Live predator stress in adolescence results in distinct adult behavioral consequences and dorsal diencephalic brain activation patterns.

Exposure to traumatic events during childhood increases the risk of adult psychopathology, including anxiety, depression, alcohol use disorders and their co-morbidity. Early life trauma also results in increased symptom complexity, treatment resistance and poor treatment outcomes. The purpose of this study was to establish a novel rodent model of adolescent stress, based on an ethologically relevant life-threatening event, live predator exposure. Rats were exposed to a live predator for 10 min. at three different time points (postnatal day (PND)31, 46 and 61). Adult depression-, anxiety-like behaviors and ethanol consumption were characterized well past the last acute stress event (two weeks). Behavioral profiles across assessments were developed to characterize individual response to adolescent stress. CNS activation patterns in separate groups of subjects were characterized after the early (PND31) and last predator exposure (PND61). Subjects exposed to live-predator adolescent stress generally exhibited less exploratory behavior, less propensity to venture into open spaces, a decreased preference for sweet solutions and decreased ethanol consumption in a two-bottle preference test. Additional studies demonstrated blunted cortisol response and CNS activation patterns suggestive of habenula, rostromedial tegmental (RMTg), dorsal raphe and central amygdala involvement in mediating the adult consequences of adolescent stress. Thus, adolescent stress in the form of live-predator exposure results in significant adult behavioral and neurobiological disturbances. Childhood trauma, its impact on neurodevelopment and the subsequent development of mood disorders is a pervasive theme in mental illness. Improving animal models and our neurobiological understanding of the symptom domains impacted by trauma could significantly improve treatment strategies.

The rostromedial tegmental nucleus modulates the development of stress-induced helpless behavior.

A growing body of clinical and preclinical research suggests that structural and functional changes in the habenula, a component of the epithalamus, are associated with major depressive disorder. A major excitatory, efferent projection from the habenula targets the rostromedial tegmentum (RMTg), a mesopontine region that provides significant input to the ventral tegmentum and raphe nuclei. While the RMTg contributes to monoaminergic responses to aversive events, its role in stress-based animal models of depression has yet to be determined. In the present study, we test the hypothesis that the RMTg is a component of the circuitry mediating the development of a maladaptive behavior in which rats repeatedly exposed to inescapable footshock, fail to avoid or escape the same stressor when subsequently given the opportunity to do so. Excitotoxic lesions of the RMTg significantly diminished the frequency of these escape failures 24 h after exposure to inescapable footshock. Conversely, electrical stimulation of the Hb during the initial uncontrollable aversive event, a manipulation that enhances excitatory input to the RMTg, increased the number of trials in which subjects failed to escape an aversive stimulus when presented the option 24 h later. These complementary results provide evidence supporting a role for the RMTg in the expression of stress-induced helpless phenotype and are an important step in understanding the contribution made by this region to the development of depression-related maladaptive behaviors.

Disruption of conditioned reward association by typical and atypical antipsychotics.

Antipsychotic drugs are broadly classified into typical and atypical compounds; they vary in their pharmacological profile however a common component is their antagonist effects at the D2 dopamine receptors (DRD2). Unfortunately, diminished DRD2 activation is generally thought to be associated with the severity of neuroleptic-induced anhedonia. The purpose of this study was to determine the effect of the atypical antipsychotic olanzapine and typical antipsychotic haloperidol in a paradigm that reflects the learned transfer of incentive motivational properties to previously neutral stimuli, namely autoshaping. In order to provide a dosing comparison to a therapeutically relevant endpoint, both drugs were tested against amphetamine-induced disruption of prepulse inhibition as well. In the autoshaping task, rats were exposed to repeated pairings of stimuli that were differentially predictive of reward delivery. Conditioned approach to the reward-predictive cue (sign-tracking) and to the reward (goal-tracking) increased during repeated pairings in the vehicle treated rats. Haloperidol and olanzapine completely abolished this behavior at relatively low doses (100microg/kg). This same dose was the threshold dose for each drug to antagonize the sensorimotor gating deficits produced by amphetamine. At lower doses (3-30microg/kg) both drugs produced a dose-dependent decrease in conditioned approach to the reward-predictive cue. There was no difference between drugs at this dose range which indicates that olanzapine disrupts autoshaping at a significantly lower proposed DRD2 receptor occupancy. Interestingly, neither drug disrupted conditioned approach to the reward at the same dose range that disrupted conditioned approach to the reward-predictive cue. Thus, haloperidol and olanzapine, at doses well below what is considered therapeutically relevant, disrupts the attribution of incentive motivational value to previously neutral cues. Drug effects on this dimension of reward processing are an important consideration in the development of future pharmacological treatments for schizophrenia.

Cognitive effects of psychotomimetic drugs in rats discriminating number cues.

RATIONALE: Deficits in memory and attention are broadly acknowledged during psychosis; however, experiments on modeled psychosis often test working memory without systematic manipulation of attentional demands. OBJECTIVES: The major research goal was discovering which neurobehavioral processes, attention, or memory contributed more to drug-provoked performance deficits. MATERIALS AND METHODS: Rats were trained to perform operant ratio discrimination (RD) tasks wherein the number of presses at a rear-wall lever was discriminated using one of two front-wall levers. Effects from four psychotomimetic drugs, the serotonin agonist 2,5-dimethoxy-4-iodoamphetamine, the noncompetitive NMDA-glutamate receptor antagonist phencyclidine (PCP), and two CB1-selective cannabinoid agonists, WIN 55,512-2 and AM 411, were assessed using a signal detection analytical overlay to dissociate cognitive from noncognitive motor and motivational disruptions. Further methods allowed dissociation of attention compromises from mnemonic deficits. RESULTS: For each test compound, at least one dose elicited decreased RD accuracy without affecting response rates, and task difficulty was shown to be a crucial dictator of accuracy effect specificities. Effects from both PCP and WIN 55,512-2 biased animals to select the response lever conditioned for denser reinforcement. The same two drugs rendered peculiar response patterns in distracter light session components, considering light blinks were included to divert subjects' attention away from task-relevant information. The response patterns determined during distracter components of PCP/WIN testing sessions, counterintuitively, suggest performance enhancement. CONCLUSION: Comprehensive viewing of RD performance patterns after drug administration indicates that sustained attention and transient information management are significantly impaired during the drug-induced psychosis state, while selective attention is less affected.

Texture of locomotor path: a replicable characterization of a complex behavioral phenotype.

A database of mouse locomotor path in spatial tests can be used to search in silico for behavioral measures that better discriminate between genotypes and are more replicable across laboratories. In this study, software for the exploration of exploration (SEE) was used to search a large database for a novel behavioral measure that would characterize complex movement paths. The database included mouse open-field behavior assessed in 3 laboratories, 7 inbred strains, several pharmacological treatments and hundreds of animals. The new behavioral measure, "path texture", was characterized using the local curvature of the path (the change of direction per unit distance, in degrees/cm) across several spatial scales, starting from scales smaller than the animal's body length and up to the scale of the arena size. Path texture analysis differs from fractal dimension analysis in that it does not assume self-similarity across scales. Path texture was found to discriminate inbred strains with relatively high broad-sense heritability (43%-71%) and high replicability across laboratories. Even genotypes that had similar path curvatures in some scales usually differed in other scales, and self-similarity across scales was not displayed by all genotypes. Amphetamine decreased the path curvature of C57BL/6 mice in small and medium scales, while having no effect on DBA/2J mice. Diazepam dose-dependently decreased the curvature of C57BL/6 mice across all scales, while 2 anxiogenic drugs, FG-7142 and pentylenetetrazole, increased it. Path texture thus has high potential for behavioral phenotyping and the study of drug effects in the mouse.

Brain stimulation and morphine reward deficits in dopamine D2 receptor-deficient mice.

RATIONALE: The rewarding effects of lateral hypothalamic brain stimulation, various natural rewards, and several drugs of abuse are attenuated by D1 or D2 dopamine receptor (D1R or D2R) antagonists. Much of the evidence for dopaminergic involvement in rewards is based on pharmacological agents with limited or "relative" selectivity for dopamine receptor subtypes. Genetically engineered animal models provide a complementary approach to pharmacological investigations. OBJECTIVES: In the present study, we explored the contribution of dopamine D2Rs to (1) brain stimulation reward (BSR) and (2) the potentiation of this behavior by morphine and amphetamine using D2R-deficient mice. METHODS: Wild-type (D2Rwt), heterozygous (D2Rhet), and D2R knockout (D2Rko) mice were trained to turn a wheel for rewarding brain stimulation. Once equivalent rate-frequency curves were established, morphine-induced (0, 1.0, 3.0, and 5.6 mg/kg s.c.) and amphetamine-induced (0, 1.0, 2.0, and 4.0 mg/kg i.p.) potentiations of BSR were determined. RESULTS: The D2Rko mice required approximately 50% more stimulation than the D2Rwt mice did. With the equi-rewarding levels of stimulation current, amphetamine potentiated BSR equally across the three genotypes. In contrast, morphine potentiated rewarding stimulation in the D2Rwt, had no effect in the D2Rhet, and antagonized rewarding stimulation in the D2Rko mice. CONCLUSIONS: D2R elimination decreases, but does not eliminate, the rewarding effects of lateral hypothalamic stimulation. After compensation for this deficit, amphetamine continues to potentiate BSR, while morphine does not.

Altered prepulse inhibition in rats treated prenatally with the antimitotic Ara-C: an animal model for sensorimotor gating deficits in schizophrenia.

RATIONALE: Sensorimotor gating disruption is one of many neurocognitive deficits seen in schizophrenia. Disorganized thought is one of the cardinal symptoms associated with sensorimotor gating. In an attempt to model sensorimotor gating deficits in rats relevant to the neurodevelopmental hypothesis for schizophrenia, we have used prenatal injections of the antimitotic drug, cytosine arabinoside (Ara-C) to subtly perturb the development of the rat CNS and disrupt sensorimotor gating. OBJECTIVE: To produce rats with either basal sensorimotor gating deficits or increased vulnerability to the disruption of sensorimotor function by apomorphine or phencyclidine (PCP). Prepulse inhibition (PPI) of the acoustic startle response was used to assess sensorimotor gating. METHODS: Three different cohorts of pregnant Sprague Dawley female rats were injected with Ara-C (30 mg/kg in saline) or saline at embryonic days 19.5 and 20.5. The Ara-C and control rats were tested for acoustic startle response and PPI at preadolescent and post-adolescent ages; postnatal day (Pnd) 35 and 56, respectively. Apomorphine (2.0 mg/kg) or phencyclidine (3.0 mg/kg), was given prior to PPI sessions in order to disrupt PPI. RESULTS: At Pnd 35, Ara-C treatment did not significantly affect acoustic startle amplitudes or PPI. However, at PND 56, Ara-C treated rats had significantly lower acoustic startle amplitudes and significantly diminished sensorimotor gating. Pharmacological challenge with the dopamine agonist apomorphine and the glutamate antagonist PCP significantly disrupted sensorimotor gating in the control subjects. Apomorphine did not further disrupt the existing deficit in the Ara-C treated rats. Ara-C treatment did not cause gross loss of neuronal tissue, although there was a subtle and variable disorganization of the pyramidal cell layer in the hippocampal CA2/3 region. CONCLUSION: The results provide evidence to suggest that late embryonic exposure to Ara-C disrupts the circuitry involved in mediating PPI. While the dopamine agonist apomorphine caused a significant disruption in the control rats it did not further disrupt the existing deficit in the Ara-C treated rats. These data provide evidence to support the contention that modest neurodevelopmental insults can significantly affect sensorimotor gating processes in an adult onset dependent manner.

Differential neuroendocrine responsiveness to morphine in Lewis, Fischer 344, and ACI inbred rats.

Preclinical evidence suggests there is a link between the responsiveness to stress and the propensity to self-administer drugs of abuse. Our previous findings, for example, have shown a significant positive correlation between the locomotor response to novelty and the acquisition of morphine self-administration in Lewis (LEW), Fischer 344 (F344) and ACI inbred rat strains. As an extension of this work, we now report on the neuroendocrine responses (i.e., corticosterone and prolactin secretion) evoked by morphine administration in these same inbred strains. Male LEW, F344, and ACI rats were surgically prepared with indwelling jugular catheters 7 days prior to the study. Following a habituation period, rats were treated with i.p. saline or morphine (1, 5 or 10 mg/kg). Repeated blood samples were withdrawn via the catheters immediately before and at 20, 40, 60 and 120 min after injection. Plasma samples were assayed for hormone levels by radioimmunoassay. No differences in baseline corticosterone levels were found across strains. There was a significant effect of genotype on the corticosterone response to saline injection (i.e., mild stress), with F344 rats exhibiting sustained elevations in corticosterone compared to LEW and ACI rats. Morphine-induced stimulation of corticosterone release differed significantly across strains, and in this case LEW rats displayed a reduced sensitivity to morphine. Similar to the corticosterone results, LEW rats also had blunted prolactin responses to morphine when compared to F344 rats. Our data demonstrate that genotype is an important factor modulating the neuroendocrine sensitivity to morphine. It is noteworthy that LEW rats acquire self-administration more rapidly than F344 or ACI rats, yet LEW rats display reduced corticosterone responses to stress and morphine. Taking into account the particular conditions of this study (high i.p. doses used here vs. low i.v. doses in self-administration studies), our results do not suggest that corticosterone response to stress and morphine is related to vulnerability to intravenous opiate self-administration. The data, however, are consistent with the idea of that genetic factors might influence the sensitivity to the morphine-induced effects of glucocorticoids across these inbred strains.

Heritability of nociception I: responses of 11 inbred mouse strains on 12 measures of nociception.

It is generally acknowledged that humans display highly variable sensitivity to pain, including variable responses to identical injuries or pathologies. The possible contribution of genetic factors has, however, been largely overlooked. An emerging rodent literature documents the importance of genotype in mediating basal nociceptive sensitivity, in establishing a predisposition to neuropathic pain following neural injury, and in determining sensitivity to pharmacological agents and endogenous antinociception. One clear finding from these studies is that the effect of genotype is at least partially specific to the nociceptive assay being considered. In this report we begin to systematically describe and characterize genetic variability of nociception in a mammalian species, Mus musculus. We tested 11 readily-available inbred mouse strains (129/J, A/J, AKR/J, BALB/cJ, C3H/HeJ, C57BL/6J, C58/J, CBA/J, DBA/2J, RIIIS/J and SM/J) using 12 common measures of nociception. These included assays for thermal nociception (hot plate, Hargreaves' test, tail withdrawal), mechanical nociception (von Frey filaments), chemical nociception (abdominal constriction, carrageenan, formalin), and neuropathic pain (autotomy, Chung model peripheral nerve injury). We demonstrate the existence of clear strain differences in each assay, with 1.2 to 54-fold ranges of sensitivity. All nociceptive assays display moderate-to-high heritability (h2 = 0.30-0.76) and mediation by a limited number of apparent genetic loci. Data comparing inbred strains have considerable utility as a tool for understanding the genetics of nociception, and a particular relevance to transgenic studies.

Heritability of nociception II. 'Types' of nociception revealed by genetic correlation analysis.

Clinical pain syndromes, and experimental assays of nociception, are differentially affected by manipulations such as drug administration and exposure to environmental stress. This suggests that there are different 'types' of pain. We exploited genetic differences among inbred strains of mice in an attempt to define these primary 'types'; that is, to identify the fundamental parameters of pain processing. Eleven randomly-chosen inbred mouse strains were tested for their basal sensitivity on 12 common measures of nociception. These measures provided for a range of different nociceptive dimensions including noxious stimulus modality, location, duration and etiology, among others. Since individual members of inbred strains are identical at all genetic loci, the observation of correlated strain means in any given pair of nociceptive assays is an index of genetic correlation between these assays, and hence an indication of common physiological mediation. Obtained correlation matrices were subjected to multivariate analyses to identify constellations of nociceptive assays with common genetic mediation. This analysis revealed three major clusters of nociception: (1) baseline thermal nociception, (2) spontaneously-emitted responses to chemical stimuli, and (3) baseline mechanical sensitivity and cutaneous hypersensitivity. Many other nociceptive parameters that might a priori have been considered closely related proved to be genetically divergent.

Discrimination and self-administration of nicotine by inbred strains of mice.

These studies aim to characterize the discriminative stimulus effects of nicotine in two inbred strains of mice that differ in many pharmacological responses, and to investigate the feasibility of IV self-administration studies with nicotine in one of the strains. For discrimination studies, three groups of C57BL/6 and one group of DBA/2 mice were trained in a two-lever operant conditioning paradigm with a tandem VI-30" FR-10 schedule of food reinforcement. After 40 training sessions, accuracy reached 57.5, 77.5 and 90.0% in C57BL/6 mice trained with (-)-nicotine (SC) in doses of 0.4, 0.8 and 1.6 mg/kg, respectively (n = 8). DBA/2 mice trained with 0.8 mg/kg nicotine attained similar (73.3 %) accuracy (n = 9). Results from extinction tests showed that all groups of mice yielded orderly dose-response curves for nicotine (0.03-1.6 mg/kg), but stimulus control remained notably weaker for the mice trained with 0.4 mg/kg nicotine than for any other group. Overall rates of responding in the undrugged state were lower for DBA/2 than for C57BL/6 mice; DBA/2 mice were also slightly less sensitive than C57BL/6 mice to the response rate-reducing effect of nicotine. The nicotine antagonist mecamylamine (1.5 mg/kg SC) blocked the discriminative stimulus effect of the training dose of nicotine in all groups. The results of the IV self-administration study suggest that nicotine (0.1 mg/kg) can serve as a positive reinforcer in drug-naive C57BL/6J mice (n = 13). Behaviour maintained by 0.1 mg/kg nicotine injections was significantly greater than behaviour maintained by vehicle injections, and it was maintained under an intermittent schedule of reinforcement (FR4). The methods described provide possible approaches for genetic analyses of strain differences in sensitivity to the discriminative and reinforcing stimulus properties of nicotine.

Opioid receptor selectivity of heroin given intracerebroventricularly differs in six strains of inbred mice.

Heroin administered i.c.v. acts on supraspinal mu opioid receptors in ICR mice but on delta receptors in Swiss Webster mice. The purpose of this study was to determine the degree to which genotype plays a role in the opioid receptor selectivity of heroin across a range of fully inbred strains of mice. Six inbred strains were given heroin i.c.v. 10 min before the tail-flick test. Differences in the descending neurotransmitter systems involved in supraspinal opioid-induced analgesia were evaluated as the first step. Antagonism by bicuculline given intrathecally indicated the involvement of supraspinal delta receptors in activating spinal gamma-aminobutyric acid (GABA) receptors; antagonism by intrathecal methysergide indicated either mu or kappa receptor involvement. Antagonism by intrathecal yohimbine implicated mu and eliminated kappa receptor involvement. Intracerbroventricular opioid antagonists (beta-funaltrexamine, 7-benzylidenenaltrexone, naltriben, or nor-binaltorphimine) provided further differentiation. Based on these initial results, receptor selectivity was determined by more extensive ED50 experiments with i.c.v. administration of heroin with opioid antagonists, beta-funaltrexamine (for mu), naltrindole (for delta), and nor-binaltorphimine (for kappa). The combined results indicated that heroin analgesia was predominantly mediated in C57BL/6J by delta, in DBA/2J and CBA/J by mu, and in BALB/cByJ and AKR/J by kappa receptors. The response in C3H/HeJ appeared to involve mu receptors. The results indicate that the opioid receptor selectivity of heroin is genotype-dependent. Because these genotypes are fully inbred, the genetically determined molecular and neurochemical substrate mediating the different opioid receptor selectivities of heroin can be studied further.

Phentermine and fenfluramine. Preclinical studies in animal models of cocaine addiction.

Combined dopamine (DA) and 5-hydroxytryptamine (5-HT) releases such as phentermine (PHEN) and fenfluramine (FEN) are reported, in open label studies, to reduce craving for alcohol and cocaine and to prevent relapse. The objective of the studies reported here was to assess the actions of these agents alone and in combination in various animal models of drug addiction. Study 1. In vivo microdialysis experiments demonstrate that these agents preferentially release mesolimbic DA (PHEN) and 5-HT (FEN). Patients who relapse and use cocaine while taking these medications report diminished cocaine-like subjective effects. Microdialysis experiments were performed in awake rats, and dialysate samples were analyzed for DA and 5-HT. PHEN (1 mg/kg, intravenously (i.v.)) elevated DA (2-3-fold) for over 1.5 hr. Administration of cocaine (3 mg/kg, i.v.) increased DA 6-fold in saline-treated rats, but only 3-fold in PHEN-treated rats. PHEN did not reduce cocaine-induced increases in 5-HT. Study 2. These agents were assessed in a mouse model of cocaine-conditioned motoric activity (CCMA). Pretreatment with non-activating doses of PHEN (4.6 mg/kg, intraperitoneally (i.p.)) enhanced CCMA, whereas non-depressing doses of FEN (0.1 mg/kg, i.p.) did not alter CCMA or the PHEN-induced increase in CCMA. In contrast, sub-effective doses of FEN reduced CCMA stereotypy-like locomotion, whereas sub-effective doses of PHEN were without effect. PHEN reversed the FEN-induced increase in CCMA stereotypy-like locomotion. Study 3. PHEN and FEN were assessed in the conditional place preference model. FEN produced marked aversions for an environment previously associated with its administration and the minimum dose producing this effect was 3.0 mg/kg. In contrast, administration of PHEN, amphetamine (1.0-3.0 mg/kg) or morphine (3.0-5.0 mg/kg) produced dose-related preferences for the drug-paired place. However, the magnitude of the response to PHEN was less than that produced by the other prototypic drugs of abuse. In rats that received FEN (0.3 or 3.0 mg/kg) in combination with PHEN (3.0 mg/kg), the conditioned rewarding effects of PHEN were abolished. These data demonstrate that the rewarding effects of PHEN can be conditioned to stimuli previously associated with its administration. However, the conditioned response to this agent is less than that produced by prototypic drugs of abuse. The finding that PHEN-induced place preferences were attenuated by doses of FEN demonstrates that the combination of FEN/PHEN is devoid of motivational effects. The preclinical data obtained with PHEN/FEN in various models of drug provide a strong rationale for pursuing controlled clinical trials in humans with agents that act via a similar mechanism of action.

The neurobiology of opiate reinforcement.

This article provides a basic introduction into two commonly used behavioral paradigms used for the assessment of the reinforcing and rewarding effects of drugs in experimental animals. Behavioral as well as neurochemical data regarding the neural basis of opiate reward are then critically reviewed in order to evaluate the neuroanatomical and neurochemical substrates mediating the primary and conditioned reinforcing effects of opiates as well as current hypotheses of drug-induced reward and aversion.

Transgenic superoxide dismutase mice: Increased mesolimbic µ-opioid receptors results in greater opioid-induced stimulation and opioid-reinforced behavior.

Consequent to the insertion of the human Cu/Zn-superoxide dismutase (SOD) transgene, SOD transgenic mice (SOD-Tg) show higher concentrations of the primary receptor thought to be involved in opioid reinforcement (µ). These increases are observed in areas specifically associated with the primary neurotransmitter thought to be involved in addiction (dopamine), and in neuroanatomical regions thought to mediate substance abuse (mesolimbic). In the present study we have tested the idea that these increases in µ-receptors are associated with parallel changes in µ-mediated behaviors. Baseline and morphine-induced locomotor activity were significantly altered in the SOD-Tg mice. A qualitative change in the nature of acute and chronic morphine-induced locomotor activity was demonstrated by a significant change in the slope of the dose-effect curve. SOD-Tg mice were significantly more sensitive to the locomotor stimulant effects of morphine. Intravenous morphine-reinforced behavior was also altered in the SOD-Tg mice. SOD-Tg mice showed significant dose-related changes in operant lever-press responding maintained by morphine injection and significantly greater amounts of behavior were maintained by the drug than by vehicle under an intermittent schedule of reinforcement. In addition, SOD-Tg mice increased operant responding for the drug when the amount of behavior required to maintain drug intake increased 10-fold under a PR schedule of reinforcement. In contrast, in wild-type mice morphine injections failed to maintain greater amounts of behavior than vehicle, there were no dose-related changes in behavior, and when response requirements increased under the PR schedule, morphine intake decreased significantly. Thus, SOD transgene insertion significantly enhanced the efficacy of morphine as a reinforcer.

Cardiovascular effects of cocaine during operant cocaine self-administration.

The aim of this study was to investigate the acute and chronic effects of cocaine self-administration behavior on cardiovascular function. Mean blood pressure and heart rate were measured by radio-telemetry during several experimental conditions. Initial control studies eliminated possible confounds related to the effects of saline injections and operant responding on heart rate and blood pressure. When rats were first allowed to self-administer 0.5-mg/kg injections of cocaine (FR(fixed ratio)10:TO 30 s), there was a significant increase in blood pressure. Tolerance developed to this effect within 3 daily sessions. A significant decrease in blood pressure and heart rate was observed during saline-substitution sessions. Increasing the injection dose of cocaine (1.0, 2.0 and 4.0 mg/kg per injection) did not produce a dramatic increase in blood pressure or heart rate despite significant cumulative cocaine intake (20-27 mg/kg). The cardiovascular effects of cocaine administration did not approach magnitudes previously reported. The results of the current study suggest that operant-conditioned behaviour and/or the direct reinforcing effects of cocaine modulates the cardiovascular effects of cocaine.

Cocaine cross-sensitization to dopamine uptake inhibitors: unique effects of GBR12909.

Repeated administration of cocaine will cross-sensitize the locomotor response to a variety of psychomotor stimulants. The ability of cocaine to cross-sensitize the locomotor effects of other psychomotor stimulants provides information relevant to the pharmacological mechanisms underlying the sensitization process. The purpose of the current experiment was to investigate the ability of cocaine to cross-sensitize the locomotor effects of several dopamine uptake blockers with unique pharmacological profiles. Cocaine (40 mg/kg, IP) or saline was administered prior to a locomotor session on day one. On day 2, a full dose-effect curve was established for the locomotor effects of cocaine, RTI-55, mazindol, and GBR12909. Previous exposure to cocaine significantly affected locomotor activity and stereotopy-like behavior produced by cocaine, mazindol, RTI-55, and GBR12909. However, GBR12909 was unique in that the maximal stimulant effect and slope of the dose-effect curve was significantly depressed and the stereotopy-like behavior was unchanged. Thus, despite the similarity of these compounds in their ability to inhibit dopamine uptake, cocaine-induced sensitization did not generalize to GBR12909. This study further demonstrates the unique pharmacology of GBR12909 and supports the further study of this compound as a potential treatment medication for cocaine abuse.

The role of specific eicosanoids in mediating the acute narcotic effects of ethanol.

The pharmacological effects of ethanol may be in part due to increased membrane fluidity, resulting in increased phospholipase A2 activity and the subsequent conversion of released arachidonic acid (AA) into pharmacologically relevant eicosanoids (prostaglandins/leukotrienes). A significant correlation between the in vivo and in vitro potency of prostaglandin synthetase (PES) inhibitors to antagonize PES activity and their ability to antagonize the acute narcotic and rate-depressant effects of ethanol support this hypothesis. However, inhibition of PES not only decreases the production of at least five prostaglandins and thromboxane but may shunt free AA into the lipoxygenase cascade with subsequent formation of leukotrienes. The purpose of the present study was to systematically investigate numerous points in the AA cascade to determine the eicosanoid products relevant to the acute narcotic effects of ethanol. Ethanol-induced loss of the righting reflex in mice was used as the behavioral endpoint. The relative importance of PES metabolites vs. lipoxygenase metabolites was determined via administration of specific enzyme inhibitors (phospholipase, lipoxygenase and dual PES/lipoxygenase inhibitors) and receptor agonists/antagonists (prostaglandin and leukotriene). Pretreatment with specific lipoxygenase inhibitors, dual PES/lipoxygenase inhibitors and leukotriene antagonists suggest a negligible role for lipoxygenase metabolites in acute ethanol-induced narcosis. Pretreatment with prostaglandin agonists and antagonists suggest a significant role for prostaglandin E (PGE) and a minor role for prostaglandin D in mediating the acute effects of ethanol. The PGE agonist 16,16-dimethyl PGE significantly enhanced the narcotic effects of ethanol (> 400%), whereas the prostaglandin receptor antagonist L-640,035 significantly decreased the effects of ethanol (-54%). These results further support the hypothesis that eicosanoid formation is important in the biochemical and behavioral effects of ethanol.

Acute sensitivity vs. context-specific sensitization to cocaine as a function of genotype.

Individual variability in the acute and chronic effects of psychomotor stimulants is due, in part, to genetic factors. The purpose of this series of studies was to utilize a behavioral model of sensitization, namely increased locomotor activity, to assess individual variability in sensitization to the chronic effects of cocaine and its relationship to the acute stimulant effects of cocaine. Because the degree of sensitization is proportional to the training dose, genetic differences in acute sensitivity to cocaine were assessed and incorporated into the sensitization paradigm. Acute sensitivity and context-dependent sensitization were determined in six inbred mouse strains. Large quantitative and qualitative differences were found in the acute potency and efficacy of cocaine to stimulate locomotor activity. The ED50 was higher in the strains in which cocaine was most efficacious. Context-specific sensitization was determined via chronic administration of equiactive doses of cocaine (ED50) specifically paired with the test apparatus or with the home colony. Sensitization was time, environment, and genotype dependent. The differences in the number of trials required to show sensitization were unrelated to the acute locomotor stimulant effects of cocaine. These findings suggest that acute cocaine-induced locomotor activity and context-specific sensitization reflect different pharmacological properties of cocaine.