at ITI15/LH12. However, at both ITI/LHs, as initial FR was increased, injections/session at the higher doses decreased while break point, total responses/session and rate did not change. A ceiling on performance, as assessed by break point, total responses/session and response rate, may have limited the number of cocaine injections an animal could take in a session. The results of this study indicate that optimal conditions for measuring the reinforcing efficacy of cocaine were obtained at the longer ITI/LH and at initial FRs above 60.