Considerations in the Evaluation of Potential Efficacy of Medications for Alcohol and Drug Use Disorders: An Editorial.

The societal burden created by alcohol and drug use disorders is estimated to be on the order of hundreds of billions of dollars, creating a need for effective medications to reduce use and prevent relapse. While there are FDA-approved medications to facilitate abstinence and prevent relapse for some indications including, alcohol, tobacco, and opiate use disorders, there are no approved treatments for other abused substances, including cocaine, methamphetamine, and cannabis, leaving these critical medical needs unmet. The development of such medications has fallen largely to the government with efforts spearheaded by the National Institute on Drug Abuse and the National Institute on Alcoholism and Alcohol Abuse. Both agencies have medication development programs with preclinical components that include the standardized evaluation of compounds using animal models. This chapter describes the rationale and considerations involved in the use of such models, including reinstatement of drug self-administration.

Lobeline inhibits the neurochemical and behavioral effects of amphetamine.

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.

Modulation of pre- and postsynaptic dopamine D2 receptor function by the selective kappa-opioid receptor agonist U69593.

The repeated administration of selective kappa-opioid receptor agonists prevents the locomotor activation produced by acute cocaine administration and the development of cocaine-induced behavioral sensitization. Previous studies have shown that dopamine (DA) D2 autoreceptors modulate the synthesis and release of DA in the striatum. Evidence that kappa agonist treatment downregulates DA D2 receptors in this same brain region has recently been obtained. Accordingly, the present studies were undertaken to examine the influence of repeated kappa-opioid receptor agonist administration on pre- and postsynaptic DA D2 receptor function in the dorsal striatum using pre- and postsynaptic receptor-selective doses of quinpirole. Rats were injected once daily with the selective kappa-opioid receptor agonist U69593 (0.16-0.32 mg/kg s.c.) or vehicle for 3 days. Microdialysis studies assessing basal and quinpirole-evoked (0.05 mg/kg s.c.) DA levels were conducted 2 days later. Basal and quinpirole-stimulated locomotor activity were assessed in a parallel group of animals. The no-net flux method of quantitative microdialysis revealed no effect of U69593 on basal DA dynamics, in that extracellular DA concentration and extraction fraction did not differ in control and U69593-treated animals. Acute administration of quinpirole significantly decreased striatal DA levels in control animals, but in animals treated with U69593, the inhibitory effects of quinpirole were significantly reduced. Quinpirole produced a dose-related increase in locomotor activity in control animals, and this effect was significantly attenuated in U69593-treated animals. These data reveal that prior repeated administration of a selective kappa-opioid receptor agonist attenuates quinpirole-induced alterations in DA neurotransmission and locomotor activity. These results suggest that both pre- and postsynaptic striatal DA D2 receptors may be downregulated following repeated kappa-opioid receptor agonist administration. Synapse 39:343-350, 2001. Published 2001 Wiley-Liss, Inc.

Repeated treatment with the selective kappa opioid agonist U-69593 produces a marked depletion of dopamine D2 receptors.

U-69593, the selective K-opioid agonist, was repeatedly administered in single daily injections (0.32 mg/kg) to male, Sprague-Dawley rats. Two or ten days later, the rats were euthanized and dopamine D1 and D2 receptors were measured using (3H]SCH 23390 or [3H]sulpiride, respectively, in caudate putamen and nucleus accumbens. Two days after the last of three injections, dopamine D2 receptors in the caudate putamen were decreased by approximately 40%, with no change in D1 receptors. Dopamine D2 receptor number had returned to normal by 10 days posttreatment. In contrast, in the nucleus accumbens there was a small, nonsignificant decrease in dopamine D2 receptors 2 days after treatment, but a large increase (65%) after 10 days. In agreement with the changes in D2 receptors, there was a significant downward shift in the locomotor activity curve for the D2 agonist quinpirole after a 2-day withdrawal. There were no differences in either the total amount of dopamine taken up or in the IC50 for cocaine to inhibit dopamine uptake following this treatment, suggesting that the dopamine transporter and presynaptic terminals were intact. The results of these studies demonstrate that repeated administration of a selective K-opioid agonist induces long-term alterations in dopamine D2 receptors. Furthermore, the finding that these changes in receptor number require both repeated injections and a withdrawal time greater than 1 day suggests that these alterations are compensatory in nature.

Atypical antipsychotic-like effects of the dopamine D3 receptor agonist, (+)-PD 128,907.

Anti-schizophrenia agents with improved efficacy and side-effect profiles are required. A dopamine D3 receptor agonist, R-(+)-trans-3,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3- b]-1,4-oxazin-9-ol HCl ((+)-PD 128,907), displayed an atypical antipsychotic profile comparable to that of clozapine. (+)-PD 128,907 blocked stereotypy produced by dizocilpine (MK-801) at 12-fold lower doses than those affecting apomorphine-induced stereotypes in mice and did not produce catalepsy. These effects of (+)-PD 128,907 were stereospecific and were blocked by a D3 antagonist. These data suggest a role for D3 receptors in antipsychotic drug action.

Characterization of unconditioned behavioral effects of dopamine D3/D2 receptor agonists.

A series of experiments examined the ability of dopamine D3/D2 receptor agonists [(+)-(4aR,10bR)-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]b enzopyrano-[4,3-b]-1,4-oxazin-9-ol hydrochloride (PD 128,907), (+/-)-7-hydroxy-dipropylaminotetralin hydrobromide (7-OH-DPAT), quinpirole and bromocriptine] to produce a variety of dopaminergically mediated behaviors. The effects of these drugs with selectivity for D3/D2 receptors over D1 receptors were compared with those produced by the selective D1 agonists [(+/-)-Phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride (SKF 38393), (+/-)-6-Chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-be nzazepine hydrobromide (SKF 82958)], a nonselective dopaminergic agonist (apomorphine), and an indirect dopamine agonist (cocaine). The D3/D2 agonists decreased locomotor activity, had no effect on gnawing and only inconsistently induced climbing in mice. Further, these agonists dose-dependently produced scratching in squirrel monkeys. In contrast, the D1 agonists, SKF 82958 and SKF 38393, did not produce scratching in squirrel monkeys. Whereas the full D1 agonist, SKF 82958, produced increases in locomotor activity and in climbing and gnawing, the partial D1 agonist, SKF 38393, did not increase the frequencies of these behaviors. The nonselective dopamine agonist, apomorphine, produced decreases in locomotor activity and increases in climbing and gnawing in mice. Apomorphine dose-dependently produced scratching in squirrel monkeys. The indirect dopamine agonist, cocaine, produced increases in locomotor activity and climbing, but had no effect on climbing or gnawing in mice and did not produce scratching in squirrel monkeys. These findings suggest that D3/D2 agonists can be distinguished on various behavioral measures from the nonselective agonist, apomorphine (gnawing), D1 agonists (scratching) and the indirect agonist, cocaine (locomotor activity and scratching). Behaviors once attributed to stimulation of D2 (locomotor activity and scratching) or D1/D2 (climbing and gnawing) receptors may also involve dopamine D3 receptors.

Localization and pharmacological characterization of pigeon diazepam-insensitive GABAA receptors.

Transduction mechanisms associated with ligand binding at diazepam-insensitive subtypes of GABAA receptors remain largely unknown, but unique behavioral effects of ligands binding at these sites have been reported in pigeons. The present study further evaluated the pharmacological characteristics of diazepam-insensitive GABAA receptors in pigeon brain, using [3H]Ro 15-4513. Autoradiography detected diazepam-insensitive benzodiazepine sites on GABAA receptors in a number of brain regions, with the highest densities present in the olfactory bulb, hippocampus, thalamic nuclei and cerebellar granule cell layers, with densities of approximately 10-20% of total benzodiazepine receptor binding. Saturation analysis revealed significant densities (approximately 10% of total benzodiazepine receptor binding) of extracerebellar diazepam-insensitive benzodiazepine receptors in optic lobe, hippocampus, and brainstem compared to 27% in cerebellum. As reported for mammalian diazepam-sensitive benzodiazepine receptors, GABA (50 microM) generally increased the affinities of agonists and partial agonists, had little effect on the affinities of antagonists, and decreased the affinity of an inverse agonist for pigeon cerebellar diazepam-sensitive benzodiazepine receptors. GABA modulation of ligand binding to diazepam-insensitive benzodiazepine receptors was less than that observed for diazepam-sensitive sites, and no positive modulation was observed. These results demonstrate the presence of cerebellar and extracerebellar diazepam-insensitive benzodiazepine receptors in pigeon brain, with distribution patterns and pharmacology similar to those reported in mammals. The comparable central localization and pharmacological properties of drugs at diazepam-sensitive and -insensitive benzodiazepine receptors in pigeons and rats attests to the evolutionary conservation of GABAA systems.

Blockade of behavioral effects of bretazenil by flumazenil and ZK 93,426 in pigeons.

Benzodiazepine receptor partial agonists manifest full efficacy in preclinical tests of anxiolytic drug action but do not fully reproduce the discriminative stimulus effects of benzodiazepine receptor full agonists in pigeons. The partial agonist, bretazenil, binds to both diazepam-sensitive and diazepam-insensitive GABAA receptors. Previous studies have suggested a role for each of these receptor populations in some behavioral effects of bretazenil in pigeons. A possible role for these receptor subtypes in the behavioral effects of bretazenil was further investigated through drug interaction studies with the benzodiazepine receptor antagonists, flumazenil and ZK 93,426. Whereas flumazenil binds with high affinity to both receptor isoforms, ZK 93,426 binds preferentially to diazepam-sensitive binding sites. Bretazenil markedly increased punished responding of pigeons without significantly affecting nonpunished responding. In pigeons discriminating the full benzodiazepine receptor agonist, midazolam, from saline, bretazenil produced only 60-75% maximal effect. Flumazenil and ZK 93,426 neither increased punished responding nor substituted for midazolam, but dose-dependently blocked the effects of bretazenil on punished responding. Flumazenil also dose-dependently blocked the effects of bretazenil in midazolam-discriminating pigeons, whereas ZK 93,426 only attenuated this effect. These results indicate that bretazenil's actions as a partial agonist at diazepam-sensitive benzodiazepine receptors mediate increases in punished responding and substitution for the discriminative stimulus effects of midazolam in pigeons. The differences in the effects of flumazenil and ZK 93,426 on the discriminative stimulus effects of bretazenil suggest a potential contribution of diazepam-insensitive sites to this behavioral effect.

Effects of benztropine on behavioral and toxic effects of cocaine: comparison with atropine and the selective dopamine uptake inhibitor 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenyl-propyl)-piperazine.

Behavioral effects of cocaine that are relevant to its abuse have been associated with pharmacological actions at the dopamine uptake carrier. Benztropine (Cogentin) is an antiparkinson agent that has limited abuse despite its ability to block dopamine uptake, and has been suggested as a candidate for the treatment of cocaine dependence. Preclinical studies were conducted to assess the behavioral and toxic effects of benztropine alone and in conjunction with cocaine. Because of the mixed pharmacology of benztropine which includes antimuscarinic as well as dopaminergic actions, results obtained from parallel experiments with atropine and the selective dopamine uptake inhibitor, GBR 12935 (1-[2-(diphenylmethoxy)ethyl]-4-(3-phenyl-propyl)-piperazine), were performed. All of the drugs stimulated locomotor activity of mice, but atropine and benztropine had much lower efficacy. Nonstimulatory doses of GBR 12935 enhanced the locomotor stimulant effects of cocaine, whereas benztropine and atropine did not share this effect. GBR 12935, benztropine and cocaine increased fixed-interval responding, whereas atropine decreased fixed-interval response rates in rats. Only GBR 12935 and cocaine increased responding during timeout periods. GBR 12935, but not benztropine or atropine, fully reproduced the discriminative stimulus effects of cocaine (10 mg/kg). GBR 12935 and atropine augmented the discriminative stimulus effects of lower cocaine doses in rats. Only GBR 12935 and cocaine had convulsant effects and only GBR 12935 significantly enhanced the convulsant effects of cocaine in mice. These results document a behavioral and toxicity profile for benztropine distinct from that of classical dopamine uptake blockers. The data underscore further the potential of benztropine as a candidate for clinical evaluation in the treatment of cocaine dependence.

Behavioral and biochemical characterization of benzodiazepine receptor partial agonists in pigeons.

The ability of benzodiazepine receptor partial agonists to exhibit full efficacy in preclinical anxiolytic tests, in conjunction with initial clinical results, has suggested the possibility of a reduced clinical side-effect profile compared to benzodiazepine receptor full agonists like diazepam. Because punished behavior of pigeons has been useful in detecting effects of novel anxiolytic drugs, effects of imidazobenzodiazepine and beta-carboline benzodiazepine receptor partial agonists and some related compounds were evaluated in this species. The abilities of these compounds to substitute for the discriminative stimulus effects of the full agonists midazolam also was determined. Intrinsic efficacy was assessed by the degree to which gamma-aminobutyric acid increased ligand potency to displace [(3)H]Ro15-1788 (flumazinil) from membranes of pigeon cerebrum, and ranged from full agonist-like efficacy (Ro 19-5470; 7-(3-cyclopropyl-1,2,4-oxodiazol-5-yl)-5,6-dihydro-5-methyl-4H- imidazo[1,5a]-thieno[3,2-f]diazin-4-one) to minimal gamma-aminobutyric acid potentiations close to that of the antagonist flumazenil (abecarnil and Ro 41-7812; 7-chloro-4,5-dihydro-3-(3-hydroxy-1-propynyl)-5-methyl-6H-imidazo[1,5-a] -[1,4 ]benzodiazepine-6-one). Punished responding was increased markedly by midazolam and by all partial agonists, except Ro 41-7812 and Ro 42-8773 (7-chloro-3-[3-(cyclopropylmethoxy)-1-propynyl]-4,5-dihyro-5 -methyl-6H-imidaz o[1,5-a][1,4]benzodiazepine-6-one), at doses that did not affect nonpunished responding. In contrast to the full substitution generally observed in mammals, all of the partial agonists produced incomplete substitution (40-70%) in the midazolam drug discrimination procedure in pigeons. A positive relationship was observed between the degree of substitution and intrinsic efficacy. The benzodiazepine antagonists, flumazenil and ZK 93,426 (ethyl-5-isopropoxy-4-methoxymethyl-beta-carboline-3-carboxylate), neither increased punished responding nor substituted for midazolam. The results of the present study suggest that benzodiazepine receptor partial agonists and related compounds may provide full anxiolytic activity at doses that do not fully reproduce the subjective effect profile of full agonists.

Discriminative stimulus effects of the benzodiazepine receptor partial agonist bretazenil in pigeons and in rats.

Bretazenil is a partial agonist at diazepam-sensitive (DS) GABA(A) receptors, and it also binds with high affinity to diazepaminsensitive (DI) GABA(A) receptors. A unique discriminative stimulus effect transduced by binding at DI benzodiazepine (BZ) receptors has been reported in pigeons, but has not been established in rats. Further, differences have been observed between rats and pigeons in results of drug discrimination experiments utilizing BZ receptor partial agonists. Therefore, to examine the discriminative stimulus effects of bretazenil and to explore the possibility of species differences in substitution profiles, pigeons and rats were trained to discriminate 0.3mg/kg bretazenil from vehicle. Flumazenil (0.03-1.0mg/kg) did not substitute for bretazenil in pigeons, despite full substitution of bretazenil for flumazenil in this species. Flumazenil (0.03-10.0mg/kg) also did not substitute for bretazenil in rats, despite the partial agonist effects of flumazenil in rats. Likewise, midazolam (0.3-1.0mg/kg) did not substitute for bretazenil in pigeons, despite the fact that bretazenil partially substitutes for midazolam in pigeons. However in rats, midazolam produced full, dose-dependent substitution (0.03-3.2mg/kg). Differences may result from different fractional receptor occupancy requirements for the mediation of discriminative stimulus effects through DS BZ receptors, and/or from a contribution of DI BZ receptor binding in pigeons.

Assessment of cocaine-like discriminative stimulus effects of dopamine D3 receptor ligands.

The highly selective dopamine D3 receptor ligand, (+)-PD 128907 4aR10bR-(+)-trans-3,4,4a,10b-tetrahydro-4-n-propyl-2H5H[4,3- b]-1,4- oxazin-9-ol), and other dopamine D3 receptor ligands, (+/-)-7-hydroxy-2-(N,N-di-n-propylamino)tetralin and (+)-7-hydroxy-2-(N,N-di-n-propylamino)tetralin, substituted for the discriminative stimulus effects of cocaine in rats, an animal model of subjective effects in humans. Substitution only occurred at doses that markedly decreased responding. These results suggest that dopamine D3 receptors may be involved in the subjective effects of cocaine, and therefore may be a target for the discovery of treatments for cocaine dependence.

Stereospecific transduction of behavioral effects via diazepam-insensitive GABAA receptors.

Previous studies reported a positive correlation between ligand affinities at diazepam-insensitive GABAA receptors and substitution for the discriminative stimulus effects of the benzodiazepine receptor antagonist, flumazenil, in pigeons. In the present experiments, bretazenil and Ro 14-5974 (ethyl-(S)-11,12,13,13 a-tetrahydro-9-oxo-9H-imidazo[1,5-a]-pyrrolo-[2,1-c] [1,4]benzodiazepine-1-carboxylate) partially substituted for, and blocked the discriminative stimulus effects of midazolam, congruent with their actions at diazepam-sensitive GABAA receptors in vitro. In addition, bretazenil and Ro 14-5974, but not their R-enantiomers, had high affinity for diazepam-insensitive receptors and fully substituted for the discriminative stimulus effects of flumazenil. The R-enantiomers of these compounds had low affinity (Ki > 1 microM) for diazepam-sensitive and diazepam-insensitive receptors, and did not share discriminative stimulus effects with flumazenil or midazolam. Ro 19-0528 (7-chloro-3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-4,5-dihydro-5-met hyl-6H- imidazo[1,5-a][1,4]benzodiazepin-6-one), a structurally related compound with full agonist actions at diazepam-sensitive GABAA receptors, had high diazepam-insensitive receptor affinity (Ki = 96 nM) and partially substituted for the discriminative stimulus effects of flumazenil. These results are consistent with stereospecific mediation of the discriminative stimulus effects of flumazenil through high affinity binding to diazepam-insensitive receptors in pigeons.

Effects of ifenprodil on stimulatory, discriminative stimulus, and convulsant effects of cocaine.

Ifenprodil, like cocaine, binds to the dopamine transporter and blocks uptake of dopamine. In this study, the ability of ifenprodil to mimic, enhance or block behavioral and toxic effects of cocaine was evaluated. Fixed-interval responding maintained by food presentation in rats was increased by cocaine but decreased by ifenprodil. Low rates of responding during timeout periods were also increased by cocaine but not ifenprodil. Ifenprodil neither increased locomotor activity nor augmented the stimulatory effect of cocaine; however, ifenprodil attenuated the stimulant effects of cocaine at doses 0.5 log unit lower than those required to reduce spontaneous activity when given alone. Ifenprodil neither substituted for nor augmented the discriminative stimulus effects of cocaine in rats discriminating 10mg/kg cocaine from saline. In contrast to cocaine, ifenprodil did not produce convulsions or signs of proconvulsant activity, and ifenprodil reduced the percentage of mice convulsing in the presence of cocaine. These results suggest that pharmacological actions in addition to blockade of dopamine uptake or novel interactions with the dopamine transporter may contribute to the non-stimulant behavioral profile and cocaine-blocking actions of ifenprodil.

Strain and age differences in acoustic startle responses and effects of nicotine in rats.

Two experiments examined the effects of age, genetic strain, and nicotine on acoustic startle response (ASR) amplitude and prepulse inhibition (PPI) in rats. ASR amplitude measures reactivity to external stimulation, and PPI is used as an index of sensory gating related to attention. Both ASR amplitude and PPI have been previously reported to be increased by nicotine in adult rats. Experiment 1 examined effects of chronically administered nicotine and saline on ASR and PPI in Wistar, Long-Evans, and Sprague-Dawley rats (40 days of age). Experiment 2 examined the effects of chronically administered nicotine and saline in Sprague-Dawley rats of two age groups: 40 and 70 days of age at the beginning of the study. ASR amplitude differed significantly across strains with the values for Wistar > Sprague-Dawley > Long-Evans, and there were no differences in percent of PPI among the three strains. In addition, results of Experiment 2 indicated that older rats had significantly greater ASR amplitudes and PPI than younger rats. Consistent with previous reports, nicotine increased ASR and PPI in the older rats; however, there were no significant differences in the younger rats. Therefore, age and genetic strain are important variables in the analysis of nicotine's effects on startle behaviors in rats.

Nicotine modulates effects of stress on acoustic startle reflexes in rats: dependence on dose, stressor and initial reactivity.

Cigarette smokers report that one reason for smoking is that smoking helps them cope with stress, but there is conflicting evidence as to whether nicotine reduces physiological and behavioral responses to stress. The acoustic startle reflex amplitude, pre-pulse inhibition, and habituation of the reflex provide quantifiable measures of behavioral reactivity that may be sensitive to stress-induced changes that are altered by nicotine. In the present experiment, rats classified as high and low reactors according to baseline startle amplitudes were administered nicotine (6 or 12 mg/kg/day) or saline by osmotic minipump for 11 days. On day 11, animals were acutely stressed by restraint or observation of restraint of conspecifics prior to startle measurement. Nicotine and stress each independently increased acoustic startle amplitude and amount of pre-pulse inhibition, but in combination, the effect of restraint stress and 12 mg/kg nicotine were indistinguishable from saline-treated, non-stressed controls. In contrast, the 6 mg/kg nicotine dose enhanced effects of both restraint and observation stressors on startle amplitude and pre-pulse inhibition. Animals classified as highly reactive prior to treatment were more responsive to nicotine, stress, and the combination, suggesting that initial reactivity is an important determinant of drug and stress effects. Results indicate that nicotine can both reduce and enhance stress effects on reflex amplitude and pre-pulse inhibition depending upon nicotine dose, stressor, and individual differences in reactivity.

Nicotine increases sensory gating measured as inhibition of the acoustic startle reflex in rats.

Chronic nicotine administration has been reported to increase acoustic startle response (ASR) amplitude in rats, which has been offered as evidence that some dosages of nicotine can enhance attention. The present experiments examined effects of acutely administered nicotine on amplitude and pre-pulse inhibition (PPI) of acoustic startle in rats. PPI, the decrease in ASR amplitude by a stimulus preceding the startle-eliciting event, reflects pre-attentive neural processes underlying sensory gating. Nicotine had a biphasic dose effect on startle amplitude, with increases at lower dosages (0.01 mg/kg) and decreases at higher dosages (0.5-5.0 mg/kg SC). Lower dosages of nicotine (0.001-0.01 mg/kg) increased PPI and the increase at 0.001 mg/kg occurred independently of changes in ASR amplitude. These results confirm that increases in PPI are not dependent upon changes in ASR amplitude. Results are consistent with nicotine's enhancements of performance on cognitive tasks in humans and are the first reported use of the PPI paradigm to model such effects. These findings indicate that ASR paradigms are useful to study effects of nicotine.

A psychophysical task to quantify smoking cessation-induced irritability: the reactive irritability scale (RIS).

A psychophysical rating scale using magnitude estimation was developed as a tool to quantify irritability as one index of drug withdrawal. The scale measures reactive irritability by using environmental sounds as probes. Three studies are described in which target and reference stimuli are selected, tested for reliability, and presented to cigarette smokers abstaining from smoking, cigarette smokers who are not abstaining, and nonsmokers. This reactive irritability scale (RIS) was found to have test/re-test reliability and content validity. The RIS significantly differentiated abstaining smokers from nonsmokers and from smokers allowed to smoke, whereas the commonly used self-report measures of irritability failed to distinguish the two groups of smokers. By measuring irritability as a type of reactivity rather than as a static attribute, a different type of irritability is measured than that which is assessed by self-report questionnaires. The RIS should be used in the study of withdrawal from nicotine and other drugs of abuse.

Conceptual and methodological considerations for tobacco addiction research.

The 1988 Surgeon General's Report on nicotine addiction has research and treatment implications. It focuses clinical treatments on tobacco use as an addiction and highlights the importance of examining actions of nicotine relevant to dependence. It also indicates the value of comparing the pharmacologic and behavioral processes underlying use of nicotine with other addictive drugs. This essay points out gaps that remain in our understanding of nicotine addiction. For example, the exact mechanisms underlying nicotine addiction are unknown. Also, the reasons for individual differences in initiation, withdrawal, relapse and reinforcing effects of tobacco use are not understood. Research designed to address these issues should be problem-driven and multidisciplinary. Parallel human and animal studies that include unconditioned as well as conditioned behaviors are particularly valuable.

Effects of nicotine on the acoustic startle reflex amplitude in rats.

The acoustic startle reflex was used to measure changes in sensorimotor reactivity in response to nicotine administration and cessation. Male rats received saline, 6 mg/kg/day or 12 mg/kg/day nicotine delivered subcutaneously by osmotic minipumps. The pumps delivered their contents during a 10-day period of implantation, after which time they were explanted. Animals were tested for startle reflex amplitudes using two levels of white noise bursts prior to pump implantation, on days 1 and 7 of nicotine or saline administration, and on several days following drug cessation. Nicotine produced a dose-dependent increase in startle amplitude during the period of administration that decreased during cessation. Results are interpreted in terms of nicotine's actions to enhance attentional processes.