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Conscious squirrel monkeys were treated i.v. with cocaine and various dopamine agonist drugs. Cocaine produced a dose-dependent increase in blood pressure, heart rate, and the rate-pressure product (RPP). The dopamine D1 receptor agonist (+/-)-6-chloro-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF 82958) produced effects comparable to cocaine. The D1 agonist (+/-)-6-chloro-7, 8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF 81297) also produced increases in blood pressure and heart rate but was much less potent than either cocaine or SKF 82958. The partial D1 agonist (+/-)-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SKF 77434) did not significantly affect any cardiovascular parameters. The D2 agonist quinpirole slightly decreased blood pressure and increased heart rate. As such, the RPP only slightly increased. The selective dopamine uptake inhibitor 1-[2-[bis-(4-fluorphenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909) produced increases in blood pressure, heart rate, and RPP, but again these effects were smaller and only seen at doses higher than cocaine. Effects similar to those with GBR 12909 were seen with the dopamine autoreceptor antagonist cis-(+)-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin (UH 232). The combination of GBR 12909, SKF 82958, or SKF 77434 with cocaine produced effects that were clearly subadditive. The effects of quinpirole in combination with cocaine were comparable to, or lower than, those of cocaine alone on blood pressure and RPP. The effects on heart rate were additive. Only UH 232 produced additive effects with cocaine for all three measures. As dopamine agonists have been proposed as potential treatments for cocaine abuse, these results suggest that dopamine D1 agonists and uptake inhibitors can be used safely in combination with cocaine. Caution may be warranted, however, with the use of dopamine autoreceptor antagonists in the treatment of cocaine abuse.

Lobeline interacts with the dopamine transporter and vesicular monoamine transporter, presynaptic proteins involved in dopamine storage and release. This study used rodent models to assess lobeline-induced inhibition of the neurochemical and behavioral effects of amphetamine. Rat striatal slices were preloaded with [(3)H]dopamine and superfused with lobeline for 30 min, and then with d-amphetamine (0.03-3.00 microM) plus lobeline for 60 min. As predicted, lobeline (1-3 microM) intrinsically increased (3)H overflow but did not inhibit d-amphetamine-evoked (3)H overflow. Consequently, the effect of lobeline on d-amphetamine-evoked endogenous dopamine and dihydroxyphenylacetic acid overflow was assessed. Lobeline (0.1-1 microM) inhibited d-amphetamine (1 microM)-evoked dopamine overflow but did not inhibit electrically evoked (3)H overflow, indicating a selective inhibition of this effect of d-amphetamine. To determine whether the in vitro results translated into in vivo inhibition, the effect of lobeline (0.3-10.0 mg/kg) pretreatment on d-amphetamine (0.1-1.0 mg/kg)-induced hyperactivity in rats and on d-methamphetamine (0.1-3.0 mg/kg)-induced hyperactivity in mice was determined. Doses of lobeline that produced no effect alone attenuated the stimulant-induced hyperactivity. Lobeline also attenuated the discriminative stimulus properties of d-methamphetamine in rats. Acute, intermittent, or continuous in vivo administration of lobeline (1-30 mg/kg) did not deplete striatal dopamine content. Thus, lobeline inhibits amphetamine-induced neurochemical and behavioral effects, and is not toxic to dopamine neurons. These results support the hypothesis that lobeline redistributes dopamine pools within the presynaptic terminal, reducing pools available for amphetamine-induced release. Collectively, the results support a role for lobeline as a potential pharmacotherapy for psychostimulant abuse.

Caffeine is a common psychoactive constituent of coffee, carbonated beverages, and over-the-counter medications. This study examined the effects of chronic caffeine exposure on the behavioral response to acute administrations of psychostimulant drugs on ambulatory activity and on the pharmacological characteristics of nicotine discrimination in rats. Rats were maintained continuously on caffeine added to the drinking water at a concentration of 0.25 or 1. 0 mg/ml that resulted in plasma caffeine concentrations ranging from 0.37 to 5.95 microg/ml. Rats maintained on tap water served as control groups. Exposure to the lower caffeine concentration (0.25 mg/ml) potentiated stimulatory effects of nicotine, amphetamine, and cocaine on ambulatory activity and failed to produce tolerance to the acute stimulatory effects of caffeine. In contrast, exposure to the higher caffeine concentration (1.0 mg/ml) did not alter the effects of the psychomotor stimulants on ambulatory behaviors but resulted in the development of complete, insurmountable tolerance to the acute stimulatory effects of caffeine. In the nicotine discrimination paradigm (0.4 mg/kg, training dose, a fixed-ratio 10 schedule of food delivery in a two-lever choice paradigm), rats exposed to the lower, but not to the higher, caffeine concentration acquired the nicotine discrimination significantly faster and were more sensitive to the effects of amphetamine and cocaine in substitution tests than water-drinking rats. Caffeine exposure did not change pharmacokinetic properties of nicotine (i.e., plasma levels, metabolism). In summary, exposure to two different caffeine solutions within a range of plasma levels observed in humans resulted in quantitatively distinct changes in psychostimulant-induced nonoperant and operant measures of behavior. These results suggest that dietary consumption of moderate doses of caffeine may be associated with enhanced reactions to some psychostimulants.

Neurochemical studies indicate that methamphetamine increases central serotonin (5-HT) levels more markedly than other psychomotor stimulants such as amphetamine or cocaine. In the present study, we investigated 5-HT involvement in the discriminative stimulus effects of methamphetamine. In Sprague-Dawley rats trained to discriminate 1.0 mg/kg methamphetamine i.p. from saline under a fixed-ratio schedule of food presentation, the effects of selected 5-HT agonists, antagonists, and uptake inhibitors were tested. Fluoxetine (1.8-18.0 mg/kg) and clomipramine (3.0-18.0 mg/kg), selective serotonin uptake inhibitors, did not produce any methamphetamine-like discriminative stimulus effects when administered alone, but fluoxetine (5.6 mg/kg), unlike clomipramine (5.6 mg/kg), significantly shifted the methamphetamine dose-response curve to the left. Both 8-hydroxy-2-dipropylaminotetralin (0.03-0.56 mg/kg), a full agonist, and buspirone (1.0-10.0 mg/kg), a partial agonist at 5-HT(1A) receptors, partially generalized to the training dose of methamphetamine but only at high doses that decreased response rate. This generalization was antagonized by the coadministration of the 5-HT(1A) antagonist WAY-100635 (1.0 mg/kg). WAY-100635 (1.0 mg/kg) also partially reversed the leftward shift of the methamphetamine dose-response curve produced by fluoxetine. (+/-)-1-(2, 5-Dimethoxy-4-iodophenyl)-2-aminopropane (0.3 mg/kg), a 5-HT(2A/2C) agonist, shifted the methamphetamine dose-response curve to the left, and this leftward shift was antagonized by the coadministration of ketanserin (3.0 mg/kg), a 5-HT(2A/2C) antagonist. Ketanserin (3.0 mg/kg) also produced a shift to the right in the methamphetamine dose-response curve and completely reversed the leftward shift in the methamphetamine dose-response curve produced by fluoxetine. In contrast, tropisetron (1.0 mg/kg), a 5-HT(3) antagonist, produced a shift to the left of the methamphetamine dose-response curve, and this effect of tropisetron was antagonized by the coadministration of m-chlorophenyl-biguanide (1.8 mg/kg), a 5-HT(3) agonist. The present data suggest that the 5-HT system plays a modulatory role in the discriminative stimulus effects of methamphetamine. These effects appear to be mediated through 5-HT release and blockade of reuptake and subsequent activation of 5-HT(2A/2C) receptors, with limited involvement of other 5-HT receptor subtypes.

Sydnocarb (3-(beta-phenylisopropyl)-N-phenylcarbamoylsydnonimine) is a psychostimulant in clinical practice in Russia as a primary and adjunct therapy for a host of psychiatric disorders, including schizophrenia and depression. It has been described as a stimulant with an addiction liability and toxicity less than that of amphetamines. The present study undertook to evaluate the psychomotor stimulant effects of sydnocarb in comparison to those of methamphetamine. Sydnocarb increased locomotor activity of mice with reduced potency (approximately 10-fold) and efficacy compared with methamphetamine. Sydnocarb blocked the locomotor depressant effects of haloperidol at doses that were inactive when given alone. The locomotor stimulant effects of both methamphetamine and sydnocarb were dose-dependently blocked by the dopamine D1 and D2 antagonists SCH 39166 and spiperone, respectively; blockade generally occurred at doses of the antagonists that did not depress locomotor activity when given alone. In mice trained to discriminate methamphetamine from saline, sydnocarb fully substituted for methamphetamine with a 9-fold lower potency. When substituted for methamphetamine under self-administration experiments in rats, 10-fold higher concentrations of sydnocarb maintained responding by its i.v. presentation. Sydnocarb engendered stereotypy in high doses with approximately a 2-fold lower potency than methamphetamine. However, sydnocarb was much less efficacious than methamphetamine in inducing stereotyped behavior. Both sydnocarb and methamphetamine increased dialysate levels of dopamine in mouse striatum; however, the potency and efficacy of sydnocarb was less than methamphetamine. The convulsive effects of cocaine were significantly enhanced by the coadministration of nontoxic doses of methamphetamine but not of sydnocarb. Taken together, the present findings indicate that sydnocarb has psychomotor stimulant effects that are shared by methamphetamine while demonstrating a reduced behavioral toxicity.

Caffeine and nicotine are the main psychoactive ingredients of coffee and tobacco, with a high frequency of concurrent use in humans. This study examined the effects of chronic caffeine exposure on 1) rates of acquisition of a nicotine discrimination (0.1 or 0.4 mg/kg, s.c., training doses) and 2) the pharmacological characteristics of the established nicotine discrimination in male Sprague-Dawley rats. Once rats learned to lever-press reliably under a fixed ratio of 10 schedule for food pellets, they were randomly divided into two groups; 12 animals were maintained continuously on caffeine added to the drinking water (3 mg/ml) and another 12 control rats continued to drink tap water. In each group of water- and caffeine-drinking rats, there were six rats trained to discriminate 0.1 mg/kg of nicotine from saline and six rats trained to discriminate 0.4 mg/kg of nicotine from saline. Regardless of the training dose of nicotine, both water- and caffeine-drinking groups required a comparable number of training sessions to attain reliable stimulus control, although there was a trend for a slower acquisition in the caffeine-drinking group trained with 0.1 mg/kg of nicotine. Tests for generalization to different doses of nicotine revealed no significant differences in potency of nicotine between water- and caffeine-drinking groups. The nicotinic-receptor antagonist mecamylamine blocked the discriminative effects of 0.1 and 0.4 mg/kg nicotine with comparable potency and efficacy in water- and caffeine-drinking groups. There was a dose-related generalization to both the 0.1 and 0.4 mg/kg nicotine cue (maximum average of 51-83%) in water-drinking rats after i.p. treatment with d-amphetamine, cocaine, the selective dopamine uptake inhibitor GBR-12909, apomorphine, and the selective dopamine D1 receptor agonist SKF-82958, but not in caffeine-drinking rats (0-22%). There was no generalization to the nicotine cues after i.p. treatment with caffeine or the selective D2 (NPA) and D3 (PD 128,907) dopamine-receptor agonists in water- and caffeine-drinking rats. The dopamine-release inhibitor CGS 10746B reduced the discriminative effects of 0.4 mg/kg nicotine in water-drinking rats, but not in caffeine-drinking rats. There was no evidence of development of tolerance or sensitization to nicotine's effects throughout the study. In conclusion, chronic caffeine exposure (average, 135 mg/kg/day) did not affect the rate of acquisition of the nicotine discrimination, but it did reduce the dopaminergic component of the nicotine-discriminative cue. The reduction of the dopaminergic component of the nicotine cue was permanent, as this effect was still evident after the caffeine solution was replaced with water in caffeine-drinking rats. That nicotine could reliably serve as a discriminative stimulus in the absence of the dopaminergic component of its discriminative cue may differentiate nicotine from "classical dopaminergic" drugs of abuse such as cocaine and amphetamine.

Neuroactive steroids are naturally occurring or synthetically derived compounds many of which have anticonvulsant, anesthetic, anxiolytic, analgesic or hypnotic properties. The major site of neuronal activity appears to be with a specific steroid-sensitive site on the gamma-aminobutyric acidA receptor/chloride ionophore complex. Ganaxolone (3 alpha-hydroxy-3 beta-methyl-5 alpha-pregnan-20-one) is a synthetic neuroactive steroid protected from metabolic attack of the 3 alpha position. Ganaxolone is an efficacious anticonvulsant agent in a variety of acute seizure models, as well as in electrical and chemical kindling models, and is currently under Phase II clinical investigation for epilepsy. A prior observation that ganaxolone appeared to reverse the marked behavioral changes induced by the convulsant pentylenetetrazol (PTZ) was systematically examined in the present study. A model to quantify PTZ-induced behaviors is described and used to evaluate ganaxolone in comparison with the anticonvulsants valproate, ethosuximide, clonazepam, diazepam and phenobarbital. All compounds were compared using dose equivalents based on their respective ED50 values in preventing convulsions induced by 70 mg/kg PTZ. The ED50 and lower doses of ganaxolone prevented the observed behavioral effects of PTZ as well as its depressant effects on locomotor activity and rearing of mice. In contrast, the other anticonvulsants, if effective, were much less potent. Strikingly, most of the other anticonvulsants were incapable of preventing all the behavioral effects of PTZ. Only phenobarbital prevented all the behavioral effects of PTZ and only at doses 4 to 8 times the anticonvulsant ED50. Rather than normalizing behavior as ganaxolone did, however, phenobarbital resulted in supranormal behavioral responses (e.g., increases in activity). Repeated administration of PTZ did not decrease the protective efficacy of ganaxolone. The results document the unique pharmacological profile of ganaxolone and suggest additional potential benefits from its use as an antiepileptic. Furthermore, because behavioral effects of PTZ have been used to model anxiety and anxiety associated with withdrawal from drugs of abuse, ganaxolone may find additional therapeutic application in those areas.

Epilepsy continues to be a significant clinical problem as current medications neither adequately control seizures nor are free of untoward side-effects. Modulation of the neuroactive steroid site on the gamma-aminobutyric acid (GABA)A receptor complex may be an important new direction for pharmaceutical interventions in epilepsy. In this study we evaluated the protective actions of four neuroactive steroids, 3alpha-hydroxy-5alpha-pregnan-20-one, the 3beta-methylated analog, ganaxolone (3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one), 3alpha-hydroxy-5beta-pregnan-20-one and Co 2-1068 (3beta-(4acetylphenyl)ethynyl-3alpha,21-dihydroxy-5beta++ +-20-one-21-hemisuccinate), against several standard convulsive tests in male, Swiss-Webster mice. Consistent with their GABAergic actions, the neuroactive steroids as well as diazepam and phenobarbital dose-dependently protected against clonic convulsions induced by pentylenetetrazol; the N-methyl-D-aspartate receptor antagonist, dizocilpine, was ineffective. In contrast to diazepam and phenobarbital, however, all of the neuroactive steroids and dizocilpine produced full protection against cocaine-induced convulsions. Some of the neuroactive steroids, as well as dizocilpine, were efficacious against the seizures and lethality induced by N-methyl-D-aspartate. Pregnenolone, a steroid devoid of GABAergic activity, was not effective in any of the convulsant models. Although all of the compounds produced motor toxicity in high doses as measured by the inverted-screen test, the neuroactive steroids demonstrated an equivalent or improved separation between anticonvulsant potency and motoric impairment. Inactive doses of the neuroactive steroids markedly enhanced the anticonvulsant effects of diazepam against pentylenetetrazol without significantly increasing motor toxicity. This adjunct treatment resulted in protective indices ranging from 60 to 360 compared to 12 for diazepam alone. The distinct profile of anticonvulsant activity of the neuroactive steroids may be related to their combined actions on gamma-aminobutyric acid, N-methyl-D-aspartate receptors, or voltage-operated Ca++ channels. These results help to define the neuroactive steroids as a novel class of antiepileptic agents and suggest their potential in clinical practice.

The effects of cocaine alone and in combination with the calcium channel blockers nimodipine, verapamil and diltiazem were determined for different groups of squirrel monkeys on cardiovascular function, schedule-controlled behavior and drug self-administration. Cocaine alone (0.3 mg/kg) produced increases in both blood pressure and heart rate. All three calcium channel blockers antagonized the pressor effect, but were ineffective against the tachycardiac effect of cocaine. Nimodipine was the most potent agent in antagonizing the pressor effect of cocaine. Response rates for monkeys responding on a second-order schedule of food presentation were increased by intermediate doses of cocaine (0.1-1.0 mg/kg) and were primarily decreased at a higher dose (3.0 mg/kg). Quarter-life values, an index of response patterning, were only decreased by cocaine. None of the calcium channel blockers altered cocaine's effects on either response rate or response patterning. In the self-administration experiments, the training dose of 56 micrograms/kg cocaine maintained high rates of responding on a simple fixed-ratio schedule. As with schedule-controlled behavior, none of the calcium channel blockers altered cocaine self-administration even when administered before self-administration sessions during 5 consecutive days. These results suggest that the calcium channel blockers may be useful in treating cardiovascular-related complications after cocaine use, but they would not be effective as long-term treatment agents for cocaine abuse.

There is a dynamic interaction between a drug's pharmacological effects and the behavioral context in which it is administered. The present study evaluated the influence of behavioral processes on the development of tolerance and cross-tolerance to the rate-decreasing effects of chlordiazepoxide in rats. Sprague-Dawley rats responded under a fixed-ratio 30 schedule of food delivery. Different groups of rats received 18 mg/kg/day of chlordiazepoxide either before (PRE, n = 8) or after (POST, n = 10) daily experimental sessions for 8 weeks. Cumulative dose-response curves for chlordiazepoxide were obtained before and during chronic chlordiazepoxide administration and during chronic saline administration. Cumulative dose-response curves for midazolam, FG 7142 (N-methyl-beta-carboline-3-carboxamide) flumazenil, pentobarbital, caffeine, morphine and d-amphetamine were determined before, during and 4.5 to 5 months after chronic chlordiazepoxide administration. Group PRE developed tolerance to chlordiazepoxide, whereas group POST did not develop tolerance. Although cross-tolerance developed to midazolam in both groups, it was greater in group PRE. Both groups showed comparable sensitization to FG7142 and neither group showed a significant change in sensitivity to any of the other drugs. Biochemical studies of gamma-aminobutyric acid (GABA)-related functioning in groups of rats that received chronic chlordiazepoxide administration either before (BIO-PRE, n = 6) or after (BIO-POST, n = 6) daily sessions found that GABA-stimulated 36Cl-uptake increased in both cortical and cerebellar preparations. However, GABA sensitivity in cerebellar tissue was significantly lower in group BIO-PRE compared with group BIO-POST. Thus, behavioral tolerance to chlordiazepoxide was associated with both pharmacological and biochemical effects, which suggests a relationship between behavioral tolerance to benzodiazepines and changes in the functional state of the GABA-benzodiazepine receptor complex.

Cocaine (0.03-5.6 mg/kg i.v.) produced a dose-dependent and prolonged increase in mean arterial blood pressure and heart rate in conscious rats. The 0.3 and 1 mg/kg doses of cocaine potentiated the pressor response to exogenous norepinephrine (0.2 microgram/kg), whereas lower (0.03 and 0.1 mg/kg) and higher (3 and 5.6 mg/kg) doses were ineffective. Desipramine (0.03-1 mg/kg), a prototype norepinephrine uptake blocker, did not alter blood pressure or heart rate. Nisoxetine (0.01-1 mg/kg), another norepinephrine selective uptake blocker, produced a small and brief (< 5 min) pressor response, but not tachycardiac response. Unlike cocaine, both desipramine and nisoxetine produced a dose-dependent potentiation of the pressor response to norepinephrine with the maximal potentiation exceeding that of cocaine. Plasma norepinephrine and epinephrine levels were increased by cocaine (3 mg/kg), but not by nisoxetine (1 mg/kg). Chemical sympathectomy by 6-hydroxydopamine selectively antagonized cocaine-induced increases in both blood pressure and plasma norepinephrine levels, but did not alter cocaine-induced increases in heart rate or plasma epinephrine levels; the converse was the case with adrenal demedullation. Both the combination of chemical sympathectomy and adrenal demedullation and pretreatment with chlorisondamine (10 mg/kg) antagonized cocaine-induced pressor and tachycardiac effects and cocaine-induced increases in plasma epinephrine and norepinephrine levels. In the control group, cocaine (3 mg/kg) produced a biphasic increase in blood pressure consisting of an early peak increase of 52 +/- 2.5 mm Hg 15 sec after its injection followed by a quick and partial recovery to an increase of 20.5 +/- 3.3 mm Hg at 1 min which gradually declined to base-line values in about 30 min. Prazosin (1 mg/kg) pretreatment decreased the magnitude of the initial peak pressor response produced by cocaine and reversed the sustained pressor response to cocaine to a depressor response; the reversal of the pressor response to cocaine to a depressor response by prazosin was not seen after erythro-dl-1-(7-methylindan-4-yloxy)-3-isopropylaminobuta n-2-ol (ICI 118,551) (3 mg/kg) treatment or adrenal demedullation. Treatment with ICI 118,551 alone enhanced the magnitude of the sustained phase of the pressor response to cocaine. These results indicate that inhibition of peripheral sympathetic neuronal amine uptake mechanism by cocaine is not critical for initiating its pressor, tachycardiac and plasma catecholamine increasing effects in conscious rats and that central stimulation of sympathoadrenal neural axis activity plays an important role in these effects.(ABSTRACT TRUNCATED AT 400 WORDS)

The antiparkinsonian agent l-deprenyl, a selective monoamine oxidase (MAO)-B inhibitor, is a phenylalkylamine derivative which is metabolized in part to l-methamphetamine and l-amphetamine. As the clinical use of amphetamine-like psychostimulants is limited by their potential for abuse, we evaluated l-deprenyl for amphetamine-like discriminative stimulus effects over a range of experimental conditions. Male Fisher rats were trained under a 5-response, fixed-ratio schedule of stimulus-shock termination or a 10-response, fixed-ratio schedule of food-presentation to discriminate between d-amphetamine (1.0 mg/kg i.p.) and saline in a two-lever, operant conditioning procedure. Full generalization was obtained to l-amphetamine (1.0-2.0 mg/kg), d-deprenyl (10.0-17.0 mg/kg) and l-deprenyl (17.0 and 30.0 mg/kg) under both the food-presentation and stimulus-shock termination schedules, and increases in responding on the lever appropriate to d-amphetamine were dose-dependent. The dose-effect functions for l-amphetamine, l-deprenyl and d-deprenyl were shifted slightly to the left under the stimulus-shock termination schedule compared to the food-presentation schedule. When l-deprenyl (3.0 or 5.6 mg/kg i.p.) was given 30 min before d-amphetamine it produced a small shift to the left in the dose-effect function for d-amphetamine under the food-presentation schedule. l-Deprenyl produced clear generalization to the d-amphetamine stimulus only at very high doses of 17.0 to 30.0 mg/kg, doses about 10-fold higher than those that have a selective action on MAO-B vs. MAO-A and which start to have marked rate decreasing actions on food-reinforced responding.(ABSTRACT TRUNCATED AT 250 WORDS)

D-16949 [6-chlor-2-(piperidyl-4-thio)-pyridine; Anpirtoline] is a novel centrally acting compound with serotonergic effects. To assess its discriminative stimulus effects, rats were trained to discriminate D-16949 (2.0 mg/kg i.p., 30 min) from no drug. D-16949 induced dose-dependent discriminative stimulus effects (ED50, 0.31 mg/kg), and did not produce sedation. The opioid analgesics codeine, pentazocine and tramadol all failed to substitute for D-16949. The opioid antagonist naltrexone did not antagonize the discriminative stimulus effects of D-16949. Phencyclidine, d-amphetamine, lysergic acid diethylamide and quipazine produced between 0 and 35% responding on the D-16949 lever. 8-Hydroxy-2-(di-n-propylamino)-tetralin substituted partially (45%) for D-16949, whereas 1-(m-trifluoromethylphenyl)-piperazine and RU 24969 completely and dose-dependently substituted for D-16949. The discriminative stimulus effects of D-16949 were not reversed by either cyproheptadine, ketanserin, pirenperone, spiperone or methylsergide. The 5-hydroxytryptamine3 (5-HT3) active antagonists ICS 205-930 and MDL 72222 were also ineffective as D-16949 antagonists. It is concluded that the discriminative stimulus effects of D-16949 are not mediated through opioid or 5-HT2 mechanisms. The present data also do not suggest the involvement of 5-HT3 mechanisms, but that D-16949 produces its discriminative stimulus effects in the rat primarily via agonistic actions at 5-HT1B receptors.

In conscious rats, continuous i.v. infusion of cocaine (2 mg/kg/min) produced a marked increase in blood pressure, an initial moderate increase followed by a decrease in heart rate, tonic-clonic convulsions and, finally, a lethal episode of status epilepticus. No change in rectal temperature was observed. Infusion of cocaine methiodide (2 mg/kg/min), a quaternary derivative of cocaine, also produced a lethal episode of status epilepticus, but it was 6 times less potent than cocaine on a molar basis. In pentobarbital-anesthetized, spontaneously breathing rats, cocaine produced death by respiratory failure. Artificial ventilation of pentobarbital-anesthetized rats elevated the lethal dose of cocaine by 15-fold and these animals died of marked hypotension. In conscious rats, pretreatment with dl-, d- or l-propranolol or the alpha 2-selective adrenoceptor antagonist yohimbine enhanced the convulsive and lethal effects of cocaine. In contrast, the alpha 2-selective adrenoceptor agonist clonidine or the alpha 1-selective adrenoceptor antagonist prazosin attenuated these effects. Yohimbine antagonized the protective effect of clonidine. The nonselective alpha adrenoceptor antagonist phentolamine, the autonomic ganglionic blocker chlorisondamine and various calcium channel blockers had no effect on the convulsive or lethal doses of cocaine. The pressor response to cocaine was attenuated by calcium channel blockers, clonidine, phentolamine and dl- or l-propranolol, but not by d-propranolol. The pressor response to cocaine was abolished by chlorisondamine, reversed to a depressor response by prazosin and enhanced by yohimbine. The initial tachycardiac response to cocaine was reversed to bradycardia by dl- and l-propranolol, prazosin, yohimbine or high doses of the calcium channel blockers, but was unaffected by phentolamine, d-propranolol, clonidine or chlorisondamine. These results indicate that in spontaneously breathing animals, acute i.v. infusions of lethal doses of cocaine produce death primarily by central effects, namely by status epilepticus in conscious rats and by respiratory arrest in pentobarbital-anesthetized rats. In artificially ventilated, pentobarbital-anesthetized rats, however, cocaine produces death by effects on the cardiovascular system. In conscious rats, endogenous alpha 1 adrenoceptors exert a deleterious influence on cocaine-induced convulsive and lethal effects, whereas alpha 2 adrenoceptors provide protective influence. Propranolol appears to enhance cocaine-induced acute lethality through a mechanism independent of beta adrenoceptors. Calcium channel blockers appear ineffective in antagonizing cocaine's lethality.

Cocaine (0.03-3 mg/kg, i.v.) produced a dose-dependent increase in mean arterial blood pressure and heart rate in conscious Sprague-Dawley rats. Pretreatment with the competitive ganglionic blockers pentolinium or hexamethonium attenuated cocaine's pressor effect, whereas noncompetitive (chlorisondamine) or mixed (mecamylamine) type blockers not only abolished, but also reversed it to a depressor effect. Cocaine's tachycardiac effect was attenuated by all four ganglionic blockers. The relative effectiveness of the four ganglionic blockers in antagonizing cocaine-induced cardiovascular effects was similar to that of antagonism of phenylephrine-induced, centrally mediated reflex bradycardia. All four ganglionic blockers at all the doses tested produced similar reductions in base-line BP, thereby suggesting that these agents produced similar degrees of maximal reduction of basal sympathetic tone. The pressor responses to norepinephrine (0.2 micrograms/kg) were potentiated, whereas those to tyramine (0.3 mg/kg) were inhibited by cocaine (0.3-3 mg/kg); the former effect was not dose dependent (bell-shaped dose-response curve), whereas the latter effect was dose-dependent. The amine uptake inhibitory potency (ED50, 0.85 mg/kg) of cocaine is about 10 times less than its potency to produce pressor (ED50, 0.075 mg/kg) and tachycardiac (ED50, 0.083 mg/kg) effects. Chlorisondamine did not antagonize the pressor effects of the indirect sympathomimetic agent, tyramine. These results suggest that the blockade of cocaine's pressor and tachycardiac effects by ganglionic blockers is not related to their ability to eliminate basal sympathetic tone and, thereby, indirectly blunt cocaine's inhibitory effect on sympathetic neuronal uptake of norepinephrine. Rather, the results indicate that these effects are mainly due to their antagonistic actions on cocaine-induced central stimulation of sympathetic activity.(ABSTRACT TRUNCATED AT 250 WORDS)

The reinforcing and subjective effects of morphine were determined in five human volunteers with histories of i.v. heroin abuse. Subjects responded under a second-order schedule of i.m. injection. Under this schedule, every 100 lever presses produced a brief stimulus light [fixed ratio (FR) 100:s]; the 30th completion of the FR 100 requirement turned on the light for 15 min and the subject received an i.m. injection of morphine [FR 30 (FR 100:s)]. Once each weekday morphine or placebo was available under this schedule. Each drug dose was available for 1 week. Under these conditions placebo did not maintain responding; 3.75 mg of morphine maintained responding in four of five subjects, and higher morphine doses (7.5, 15 and 30 mg) maintained responding in all five subjects. Subjective effects were measured concurrently: these included measures of drug liking, the Morphine Benzedrine Group scale of the Addiction Research Center Inventory, drug detection and identification. Subjects did not report subjective effects different from placebo for the lowest dose of morphine; the intermediate doses of morphine produced inconsistent effects, and the highest dose of morphine occasioned reports of drug liking and "dope" identifications. These results indicate that there can be a significant dissociation of the reinforcing and the subjective effects of opioids, which has implications for theories of opioid abuse, particularly those assuming that the reinforcing effects are causally related to the euphoric effects of opioids. Furthermore, these results confirm that measures of reinforcing effects and measures of subjective effects do not necessarily lead to identical predictions when used to assess the liability for abuse of a substance.

Studies of ethanol drinking suggest an inverse correlation between innate sensitivity to ethanol and behavior reinforced by this drug. The present study investigated ethanol reinforced behavior in mice selectively bred for high, Long Sleep/Institute for Behavioral Genetics (LS), and low, Short Sleep/Institute for Behavioral Genetics (SS), sensitivity to ethanol. Results show that both lines will drink large amounts of ethanol postprandially. However, in the absence of food presentation, LS and SS mice differed significantly in ethanol reinforced behavior. Ethanol maintained higher rates of responding, greater intake and higher blood ethanol levels in LS relative to SS mice across increasing fixed-ratio values. Ethanol did not maintain fixed-ratio lever pressing above rates maintained by vehicle in SS mice. Responding for and consumption of 8% ethanol significantly exceeded that of vehicle only in LS mice. Response rates of LS mice showed a typical inverted U-shaped relationship to ethanol concentration. Postsession blood ethanol levels and body temperatures indicated pharmacologically significant ethanol intake only in LS mice. Thus, ethanol served as an effective reinforcer in LS mice across a range of environmental conditions. Conversely, ethanol was not established as a positive reinforcer in SS mice under any of the broad range of conditions studied. These results are not consistent with the frequently reported negative correlation between ethanol intake and sensitivity to ethanol and rule out a causal basis for correlations seen between these traits.

The effects of cocaine on cardiovascular function were studied in six conscious squirrel monkeys. Cocaine (0.01-3 mg/kg i.v.) increased mean arterial blood pressure and heart rate (HR) in a dose-dependent manner. The effect of cocaine on HR reached a maximum at 0.3 mg/kg. Doses of cocaine up to 3 mg/kg did not evoke cardiac rhythm disturbances. Pentobarbital or halothane anesthesia attenuated the pressor and tachycardiac effects of 3 mg/kg of cocaine. Antagonism of the pressor response to cocaine by halothane was significantly greater than that by pentobarbital. Halothane, but not pentobarbital, also significantly reduced the pressor response to norepinephrine (1 micrograms/kg i.v.). Blockade of autonomic ganglia by hexamethonium failed to antagonize the pressor and tachycardiac effects of 3 mg/kg of cocaine. The pressor response to 3 mg/kg of cocaine was antagonized by alpha adrenoceptor blockade with phentolamine, whereas the tachycardiac response to cocaine was antagonized by beta adrenoceptor blockade with propranolol. These results suggest that the blood pressure and HR increasing effects of cocaine in conscious squirrel monkeys are not due to stimulation of the central nervous system-sympathoadrenal neural axis, but are due to its peripheral actions on catecholaminergic systems. The 1- and 3-mg/kg doses of cocaine caused an initial reduction in HR of 5 to 30 beats/min in three monkeys and 90 to 110 beats/min in one animal before the onset of their tachycardiac effect. None of the above pharmacological interventions were effective in preventing this initial, moderate reduction in HR in three monkeys.(ABSTRACT TRUNCATED AT 250 WORDS)

Rats were trained on a fixed-ratio schedule under which every 30th response produced food reinforcement. Five 3-min periods of fixed-ratio reinforcement were each preceded by a 10-min time-out in which responding had no scheduled consequence. Cumulative dose-effect functions for naltrexone were determined once per week by administering increasing doses during each successive time-out. Initially, only a dose of 100 mg/kg suppressed fixed-ratio responding. After eight exposures to cumulative naltrexone, however, a dose of 10 mg/kg suppressed responding. This shift to the left of the dose-effect function, or supersensitivity, persisted for at least 10-wk when naltrexone was not injected. Pretreatment with either morphine (3.0 mg/kg) or ethylketocyclazocine (0.1 and 1.0 mg/kg) partially prevented the naltrexone-induced decreases in response rates. Neither chlordiazepoxide nor [D-pen2, D-pen5]enkephalin pretreatments appreciably altered the effects of naltrexone. When cumulative doses of 1.0-10.0 mg/kg naltrexone were followed by two saline injections instead of the higher doses of naltrexone, over 8 wk, the naltrexone dose-effect function shifted back to the right. The return to normal naltrexone sensitivity after elimination of the two highest doses suggests that a reliable association between the lower and higher doses in a cumulative dosing procedure can result in conditioned effects to the lower doses. Similar observations of salivation elicited by cumulative naltrexone injections further support the hypothesis that the present naltrexone supersensitivity may involve conditioning processes.

Behavior of squirrel monkeys was maintained under comparable 30-response fixed-ratio schedules of cocaine injection or fooc presentation. Every 30th key press in the presence of a green light produced an intravenous injection of 25 mug/kg of cocaine in one group of monkeys or delivery of a food pellet in a second group of monkeys. Each cocaine injection or food presentation was followed by a 1-minute timeout period, during which the green light was absent and responses had no programmed consequences. Responding at a mean rate of more than 1/sec was maintained in the presence of the green light during each daily session. Propranolol doses from 0.3 to 3.0 mg/kg i.m. had no effect on food-maintained responding but decreased cocaine-maintained responding by approximately 30%. The selective disruption of cocaine-maintained responding by propranolol appeared to depend on the cumulative cocaine dose. Decreases in cocaine-maintained responding after propranolol became increasingly pronounced as the session progressed. Similar progressive decreases in cocaine-maintained responding were produced by increasing the dose of cocaine per injection.

Lever pressing by squirrel monkeys was maintained by i.v. injections of nicotine (3-560 microgram/kg) or cocaine (3-300 microgram/kg) under two intermittent schedules of self-administration. Under a fixed-interval schedule, the first response after a specified interval of time produced an injection. Under a second-order fixed-interval schedule, the completion of every 10-response fixed-ratio unit produced a brief visual stimulus and the first fixed-ratio unit completed after a specified interval produced both the brief stimulus and an injection. As the dose of either drug was increased, the rate of responding first increased and then decreased; maximal response rates maintained by nicotine were approximately equal to those maintained by cocaine in some monkeys, but less than those maintained by cocaine in other monkeys. Patterns of responding maintained by the two drugs were qualitatively similar in all monkeys and were characteristic of performances maintained by other reinforcers under fixed-interval or second-order fixed-interval schedules. Doses of nicotine greater than 30 microgram/kg/injection usually produced vomiting, but often maintained responding well above the rates maintained by saline. When the nicotinic antagonist, mecamylamine (1.0 mg/kg i.m.) was administered before every experimental session, responding maintained by nicotine, but not by cocaine, fell to within saline-control levels; increasing the dose of nicotine to as high as 1700 microgram/kg/injection did not restore responding. Under the intermittent schedules studied here, nicotine served as an effective reinforcer to maintain responding and the reinforcing effects of nicotine were blocked by mecamylamine.

Dose-effect curves were obtained for the influence of naltrexone, of naloxone and of morphine on lever-pressing responses of squirrel monkeys and key-pecking responses of pigeons maintained by food presentation during fixed-interval (FI) and fixed-ratio (FR) components of a multiple schedule. Morphine caused dose-related decreases in FI and FR responding, with complete suppression occurring after 3 mg/kg was administered to monkeys and after 10 mg/kg was administered to pigeons. Naltrexone doses as low as 0.03 mg/kg (monkeys) or 0.1 mg/kg (pigeons) and naloxone doses as low as 0.1 mg/kg (monkeys) or 1 mg/kg (pigeons) shifted morphine dose-effect curves by one or more log units to the right. The effects of a 3 mg/kg injection of morphine were blocked completely by naltrexone (0.1-0.3 mg/kg) injected up to 16 hr before morphine, but not by naloxone (0.3-1 mg/kg) injected more than 2 hr before morphine. Thus, naltrexone was 3 to 10 times more potent than naloxone as an antagonist of morphine and was longer acting. Given alone, only high doses of naltrexone or naloxone (10 mg/kg, monkeys; 56 mg/kg, pigeons) had pronounced actions; FR and FI responding were markedly decreased and vomiting often occurred. Repeated daily injections of these high doses of naltrexone or naloxone resulted in little or no tolerance. One to 6 months after termination of chronic treatment, dose-effect curves for naltrexone on FR and FI responding maintained by food presentation were shifted markedly to the left with the monkeys, but not with the pigeons.

Apomorphine and cocaine and their long-acting derivatives, diisobutyrylapomorphine and Win 35,428 (a fluorine-substituted phenyltropane analog of cocaine), were compared for their effects in producing conditioned taste aversions and altering schedule-controlled behavior in rats. The drugs had qualitatively similar effects in both types of experiments; suitable doses of each drug produced marked decreases in consumption of flavored solutions associated with their injection and suppressed key-press responding maintained under a 30-response fixed-ratio scheduled of food presentation. Potency ratios for apomorphine and cocaine relative to their long-acting derivatives were similar in both experiments; Win 35,428 was approximately 34 times more potent than cocaine, whereas apomorphine and diisobutyrylapomorphine did not differ appreciably in potency. Extending the duration of action of cocaine by administering an initial dose of 53 micromol/kg of cocaine followed by two additional doses of 26.5 micromol/kg at 30-min intervals failed to produce a greater degree of taste aversion than administration of only a single dose of 53 micromol/kg of cocaine. The observations with Win 35,428 and diisobutyrylapomorphine confirm previous work with these compounds and extend its generally to other species of animal and types of behaviors. None of the findings support the view that the potency of a drug in producing conditioned taste aversions is correlated with its duration of action.

Intramuscular injections of the stereoisomers of cocaine and of its phenyltropane analog were compared for their effects on schedule-controlled behavior of squirrel monkeys. Monkeys responded by pressing a lever under a multiple schedule with alternating fixed-interval and fixed-ratio components; responding was maintained by presentation of food in some monkeys and by termination of a stimulus associated with electric shock in other monkeys. The levorotatory isomers, (-)-cocaine (0.09-2.7 mg/kg) and WIN 35,065-2 (0.006-0.2 mg/kg), had qualitatively similar effects which depended primarily on the type of component schedule (fixed-interval or fixed-ratio) that maintained responding. In the fixed-interval components, intermediate doses of each drug increased responding, whereas higher doses decreased responding. In the fixed-ratio components, each drug only decreased responding in a dose-related manner. The minimal effective dose of (-)-cocaine was about 10 times that of WIN 35,065-2. Although the dextrorotatory isomers, (+)-cocaine and WIN 35,065-3, also increased responding in the fixed-interval components and decreased responding in the fixed-ratio components in some monkeys, the doses required were 100 to 622 times the minimal effective doses of their enantiomers. The results show a high degree of stereoselectivity in the behavioral effects of both cocaine and its phenyltropane analog.

Squirrel monkeys pressed a key under second-order schedules in which every nth response resulted in a 2-sec visual stimulus (n-response fixed ratio; n = 10, 20 or 30); after a minimum fixed-interval of time elapsed (second-order t-min fixed-interval; t = 5 or 60), the completion of a fixed-ratio resulted in both the brief stimulus and either presentation of food or i.v. injection of cocaine. Under a second-order 5-min fixed-interval schedule with 15 intervals per session, rates of responding increased to a maximum and then decreased with increases in the amount of food (from 250 to 4000 mg/presentation) or cocaine (from 25 to 400 micrograms/kg/injection). Cocaine injections maintained higher maximal rates of responding than food presentation. When the brief stimuli were omitted during the 5-min intervals, average rates of responding maintained by cocaine decreased, but those maintained by food presentation did not. The presession administration of cocaine (0.3-1.0 mg/kg i.m.) increased rates of responding maintained by food to about the same level as those maintained by cocaine; these elevated rates did not decrease when the brief stimuli were omitted. Under a second-order 60-min fixed-interval with one interval per session, both food and cocaine maintained relatively high rates of responding even with large amounts of food (7.5-14 g/presentation) or cocaine (375-1500 micrograms/kg/injection). When the brief stimuli were omitted during the 60-min interval, rates of responding maintained by either food or cocaine decreased. Thus, the brief-stimulus presentations were essential for maintaining performance under the second-order 60-min fixed-interval schedule.

Morphine, naloxone and nalorphine were studied for their effects on the performance of squirrel monkeys and pigeons responding under multiple fixed-interval (FI), fixed-ratio (FR) schedules of food presentation. Morphine generally produced only dose-related decreases in responding in both monkeys and pigeons; monkeys were 10 times more sensitive to morphine than pigeons. The only effect of lower doses of naloxone (0.01-1 mg/kg, monkeys; 1-10 mg/kg, pigeons) was to increase FI responding in some pigeons. Higher doses of naloxone (10-56 mg/kg), produced gross disturbances such as tremors and vomiting and decreased FI and FR responding of both monkeys and pigeons. Nalorphine had strikingly different effects on the behavior of the two species. In the pigeons, nalorphine consistently increased both FI and FR response rates at doses from 0.3 to 10 mg/kg and decreased responding only at doses of 30 to 100 mg/kg. Nalorphine did not increase responding at any dose in the monkeys and the pigeons, nalorphine was only one-tenth as potent as naloxone in antagonizing the effects of morphine on FI and FR responding. Decreasing response rates caused by nalorphine appeared to limit further its usefulness as a morphine antagonist. Antagonism of the rate-decreasing effects of morphine on FI and FR responding occurred over a narrower range of doses with nalorphine than with naloxone, especially in monkeys.

The behavioral effects of two phenyltropane derivatives of coaine were compared with those of cocaine. Squirrel monkeys responded under multiple fixed-interval, fixed-ratio schedules of either stimulus-shock termination or food presentation or under a fixed-ratio schedule of food presentation. The effects of the three drugs were independent of the type of event that maintained responding. Under the fixed-interval schedules, some doses of each drug increased responding, whereas larger doses generally decreased responding. Maximal increases in responding were similar with each drug. Appropriate doses of each drug increased low response rates, which occurred during the initial segments of the fixed intervals, but had little effect on or decreased higher response rates, which occurred during the later segments of the fixed intervals. Under the fixed-ratio schedules, each drug decreased responding in a dose-related manner. Decreases in fixed-ratio responding resulted both from increased periods of no responding at the beginning of the fixed ratios and from decreased rates of responding once responding began. Each cocaine analog had a slower onset of effect and longer responding began. Each cocaine analog had a slower onset of effect and a longer duration of effect than cocaine. The behavioral effects of the two cocaine analogs were qualitatively similar to those of cocaine, but each was 3 to 10 times more potent than cocaine.

The behavioral effects of morphine and ethylketazocine were compared in squirrel monkeys and pigeons responding under fixed-interval schedules of food presentation, and in monkeys responding under fixed-interval schedules of electric-shock presentation. Both morphine and ethylketazocine produced dose-related decreases in rates of responding maintained by food presentation in either species. However, intermediate doses of both drugs increased rates of responding maintained by shock presentation in monkeys; at higher doses both drugs decreased rates of shock-maintained responding. In monkeys and pigeons, the dose-effect curves for both ethylketazocine and morphine were shifted to a comparable degree of naloxone. Maximal effects of morphine were observed 16 to 24 min after injection and typically lasted the entire 40-min observation period. Effects of ethylketazocine had a faster onset (maximal effects were observed by 8 to 16 min after injection), and shorter duration (effects diminished by 24 to 40 min after injection). Ethylketazocine was 30 to 100 times more potent than morphine under either the schedule of food or shock presentation in squirrel monkeys, whereas the two drugs had similar potencies in pigeons. Thus, the effects of at least one of the drugs may be mediated differently in one of the two species.

Responding of squirrel monkeys was maintained under a fixed-interval schedule of food presentation in one group of subjects or electric-shock presentation in a second group. Rates of responding were decreased in a dose-dependent manner by the (-)-isomer of 6N-[1-methyl-2-phenylethyl]-adenosine (PIA) under both schedules. Caffeine shifted the (-)-PIA dose-effect curve to the right in a dose-dependent manner. Single administrations of 15.0 mg/kg of caffeine had (-)-PIA-antagonist effects for up to 48 hr. Caffeine administered alone increased rates of responding at intermediate doses, and decreased rates at the highest doses. The increases in response rates produced by intermediate doses of caffeine were appreciably diminished at 24 hr. Doses of (-)-PIA that were inactive when administered alone had little effect on the increases in response rate produced by caffeine. Doses of (-)-PIA that decreased response rates when administered alone attenuated the increase in response rates produced by caffeine. Increases in response rates produced by (+)-amphetamine were altered by (-)-PIA similarly to the manner in which (-)-PIA altered the effects of caffeine. Increases in response rates produced by caffeine were altered by chlorpromazine similarly to the manner in which (-)-PIA altered effects of caffeine. When caffeine was administered daily, as one 15.0-mg/kg injection after experimental sessions, tolerance developed to the response rate increasing effects of caffeine.(ABSTRACT TRUNCATED AT 250 WORDS)

Beagle dogs pressed a lever under a 15-response fixed-ratio schedule of i.v. nicotine or cocaine infusion or water presentation. A 4-min time-out period followed each fixed-ratio trial and each daily session ended after 16 successive fixed-ratio trials. Both nicotine and cocaine were self-administered above saline levels, with the maximum number of infusions occurring at a dose of 30 micrograms/kg of nicotine and 100 micrograms/kg of cocaine. Rates of responding first increased, reaching a maximum at 10 to 30 micrograms/kg/infusion and then decreased, as the dose of nicotine or cocaine was varied between 3 and 300 micrograms/kg/infusion. The rate of responding and number of infusions obtained per session were higher under the schedule of cocaine self-administration than under the schedule of nicotine self-administration. Presession treatment with the nicotinic antagonist, mecamylamine (1.0 mg/kg i.v.), for seven consecutive sessions, decreased nicotine-maintained responding to levels not unlike those seen when saline was substituted for drug. Neither cocaine- nor water-maintained responding was affected by presession treatment with mecamylamine. A second group of beagle dogs pressed a lever under a schedule of i.v. nicotine (50-400 micrograms/kg/infusion) or cocaine (200-1600 micrograms/kg/infusion) infusion in which the fixed-ratio requirement was increased daily (i.e., a progressive-ratio schedule). The maximum fixed-ratio value at which responding was maintained first increased as the dose per infusion increased and then, at the highest dose, either remained the same or decreased. Cocaine maintained considerably higher fixed-ratio values than did nicotine, but maximum fixed-ratio values for nicotine were well above those seen with saline. The effects of i.v. nicotine (3, 30 or 300 micrograms/kg) or mecamylamine (1.0 mg/kg) on heart rate, rectal temperature and pupillary diameter were measured in a third group of beagle dogs. Nicotine produced dose- and time-related changes in all three physiological parameters; the effects of mecamylamine were considerably greater than those seen with nicotine.

The behavioral effects of nicotine were compared with those of its metabolites, nornicotine and cotinine, in beagle dogs and squirrel monkeys. Subjects responded under a multiple fixed-interval (FI) 300-sec, fixed-ratio (FR) 30 response schedule of food presentation. Nicotine (0.01-1.0 mg/kg i.m.) and nornicotine (0.03-3.0 mg/kg i.m.) produced qualitatively similar effects in both dogs and monkeys. Nicotine produced dose-related increases, then decreases in rates of responding during FI components; rates of responding during FR components were only decreased. Nornicotine produced only dose-dependent decreases in responding during both FI and FR components. In the dogs, cotinine (0.01-10.0 mg/kg i.m.) produced only dose-dependent decreases in rates of responding during both FI and FR components. In the squirrel monkeys, however, cotinine (0.1-3.0 mg/kg i.m.) increased responding during FI components; a high dose of 30.0 mg/kg decreased responding during both FI and FR components. The behavioral effects of cocaine (0.03-3.0 mg/kg i.m.) and its metabolite norcocaine (0.01-1.0 mg/kg i.m.) were compared in the dogs. FI rates of responding first increased and then decreased with increasing doses of each drug, whereas FR rates of responding only decreased in a dose-related manner. Norcocaine was slightly more potent than cocaine in producing these effects on schedule-controlled responding in dogs. These experiments indicate the metabolites of nicotine and cocaine are behaviorally active and may contribute to the pharmacological profile of the parent compounds.

Squirrel monkeys responded under a two-component fixed-ratio schedule of food presentation with both nonpunishment and punishment components. In both components of the multiple schedule, every 30th key-pressing response resulted in food presentation. In the punishment component, the first response in each 30-response fixed ratio also produced either an i.v. injection of nicotine (10-30 micrograms/kg) or an electric shock (1-5 mA). Response-produced nicotine injections or electric shocks functioned similarly to suppress responding by over 70% in the punishment component. Presession treatment with chlordiazepoxide (5.6-10 mg/kg i.m.) markedly increased responding that had been suppressed by either nicotine injection or electric shock. In contrast, presession treatment with the nicotinic antagonist, mecamylamine (0.1-0.3 mg/kg i.m.) increased responding that had been suppressed by nicotine injection but did not increase responding that had been suppressed by electric shock. Thus, chlordiazepoxide appeared to have general rate-increasing effects on suppressed responding, regardless of the nature of the event suppressing responding, whereas mecamylamine appeared to selectively antagonize the suppressant effects of nicotine. Doses of chloridazepoxide and mecamylamine that increased suppressed responding in punishment components either had little effect on or slightly increased responding in nonpunishment components. These results show that under suitable environmental conditions response-produced i.v. injection of nicotine can function effectively as a punisher.

Rats were trained to discriminate the novel analgesic flupirtine (10.0 mg/kg i.p., 10 min) from no drug under a two-choice fixed-ratio 5 shock-termination schedule. Flupirtine yielded a dose-response curve with an ED50 of 3.87 mg/kg. The opioid analgesics pentazocine, codeine and tramadol failed to produce flupirtine appropriate responding. The opioid antagonist naltrexone did not antagonize the discriminative effects of flupirtine. The mixed alpha-1/alpha-2 adrenergic agonist clonidine and the highly specific alpha-2 adrenergic agonist UK-14304, both partially and dose-dependently produced flupirtine appropriate responding. The mixed alpha-1/alpha-2 antagonist yohimbine and the highly specific alpha-2 antagonists idazoxan and L-654,284 all partially and dose-dependently antagonized flupirtine appropriate responding. Neither of the alpha-1 agonists phenylephrine or ST 587 produced flupirtine appropriate responding, nor did the alpha-1 antagonist prazosin antagonize flupirtine responding. It is concluded that the discriminative effects of flupirtine are neither of opioid nor of alpha-1 adrenergic type, but are primarily mediated through alpha-2 adrenergic mechanisms.

Squirrel monkeys pressed a key under a two-component, 30-response fixed-ratio schedule of food presentation. In both nonpunishment and punishment components, every 30th key-pressing response resulted in food presentation. In the punishment component, the 11th and 22nd response in each 30-response fixed-ratio also produced a 200msec i.v. injection of 30 to 100 microgram/kg of histamine; this resulted in about an 80% suppression of responding in the punishment component. A second group of squirrel monkeys, with arterial catheters for monitoring of blood pressure and heart rate, received automatic i.v. injections of 30 and 100 microgram/kg of histamine; key presses had no programmed consequences. Mean arterial blood pressure decreased by 5 to 20 min Hg and heart rate increased by 60 to 120 beats/min after each injection of histamine. As an effective punisher, histamine was functionally similar to other noxious stimuli such as electric shock. Behavior suppressed by histamine could be markedly increased by presession i.m. treatment with pentobarbital (3-5.6 mg/kg) or chlordiazepoxide (10-30 mg/kg). Presession i.m. treatment with 1 to 3 mg/kg of the H1-receptor antagonist, diphenhydramine, reversed the punishment effects of histamine but only enhanced the cardiovascular effects of histamine. In contrast, 10 to 30 mg/kg of the H2-receptor antagonist, cimetidine, failed to reverse the punishment effects of histamine but markedly attenuated the cardiovascular effects of histamine. Thus, histamine's suppression of responding appeared to be an H1 effect and did not appear to be related to its effects on blood pressure and heart rate.

Dose-response functions were determined for the effects of cocaine and d-amphetamine on lever-pressing responses maintained under three schedules of food presentation: 1) a simple fixed-ratio schedule, 2) a multiple fixed-ratio, fixed-interval schedule and 3) a second-order fixed-interval schedule with fixed-ratio components. These schedules generated a variety of rates and patterns of responding. The effects of the drugs on response rate depended on the control rates of responding. The highest overall rates of responding were maintained under the fixed-ratio schedule and under the fixed-ratio component of the multiple schedule. Both cocaine and d-amphetamine produced dose-related decreases in these high response rates. Lower overall rates of responding were maintained under the second-order schedule and under the fixed-interval component of the multiple schedule. Intermediate doses of cocaine or d-amphetamine (0.1-1.0 mg/kg) increased these lower rates of responding. Under the second-order schedule and the multiple schedule, local response rates during successive segments of the fixed-intervals were differentially affected by the drugs. Cocaine and d-amphetamine markedly increased low response rates that occurred during initial segments of the fixed intervals, but either had little effect on or decreased higher responses rates that occurred during later segments of the fixed intervals. Cocaine and d-amphetamine had similar qualitative and quantitative effects on responding, but d-amphetamine was longer lasting than cocaine.

The behavioral effects of the antipsychotic drug, clozapine, were compared with those of thioridazine, chlorpromazine, haloperidol and chlordiazepoxide. Behavior of squirrel monkeys was controlled by different consequences of a lever-pressing response (presentation of food, presentation of electric shock or termination of a stimulus associated with electric shock) under different schedules of reinforcement (a fixed-interval schedule or a multiple schedule with alternating fixed-ratio and fixed-interval components). The effects of thioridazine (0.2-24.6 mumol/kg), chlorpromazine (0.03-2.8 mumol/kg) and haloperidol (0.001-0.08 mumol/kg) were largely independent of the type of schedule or the type of consequent event that maintained responding: each drug produced dose-related decreases in responding under all conditions in which they were studied. Clozapine (0.1-9.2 mumol/kg) and chlordiazepoxide (0.9-167.4 mumol/kg) also only decreased responding under most schedule conditions; however, intermediate doses of either drug markedly increased responding maintained by presentation of food under the fixed-interval schedule (whether programmed singly or as a component of the multiple schedule). Only clozapine increased responding maintained by presentation of electric shock under the fixed-interval schedule. Thus, the behavioral effects of clozapine differed qualitatively from those of representative antipsychotic and antianxiety drugs.

Three rhesus monkeys lived in primate cages provided with response keys and enclosed in isolation chambers. During experimental sessions on Monday, Wednesday and Friday, the chamber door was closed and every 10th key-pressing response during a 60-minute interval produced a 2-second red light, but had no other programmed consequences (the 10-response fixed-ratio component of the second-order schedule; FR 10). The first FR 10 component completed after the 60-minute interval had elapsed produced a red light which remained on for 2 minutes while the chamber door was opened; the monkey then extended his arm and was given an intramuscular injection of drug (the 60-minute fixed-interval component of the second-order schedule; FI 60 min). Under this second-order schedule of intramuscular drug injection, repeated sequences of rapid responding were maintained during each session by 0.75 to 3.0 mg/kg injections of either morphine or cocaine. Patterns of responding characteristic of FR schedules were controlled by the 2-second red lights; a pause in responding after each 2-second red light was followed by a sustained high rate of responding until the light was produced again. Pauses in responding became progressively shorter as time elapsed in the 60-minute interval. When saline injections were substituted for drug injections, responding markedly decreased. When responding was maintained by 3.0 mg/kg morphine injections, pretreatment with 0.03 mg/kg of nalorphine increased responding, while pretreatment with 0.1 or 0.3 mg/kg of nalorphine decreased responding.