Considerations on nonclinical approaches to modeling risk factors of suicidal ideation and behavior.

Given the serious nature of suicidal ideation and behavior (SIB) and the possibility of treatment-emergent SIB, pharmaceutical companies are now applying more proactive approaches in clinical trials and are considering the value of nonclinical models to predict SIB. The current review summarizes nonclinical approaches to modeling three common risk factors associated with SIB: aggression, impulsivity, and anhedonia. For each risk factor, a general description, advantages and disadvantages, species considerations, nonclinical to clinical translation, and pharmacological validation with respect to treatments associated with SIB are summarized. From this review, several gaps were identified that need to be addressed before use of these nonclinical models can be considered a viable option to predict the relative risk for SIB. Other future directions that may compliment these nonclinical approaches, including the use of selectively-bred or genetically-modified rodent models, transgenic models, gene expression profiling, and biomarker analysis, are discussed. This article was developed with the support of the DruSafe Leadership Group of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ, www.iqconsortium.org).

Moxonidine, a selective imidazoline-1 receptor agonist, suppresses the effects of ethanol withdrawal on the acoustic startle response in rats.

BACKGROUND: There is a need for improved treatments for ethanol withdrawal in humans. Previously, ethanol withdrawal has been shown to enhance the acoustic startle response in rats. Because many ethanol withdrawal symptoms are caused by autonomic hyperactivity, we examined the effects of two antihypertensives, the imidazoline(I)(1) agonist moxonidine and the alpha(2)-adrenergic partial agonist clonidine, on the ethanol-withdrawal-enhanced acoustic startle response in rats. d-amphetamine-enhanced startle served as a positive control. METHODS: Male, Long-Evans rats were made ethanol-dependent through unlimited access to liquid diet containing 6.7% v/v ethanol for 10 days. The concentration of ethanol was reduced to 3.3% v/v on the 11th day. On the 12th day, the rats received control diet. The acoustic startle response was tested 24 hours following the withdrawal of ethanol. Control rats were maintained on control liquid diet throughout the experiment. RESULTS: As has been shown previously, withdrawal from the chronic ingestion of ethanol significantly enhanced the acoustic startle response. Pretreatment with moxonidine (0.01, 0.1, and 1.0 mg/kg, subcutaneously), but not clonidine (0.3, 1.0, and 3.0 mg/kg, subcutaneously), significantly attenuated the ethanol withdrawal-induced elevation of the acoustic startle response. Moxonidine did not suppress the elevation in the startle response caused by d-amphetamine. CONCLUSIONS: These results indicate that I(1) receptors can play an important role in ethanol withdrawal and that moxonidine may be useful for the treatment of ethanol withdrawal in humans.

LY354740: a metabotropic glutamate receptor agonist which ameliorates symptoms of nicotine withdrawal in rats.

LY354740 is a conformationally constrained analog of glutamate with high selectivity and nanomolar agonist activity at Group II metabotropic glutamate receptors (mGluRs). This orally active compound is a new drug candidate which is being developed for the treatment of anxiety. In this study, LY354740 was investigated in a model of nicotine withdrawal using the acoustic startle reflex (sensorimotor reactivity) in rats. Nicotine (6 mg/kg/day) was administered for 12 days subcutaneously by osmotic minipumps. After 12 days the pumps were removed and the animals were allowed to go through spontaneous withdrawal. Cessation of chronic nicotine exposure led to increased startle responding for 4 days following withdrawal. Treatment with LY354740 (0.0001-0.1 mg/kg, i.p.; 0.03-3 mg/kg, oral) produced a dose-dependent attenuation of the enhanced auditory startle responding following withdrawal of nicotine with intraperitoneal and oral ED50 values of 0.003 mg/kg and 0.7 mg/kg, respectively. These effects were stereoselective since the (-)-enantiomer of LY354740, LY366563, was without effect in this model. LY354740 produced no changes in the sensorimotor reactivity of rats not exposed to nicotine at oral doses up to 10 mg/kg. These data support the functional role of mGluR agonists in nicotine withdrawal and indicate that LY354740 may be efficacious in reducing the symptoms associated with nicotine withdrawal during smoking cessation in humans.

2-substituted (2SR)-2-amino-2-((1SR,2SR)-2-carboxycycloprop-1-yl)glycines as potent and selective antagonists of group II metabotropic glutamate receptors. 2. Effects of aromatic substitution, pharmacological characterization, and bioavailability.

In this paper we describe the synthesis of a series of alpha-substituted analogues of the potent and selective group II metabotropic glutamate receptor (mGluR) agonist (1S,1'S,2'S)-carboxycyclopropylglycine (2, L-CCG 1). Incorporation of a substitutent on the amino acid carbon converted the agonist 2 into an antagonist. All of the compounds were prepared and tested as a series of four isomers, i.e., two racemic diastereomers. On the basis of the improvement in affinity realized for the alpha-phenylethyl analogue 3, in this paper we explored the effects of substitution on the aromatic ring as a strategy to increase the affinity to these compounds for group II mGluRs. Affinity for group II mGluRs was measured using [3H]glutamic acid (Glu) binding in rat forebrain membranes. Antagonist activity was confirmed for these compounds by measuring their ability to antagonize (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid-induced inhibition of forskolin stimulated cyclic-AMP in RGT cells transfected with human mGluR2 and mGluR3. Meta substitution on the aromatic ring of 3 with a variety of substituents, both electron donating (e.g., methyl, hydroxy, amino, methoxy, phenyl, phenoxy) and electron withdrawing (e.g., fluorine, chlorine, bromine, carboxy, trifluoromethyl) gave from 1.5- to 4.5-fold increases in affinity. Substitution with p-fluorine, as in 97 (IC50 = 0.022 +/- 0.002), was the exception. Here, a greater increase in affinity was realized than for either the ortho- or meta-substituted analogues; 97 was the most potent compound resulting from monosubstitution of the aromatic. At best, only modest increases in affinity were realized for certain compounds bearing either two chlorines or two fluorines, and two methoxy groups gave no improvement in affinity (all examined in a variety of substitution patterns). Three amino acids, 4, 5, and 104, were resolved into their four constituent isomers, and affinity and functional activity for group II mGluRs was found to reside solely in the S,S,S-isomers of each, consistent with 1. With an IC50 = 2.9 +/- 0.6 nM, the resolved xanthylmethyl compound 168 was the most potent compound from this SAR. Amino acid 168 demonstrated high plasma levels following intraperitoneal (i.p.) administration and readily penetrated into the brain. This compound, however, had only limited (approximately 5%) oral bioavailability. Systemic administration of 168 protected mice from limbic seizures produced by the mGluR agonist 3,5-dihydroxyphenylglycine, with an ED50 = 31 mg/kg (i.p., 60 min preinjection). Thus, 168 represents a valuable tool to study the role of group II mGluRs in disease.

Design, synthesis, and pharmacological characterization of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740): a potent, selective, and orally active group 2 metabotropic glutamate receptor agonist possessing anticonvulsant and anxiolytic properties.

2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (9) was designed as a conformationally constrained analog of glutamic acid. For 9, the key torsion angles (tau 1 and tau 2) which determine the relative positions of the alpha-amino acid and distal carboxyl functionalities are constrained where tau 1 = 166.9 degrees or 202 degrees and tau 2 = 156 degrees, respectively. We hypothesized that 9 would closely approximate the proposed bioactive conformation of glutamate when acting at group 2 metabotropic glutamate receptors (mGluRs). The racemic target molecule (+/-)-9, its C2-diastereomer (+/-)-16, and its enantiomers (+)-9 (LY354740) and (-)-9 (LY366563) were prepared by an efficient, stereocontrolled, and high-yielding synthesis from 2-cyclopentenone. Our hypothesis that 9 could interact with high affinity and specificity at group 2 mGluRs has been supported by the observation that (+/-)-9 (EC50 = 0.086 +/- 0.025 microM) and its enantiomer (+)-9 (EC50 = 0.055 +/- 0.017 microM) are highly potent agonists for group 2 mGluRs in the rat cerebral cortical slice preparation (suppression of forskolin-stimulated cAMP formation) possessing no activity at other glutamate receptor sites (iGluR or group 1 mGluR) at concentrations up to 100 microM. Importantly, the mGluR agonist effects of (+)-9 are evident following oral administration in mice in both the elevated plus maze model of anxiety (ED50 = 0.5 mg/kg) and in the ACPD-induced limbic seizure model (ED50 = 45.6 mg/kg). Thus, (+)-9 is the first orally active group 2 mGluR agonist described thus far and is an important tool for studying the effects of compounds of this class in humans.

Evaluation of the activity of a novel metabotropic glutamate receptor antagonist (+/-)-2-amino-2-(3-cis and trans-carboxycyclobutyl-3-(9-thioxanthyl)propionic acid) in the in vitro neonatal spinal cord and in an in vivo pain model.

The cyclobutylglycine (+/-)-2-amino-2-(3-cis and trans-carboxycyclobutyl-3-(9-thioxanthyl)propionic acid) (LY393053) has been identified as a functionally potent metabotropic glutamate receptor antagonist. It is most potent on the two group I metabotropic glutamate receptors, 1alpha and 5alpha, with IC50 values of 1.0+/-0.4 microM and 1.6+/-1.4 microM, respectively. In this study, LY393053 has also been evaluated electrophysiologically on native group I metabotropic glutamate receptors in an in vitro spinal cord preparation as well as behaviourally, in a mouse model of visceral pain. LY393053 dose-dependently antagonised group I agonist, (RS)-3, 5-dihydroxyphenylglycine, or a broad-spectrum agonist (1S,3R)-amino-1,3-cyclopentanedicarboxylic acid-induced depolarisation of spinal motoneurons. The apparent Kd values were estimated to be 0.3 microM against (RS)-3, 5-dihydroxyphenylglycine-induced depolarisation and 0.5 microM against (1S,3R)-amino-1,3-cyclopentanedicarboxylic acid-induced depolarisation, respectively. On the other hand, the dorsal root-ventral root potential elicited at 8 x threshold was depressed by LY393053 with IC50 values of 9.0+/-0.7 microM and 12.7+/-1.7 microM on monosynaptic and polysynaptic responses, respectively. When investigated using the mouse acetic acid writhing test, LY393053 showed significant analgesic effects at doses of 1-10 mg/kg intraperitoneally. An ED50 value of 6.0 mg/kg was obtained in this test. By revealing a potent effect of LY393053 in antagonising the native group I metabotropic receptor-mediated responses in the spinal cord in rodents, and an antinociceptive efficacy in a mouse visceral pain model, these results, therefore, provide additional evidence in support of the analgesic potential of metabotropic glutamate receptor antagonists.

A comparison of testing procedures on the discriminative morphine stimulus.

The study investigated the effects of reinforcement and non-reinforcement during test sessions, and the effects of duration of generalization test sessions on the generalization of a morphine-induced discriminative stimulus. Rats were trained to discriminate 3 mg/kg morphine from saline in a two-lever drug discrimination task and were then tested for generalization of 0, 1, 2, 3, 4, and 5 mg/kg morphine with the training drug under both reinforced and non-reinforced contingencies during 4-min test periods. The percentage of drug-appropriate responses and response rates were recorded for the first 2 min and the second 2 min of each test session. A higher proportion of drug-appropriate responding occurred with an intermediate dose of morphine when reinforcement was available during test sessions. The frequency of responding was higher during the last 2 min than during the first 2 min of reinforced test sessions. The changes in response rate observed between the first 2 min and the last 2 min of the test sessions also depended on the reinforcement contingency available and the dose of morphine administered presession. The testing parameters thus altered the degree of generalization and the shape of the generalization curve of the morphine discrimination.

Hallucinogenic agents as discriminative stimuli: a correlation with serotonin receptor affinities.

A choice between two levers in an operant chamber was used to train 24 rats, under a variable-interval 15 s schedule of sweetened milk reinforcement, to discriminate a hallucinogenic (psychotomimetic) agent, 5-methoxy-N,N-dimethyltryptamine (5-OMe DMT), from saline administration. The 5-OMe DMT stimulus generalized in a dose-related manner to each of 14 tryptamine related analogs. With the exception of one compound, the effective dose for the 5-OMe DMT response correlated highly (r = -0.86) with 5-HT receptor affinity (as determined using an isolated rat fundus preparation).

Effects of variation in chronic dose of cocaine on contingent tolerance as assessed in a milk-drinking task.

Tolerance to the suppressive effects of cocaine on milk drinking by rats was studied using a contingent tolerance experimental design. Three separate groups (n = 6) of rats received 8.0, 16.0, or 32.0 mg/kg cocaine daily 15 min before a 15-min period of access to sweetened condensed milk for 20 days. Three additional groups of six rats each received the same chronic doses 15 min after access to milk. Milk, water, and food intake as well as body weight were measured daily. Tolerance effects were assessed by comparing initial acute dose-effect determinations with a probe dose-effect redetermination in which all rats again received doses of cocaine pre-session after having experienced the differential pre- or post-session chronic treatment. Behavioral tolerance on the milk intake measure was observed for the 8.0 mg/kg and 16.0 mg/kg doses, but not for the 32.0 mg/kg chronic treatment, even though the latter group exhibited evidence of tolerance in the water intake measure. Chronic treatment with 8.0 and 16.0 mg/kg produced different outcomes in that chronic exposure to 16.0 mg/kg in the presence of milk resulted in generalization of tolerance to both a lower (8.0 mg/kg) and a higher dose (32.0 mg/kg), but the group receiving 8.0 mg/kg did not exhibit generalization of tolerance to higher doses. Modest sensitization effects were observed in the rats treated post-session with either 8.0 or 16.0 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

Behavioral tolerance to the force differentiation effects of diazepam and midazolam in rats.

RATIONALE: Several benzodiazepines (BZs) have been shown to increase the peak force of operant responses at doses that increased, decreased, or had no effect on response rate, suggesting that operant response force may be a sensitive index of BZs' effects rather than solely a correlate of rate-dependent effects. In addition, contingent tolerance to the rate-dependent effects of BZs has been reported, but the degree of contingent tolerance that develops when the critical variable of the task is force of the response has not been explored. OBJECTIVES: These experiments examined the effects of acute and repeated oral administration of diazepam (DZ) and midazolam (MZ) on a force-differentiation task to explore the importance of task requirements on the development of contingent tolerance. METHODS: Two groups of rats were trained to press a force-sensing operandum, and responses having peak forces falling within fixed lower and upper limits [low force (8-10 g) or high force (40-50 g)] were reinforced with water. Acute effects of the oral administration of DZ (0.3, 1.0, 3.0, 10.0, 30.0 mg/kg) and MZ (same doses) were determined for the discriminated-force task before and after a repeated-administration procedure. RESULTS: When administered acutely, both drugs increased the peak force of responses in a dose-related manner and concomitantly reduced the proportion of reinforced responses, with MZ exhibiting greater potency. For the next 36 days, one group received drug before experimental sessions and the other group received drug after the experimental session. A second dose-effect determination demonstrated that rats chronically dosed with DZ or MZ pre-session displayed more contingent tolerance to alterations in peak force than rats that had received 36 drug injections postsession, where there was no opportunity to practice the force-discrimination response while under the drug state. CONCLUSIONS: These results suggest that perceptual motor difficulty of the task rather than effort may be an important variable in predicting the degree of contingent tolerance that develops. Additionally, these results suggest that both behavioral and pharmacological mechanisms are involved in the development of drug tolerance to the BZs.

In a drug discrimination procedure isolation-reared rats generalize to lower doses of cocaine and amphetamine than rats reared in an enriched environment.

Rats with different behavioral histories, defined by rearing and housing in either an enriched condition (EC) or an isolation condition (IC), were trained in a two-lever operant procedure to discriminate 5.0 mg/kg cocaine from saline. In cocaine dose-generalization tests, the IC rats exhibited an ED50 (1.01 mg/kg) significantly lower than the EC rats (ED50: 1.55 mg/kg). The cocaine-appropriate responding was emitted when the rats were treated with d-amphetamine, and for the d-amphetamine test doses the ED50 (0.19 mg/kg) was again significantly lower for the IC rats compared to the ECs (ED50: 0.33 mg/kg). These data suggest that IC rats are more sensitive to the stimulus properties of indirect dopaminergic agonists than EC rats and highlight the importance of environmental variables in governing an organism's response to the stimulus properties of abused drugs.

The CCK-B antagonist LY288513 blocks the effects of nicotine withdrawal on auditory startle.

In order to explore the potential clinical utility of CCK-B antagonists for the treatment of nicotine withdrawal symptoms, the auditory startle reflex was examined in rats undergoing withdrawal from the chronic administration of nicotine. Rats were exposed to nicotine continuously for 12 days (6 mg kg-1 day-1) via osmotic minipumps. After 12 days the pumps were removed and the animals allowed to go through spontaneous withdrawal for several days. Acute treatment with the CCK-B antagonist LY288513, at doses that have no effect on startle responses in naive rats, blocked the nicotine withdrawal-induced increase in the acoustic startle reflex. These results indicate that CCK-B antagonists may be an efficacious treatment for some nicotine withdrawal symptoms in man and may represent a novel pharmacotherapy for smoking cessation.

Practice-augmented tolerance to triazolam: evidence from an analysis of operant response durations and interresponse times.

In order to investigate contingent tolerance to triazolam (TZ), 16 rats were trained with a water reinforcer to respond under a multiple fixed ratio 30 (FR 30)-differential reinforcement of low rate 20-s (DRL 20) schedule, during daily 20-min sessions. FR 30 and DRL 20 performances were assessed with measures of response rate, response duration, interresponse times, and reinforcers delivered. In addition, operant responses for each schedule component were divided into fast and slow subclasses, based on interresponse times less than 1s and greater than 1s. Initial dose-effect functions for these behavioural measures were obtained for TZ (0.05-0.5mg/kg). After a 30-day chronic TZ (0.5mg/kg) exposure period, during which half of the rats were gavaged pre-session (PRE) and the other half were gavaged post-session (POST), dose-effect functions were redetermined with a wider dose range (0.05-3.0mg/kg). The redetermined dose-effect functions for FR rate indicated that both PRE and POST groups developed resistance to the rate-suppressing effects of TZ. In addition, the PRE group displayed more tolerance than the POST group on some, but not all, measures, especially at doses higher than 0.5mg/kg. The greater tolerance in the PRE group was observed for number of reinforcers in the DRL 20 component, for response duration for the slow subclass of responses in both FR 30 and DRL 20 components, and for the fast subclass of responses in the DRL 20 component. Moreover, in the PRE group, tolerance occurred to the response duration measure even though the chronic dose of 0.5mg/kg had little effect on this measure. These results demonstrate the value of microanalytic methods in addressing the problem of contingent tolerance. In addition, the data suggest that extensive experience of response execution under the influence of a drug can have an "inoculating effect" against the higher doses of the drug even in the absence of large disruptions in behaviour during the drugged practice itself.

The effects of various levels of ascorbic acid on the response of the ODS rat to trimethyltin.

The effects of trimethyltin (TMT) on behavioral and histological parameters were investigated in rats maintained on low, mid, and high levels of ascorbic acid (AA). Male osteogenic disorder Shionogi (ODS) rats were used. Like man, ODS rats are unable to synthesize AA. AA was administered in the drinking water. Radial arm maze (RAM) performance and locomotor activity were measured before (i.e., baseline) and after (i.e., retest) TMT administration. During baseline, all rats learned the RAM task. Also during baseline, locomotor activity of rats maintained on high levels of AA was found to be lower than the other groups. After administration of 7.5 mg/kg TMT chloride (p.o.), RAM performance of all the groups declined, but RAM performance of rats maintained on low levels of AA appeared least affected by TMT. Also, rats in the high AA group had a significant increase in locomotor activity compared to baseline. These results suggest that in the ODS rat, TMT toxicity may be influenced by levels of AA intake.

Superior colliculus involvement in the locomotor effects of ambient noise and the stimulants.

Partial destruction of the superior colliculus (45%) significantly decreased the normal facilitatory effect of ambient white noise on locomotor activity levels in young rats. As recovery from surgery occurred and as test experience increased, the loss observed immediately following surgery was reduced. Presumably because of the age of the rats examined, destruction of the superior colliculus failed to potentiate the stimulant effects of d-amphetamine or methylphenidate on locomotion. These data suggest that the superior colliculus is involved in changes in general activity that result from manipulation of auditory stimuli in the environment in addition to the documented involvement of the superior colliculus in alterations of general responsivity resulting from manipulations of visual stimuli in the environment. Moreover, the superior colliculus is implicated in maintaining both excitatory and inhibitory changes in response to the environment of the organism.

Efficacy of choice testing to predict chronic ingestion of drinking solutions adulterated with chemicals.

The feasibility of using a measure of palatability in a 2-bottle choice paradigm to determine detriments in fluid intake when unpalatable solutions containing drugs or chemicals were provided as a sole source of fluid was examined. Palatability measures obtained from testing various concentrations of quinine with water in a two-bottle choice paradigm were compared with intake of these same solutions when they were the sole fluid source for 20 consecutive days. Mice were observed to significantly avoid quinine solutions at concentrations as low as 0.0001 mg/ml in a choice situation while fluid intake was reduced in a forced drinking situation only at a concentration of 0.1 mg/ml. Palatability altered forced fluid intake only when quinine solutions comprised 20% or less of total intake in a choice situation. This approach was successfully employed to predict whether various concentrations of halogenated hydrocarbons could be administered in a repetitive forced drinking situation without reducing total fluid intake of mice.

The discriminative stimulus properties of the R2 isomer of viminol.

Viminol is a pyrrylethanolamine derivative which exists naturally as a racemic mixture containing six different stereoisomers. Viminol has been reported to exert both potent analgesic activity and minimal dependence liability. The analgesic component of racemic viminol has been attributed to the R2 isomer, while the antagonistic S2 isomer appears to be responsible for minimizing the dependence liability of the racemate. We tested the R2 isomer of viminol in rats trained to discriminate 3 mg/kg morphine sulfate from saline on a VI-15 sec schedule for sweetened milk reinforcement. The R2 isomer resulted in dose dependent morphine-like responding, with complete generalization to the 2.5 mg/kg dose of R2 viminol. The morphine-like discriminative stimulus properties of R2 viminol were reversed by naloxone in a dose-dependent fashion, with total blockade by 0.1 mg/kg naloxone. R2 viminol, like morphine, also had a biphasic effect on response rate with low doses increasing and high doses suppressing response rates. R2 viminol had a overall shorter time course than that reported for morphine, and its different physiological and behavioral effects may not occur simultaneously. These data suggest that R2 viminol exerts a subjective effect similar to that of morphine and supports the hypothesis that R2 viminol has opiate activity despite its lack of structural relationship to the opiate series.

Central nervous system characterization of the new cholecystokininB antagonist LY288513.

The activity of LY288513, an investigational cholecystokinin (CCK)B antagonist, was evaluated in a wide range of pharmacological tests in mice and rats. The anxiolytic benzodiazepine, diazepam, served as a reference standard for LY288513 in many of the tests. In the elevated plus-maze, LY288513 (3, 10 mg/kg, IP; 10, 30 mg/kg, PO) produced an anxiolytic-like action in mice with a magnitude of effect similar to that of diazepam. However, unlike diazepam, LY288513 produced no overt clinical signs and did not affect muscle tone, neuromuscular coordination, or sensorimotor reactivity. Also, in contrast to diazepam, LY288513 did not produce changes in the thresholds for electroshock- or pentylenetetrazol-induced convulsions. High doses of LY288513 (1000 mg/kg, PO) were required to reduce spontaneous activity levels, decrease body temperature, or potentiate the CNS-depressant effects of hexobarbital. LY288513 had no analgesic activity in mouse writhing or tail-flick tests. Electrophysiological studies in anesthetized rats showed that acute administration of LY288513 decreased the number of spontaneously active dopamine neurons in the substantia nigra and ventral tegmental area. However, LY288513 did not produce catalepsy. These data indicate that LY288513 possess both anxiolytic and antipsychotic potential.

Characterization of the interaction of pentazocine and tripelennamine: drug discrimination and mu-receptor binding assay.

Abuse of the combination of pentazocine (P) and tripelennamine (T) reputedly produces an opiate-like euphoria not obtainable from either drug alone. To determine if this effect is related to interactions at the behavioral or receptor levels we tested this combination in rats trained to discriminate morphine from saline and in mu-receptor binding assays. Displacement of 3H-DHM was compared in morphine-naive, dependent and withdrawn states to determine the importance of prior morphine exposure. The morphine training cue (3 mg/kg) generalized to P but not to T. Combinations of T (0.3 and 1.0 mg/kg) with "no effect" doses of P (1 and 3 mg/kg) resulted in greater than additive increases in morphine-like responding. 3H-DHM was displaced by P but not T in naive, dependent and withdrawn states. Specific dose combinations of T (1 nM) with P (1 nM, 10 nM, 100 nM) resulted in enhanced displacement of 3H-DHM and was not related to prior morphine exposure. We conclude that the addition of T to P increases the mu-like subjective effects of P and this effect may be due to enhanced affinity of P for the mu-receptor.

Effects of nicotine on the visual evoked response.

The effects of smoking cigarettes differing in nicotine content (0.14 vs 1.34 mg/cigarette) on the peak-to-peak amplitude and peak latency of the human averaged visual evoked response (AVER) were measured in 10 male smokers after a 2-hr smoking deprivation period. The AVER was obtained under five different flash intensities. Eight different peaks were involved in the amplitude and latency measurements. The nicotine dosage and flash intensity factors both had significant effects on peak-to-peak amplitudes while only the flash intensity factor affected peak latencies. The general enhancement of peak-to-peak amplitudes by the 1.34 mg cigarette, relative to the 0.14 mg cigarette, indicates that the effects of cigarette smoking on the AVER are predominantly due to nicotine's psychopharmacologic action, as opposed to other elements in tobacco smoke or as opposed to nonpharmacologic mechanisms involving learning processes. Past research, on an electrophysiological and behavioral level, indicating that nicotine, as administered via cigarette smoking, may have enhancing and/or restorative effects on visual attentional processes in the quiescent smoker was supported.