Continuous cocaine induces persisting alterations in dopamine overflow in caudate following perfusion with a D1 agonist

The present study examined whether exposure to 5 days of continuous cocaine in rats would produce any persisting alterations of the decrease in striatal dopamine (DA) overflow produced by local infusion of a D1 receptor agonist. Using a microdialysis probe in striatum, changes in DA, DA metabolites, and GABA were assessed 14 to 21 days following a 5-day continuous cocaine treatment. There were no differences in baseline levels of DA and it's metabolites. SKF 38393 (10(-6) infusion into the striatum decreased striatal DA levels in the controls and this effect was attenuated in cocaine-pretreated rats. This result, together with other observations, supports the hypothesis of a persistently altered D1-mediated negative feedback produced by previous exposure to continuous cocaine.     

Amnesic actions of diazepam and scopolamine in man

In man, diazepam alone and in combination with scopolamine interferes with the memory of visual and painful stimuli. With a 15-minute interval between injection of the drug and the showing of emotionally neutral pictures, scopolamine (0.5 mg/70 kg) produces 14 per cent forgetting when evaluated 24 hours later. Under these conditions diazepam (10 mg/70 kg) produces 41 per cent forgetting, while the combination causes 64 per cent. Under conditions designed to insure selection of subjects in whom registration was clearly quite intact at the time of the initial exposure to the pictures, memory was still found to be impaired when tested 24 hours later. Graded doses of diazepam to as much as mg/70 kg in combination with 0.5 mg/70 kg scopolamine produced a virtually linear dose-response curve for amnesia. These results are compatible with the interpretation that the diazepam-scopolamine mixture interferes with memory by blocking consolidation of the memory trace.     

Cardiac and behavioral responsivity to tactile stimulation in premature and full-term infants.

Attempted to determine whether psychophysiological differences exist between prematurely born and full-term infants in their responsivity to tactile stimulation and in their ability to discriminate among different intensities of such stimulation. The performance of 20 full-term neonates in active sleep was compared with that of 20 premature infants of comparable conceptional age (average, 38.5 wks). Whereas the full-term Ss showed both behavioral responsiveness and heart rate acceleration to the stronger levels of stimulation, the premature Ss showed weaker behavioral responses and no significant cardiac response. Even on those trials where the premature infants did show strong behavioral response, their cardiac response was smaller than that of the full-term infants. A significant sex difference for premature Ss indicated that the lower behavioral responsiveness was due mainly to males. Issues raised were whether the lack of cardiac responsivity in the premature infant is secondary to his/her heightened level of autonomic arousal whether it reflects a lack of integration between motor and autonomic systems. (38 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Modulation of spatial alternation and anxiety by septal scopolamine systemic diazepam in mice

To investigate the behavioral consequences of benzodiazepines in subjects whose septo-hippocampal cholinergic (ACh) activity was impaired, C57BL/6 mice received an injection of 2.5 microg/0.2 microl of scopolamine into the medial septal area with an i.p. injection of 0.5 mg/kg of diazepam. The consequences of these treatments administered in combination or alone were evaluated on anxiety measured in an elevated plus-maze and on spontaneous alternation carried out in a T-maze, using two different intertrial intervals (ITI: 5s or 30s). In these conditions, only the combined treatment provoked a decrease of the anxiety level, which was associated with an impairment of spontaneous alternation restricted to the 5s ITI. Because mice were not impaired during the sequential 30s ITI, this seems to rule out the possibility that this alternation deficit resulted from a working memory loss. These results suggest an involvement of a septal ACh-GABA-A/BDZ interaction in the exaggeration of cognitive deficits produced by benzodiazepines in patients characterized by a cholinergic hypofunction.     

Effects of scopolamine upon behavioral reactivity and visually evoked potential to flashes in rats.

Examined the averaged visual evoked response (VER) at cortex and behavioral reactivity to photic stimuli in 21 male albino Holtzman rats following administration of varying dosages of scopolamine hydrobromide, scopolamine methyl nitrate, or saline. The pattern of behavioral and electrophysiological results with scopolamine paralleled earlier findings with septal lesions. The drug impaired habituation of behavioral reactivity of flashes and altered VERs in 2 ways that appeared to relate to the behavioral impairment. It augmented the positive component of the early negative-positive complex and produced a dissociation between the amplitude of the late negative wave of VER and behavioral activity. These effects are viewed in terms of ascending cholinergic arousal processes and interrelationships of arousal and behavioral patterns. (26 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Abnormal behavioral responses to fenfluramine in patients with affective and personality disorders. Correlation with increased serotonergic responsivity

Serotonergic responsivity was assessed in 20 psychiatric patients by the prolactin response to a fenfluramine challenge test. During the fenfluramine challenge 6 of 20 patients (30%) spontaneously reported psychopathologic reactions that included: increased anxiety/agitation, psychotic symptoms, illusions, mood elevation, and anergia. The time of peak behavioral symptoms (2.5 +/- 0.8 hrs) corresponded closely to the time of peak increase in prolactin levels (3.0 +/- 1.1 hr). Abnormal behavioral responders had statistically significant greater increases in prolactin 1 to 4 hr after fenfluramine when compared to normal responders. Patients who developed an abnormal psychopathologic response to fenfluramine were characterized by higher levels of anxiety and agitation at the time of admission to the hospital but otherwise were not distinguishable on the basis of severity of other psychiatric symptoms. This study suggests that increased serotonergic transmission may trigger anxiety, psychosis, and mood elevation in specific vulnerable individuals, whereas other patients with similar psychiatric illnesses are not affected.     

Comparative effects of scopolamine and amphetamine upon behavioral reactivity and visual evoked potentials to flashes in rats.

Two experiments employed a total of 14 male Holtzman rats in which averaged visual evoked response (VER) at cortex and behavioral reactivity to photic stimuli were examined following administration of varying dosages of either scopolamine (and methyl scopolamine) or dextroamphetamine, and of saline. The augmentation in behavioral activity produced by scopolamine and dextroamphetamine was associated with differential patterns of changes in VERs. Scopolamine reduced the amplitude of the early negative component, enhanced the early positive component, and blocked the attenuation of the late negative wave normally associated with heightened behavioral activity. Amphetamine produced relatively selective decrements in the late negative wave, which at higher dosages related to flash sequence. This information is of interest in utilizing VERs to help distinguish different antecedents of "behavioral arousal" to photic stimulation. (18 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Tolerance and sensitization to the behavioral effects of cocaine in rats: relationship to benzodiazepine receptors

Tolerance and sensitization to the behavioral effects of cocaine were investigated in rats responding under a fixed-consecutive-number eight schedule of food reinforcement. The development of tolerance or sensitization was induced by delivering the drug either immediately before or after each behavioral session during chronic administration. Chronic cocaine administered before each session resulted in tolerance, as indicated by the shift to the right in the cocaine dose response curve. This tolerance was more likely to develop in the presence of an external discriminative stimulus. On the other hand, when cocaine was delivered after each session, the injections did not disrupt responding and sensitization or increased sensitivity rather than tolerance developed. This sensitization was more likely to occur when the external discriminative stimulus was not present. These data suggest that either tolerance or sensitization to the behavioral effects of cocaine can occur following the same number of chronic injections, with the effect dependent on the context under which the drug is delivered. Significant differences in benzodiazepine receptor binding measured autoradiographically using [3H]flumazenil were observed between rats that received cocaine before or after each session, suggesting that the development of tolerance and sensitization may be mediated through changes in benzodiazepine receptors in discrete brain regions.     

Chronic demands and responsivity to challenge

Certain kinds of arousal in response to challenge situations reflect conditioning that makes one adaptive to task demands. A growing literature implicates chronic stress as a factor degenerating this conditioning. This study investigated the relation between objective occupational demands to which workers were classified for at least 2 years and various indicators of adaptive responsivity to challenge situations. There were consistently significant and negative relations between the occupational exposures and cardiovascular and skin temperature responsivity to the acute challenges administered in the laboratory, the corresponding speed of recovery to baseline after removal of the challenge stimulus, and peripheral catecholamine changes during a work shift.     

Intravenous cocaine induces platelet activation in the conscious dog

BACKGROUND: Cocaine consumption has been associated with thrombosis of coronary and peripheral arteries. Since cocaine has been found to induce platelet activation in vitro, we sought to establish whether cocaine induced platelet activation in vivo. METHODS AND RESULTS: Chronically instrumented, conscious dogs were infused with cocaine (1 mg/kg), norepinephrine (0.2 to 0.4 mg/kg), or saline intravenously over 1 minute. Activated canine platelets were identified in whole blood collected from an indwelling aortic catheter by flow cytometric detection of the binding of a monoclonal antibody directed against the activation-dependent antigen P-selectin. Infusion of cocaine resulted in an elevation of mean arterial pressure (91 +/- 3 to 128 +/- 7 mm Hg [P < .01]) and heart rate (87 +/- 9 to 125 +/- 11 beats per minute [P < .01]). A similar change (P = NS) in mean arterial pressure followed norepinephrine infusion (100 +/- 5 to 137 +/- 13 mm Hg [P < .04]), whereas saline infusion had no effect. Cocaine resulted in a substantial but delayed increase in platelet P-selectin expression (14 +/- 7% [P < .08], 31 +/- 12% [P < .04], and 55 +/- 22% [P < .04] at 17, 22, and 27 minutes after drug infusion, respectively). The magnitude of this increase was similar to that found in blood treated ex vivo with the agonists ADP or PAF (23 +/- 7% and 53 +/- 15%, respectively). No significant increase in P-selectin expression was detected in the blood of animals that received norepinephrine or saline. Serum cocaine concentrations were highest immediately after infusion (538 +/- 55 ng/mL at 2 minutes) but declined rapidly (185 +/- 22 and 110 +/- 25 ng/mL at 17 and 32 minutes after infusion); in contrast, the increase in benzoylecgonine concentrations was delayed (from < 25 ng/mL in all but one animal [34 ng/mL] at 2 minutes to 46 +/- 4 and 71 +/- 11 ng/mL at 17 and 32 minutes, respectively, after infusion). CONCLUSIONS: Intravenous cocaine induces activation of individual circulating platelets; this effect is not reproduced by infusion of norepinephrine at doses sufficient to exert similar hemodynamic effects. The delay in detection of activated platelets after treatment with cocaine may result from the adhesion and subsequent detachment of activated platelets; alternatively, cocaine metabolites, rather than the drug itself, may induce platelet activation.     

Insulin receptor substrate-2 in the ventral tegmental area regulates behavioral responses to cocaine.

Neurotrophic factor signaling modulates cellular and behavioral responses to drugs of abuse. Among other biochemical adaptations, chronic exposure to abused drugs decreases the expression of insulin receptor substrate-2 (IRS-2; a protein involved in neurotrophic signaling) in the ventral tegmental area (VTA), a neural substrate for many drugs of abuse. Using viral-mediated gene transfer to locally alter the activity of IRS-2, the authors show that overexpression of IRS-2 in the VTA results in an enhanced preference for environments previously paired with cocaine, as measured by the place conditioning paradigm, whereas blockade of IRS-2 activity results in avoidance of cocaine-paired compartments. In addition, IRS-2 overexpression leads to enhanced cocaine-induced locomotor activity, and blockade of IRS-2 expression significantly blunts behavioral responses to cocaine. These results demonstrate that levels of IRS-2 in the VTA regulate responsiveness to the behavioral effects of cocaine. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Using subordinate ratings to elicit behavioral changes in supervisors.

Determined whether feedback of subordinates' ratings of supervisors leads to positive changes in the supervisors' behavior. The employees of the 56 supervisors in the experimental and control groups completed an information-opinion survey using a modified Likert scale format. Feedback reports were given to the experimental supervisors, and a 2nd survey was conducted 10 wks later to measure change. 2 independent measures showed significant positive change for the experimental supervisors. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Continuous treatment with morphine increases diazepam binding inhibitor mRNA in mouse brain

Effects of acute and chronic morphine treatment on the expression of diazepam binding inhibitor (DBI) mRNA in the mouse brain were examined. Cerebral DBI mRNA expression significantly increased in morphine-dependent mice, and this increase is more remarkable in morphine-withdrawn mice, whereas a single administration of morphine (50 mg/kg) produced no changes in the expression. Simultaneous administration of naloxone (3 mg/kg) with morphine completely abolished the increase in cerebral DBI mRNA expression observed in morphine-dependent and -withdrawn mice. These results indicate that a chronic functional interaction between morphine and opioid receptors has a critical role in increases in DBI mRNA expression.     

Tolerance to diazepam and changes in GABA(A) receptor subunit expression in rat neocortical areas

Long-term treatment with diazepam, a full allosteric modulator of the GABA(A) receptor, results in tolerance to its anticonvulsant effects, whereas an equipotent treatment with the partial allosteric modulator imidazenil does not produce tolerance. Use of subunit-specific antibodies linked to gold particles allowed an immunocytochemical estimation of the expression density of the alpha1, alpha2, alpha3, alpha5, gamma(2L&S) and beta(2/3) subunits of the GABA(A) receptor in the frontoparietal motor and frontoparietal somatosensory cortices of rats that received long-term treatment with vehicle, diazepam (three times daily for 14 days, doses increasing from 17.6 to 70.4 micromol/kg), or imidazenil (three times daily for 14 days, doses increasing from 2.5 to 10.0 micromol/kg). In this study, tolerance to diazepam was associated with a selective decrease (37%) in the expression of the alpha1 subunit in layers III-IV of the frontoparietal motor cortex, and a concomitant increase in the expression of the alpha5 (150%), gamma(2L&S) and beta(2/3) subunits (48%); an increase in alpha5 subunits was measured in all cortical layers. In the frontoparietal somatosensory cortex, diazepam-tolerant rats had a 221% increase in the expression of alpha5 subunits in all cortical layers, as well as a 35% increase in the expression of alpha3 subunits restricted to layers V-VI. Western blot analysis substantiated that these diazepam-induced changes reflected the expression of full subunit molecules. Rats that received equipotent treatment with imidazenil did not become tolerant to its anticonvulsant properties, and did not show significant changes in the expression of any of the GABA(A) receptor subunits studied, with the exception of a small decrease in alpha2 subunits in cortical layers V-VI of the frontoparietal somatosensory cortex. The results of this study suggest that tolerance to benzodiazepines may be associated with select changes in subunit abundance, leading to the expression of different GABA(A) receptor subtypes in specific brain areas. These changes might be mediated by a unique homeostatic mechanism regulating the expression of GABA(A) receptor subtypes that maintain specific functional features of GABAergic function in cortical cell layers.     

Transplacental cocaine exposure: a mouse model demonstrating neuroanatomic and behavioral abnormalities

Between 10% and 15% of infants born in urban America today have been exposed to cocaine in utero. Clinical studies have suggested that impairment of brain growth is the single best marker of significant prenatal cocaine exposure, and postnatal developmental compromise seen in a subset of affected children as a consequence of that exposure. We have developed an animal model, in mice, of prenatal cocaine exposure that has allowed us to dissociate the direct effects of cocaine in altering fetal development from the indirect effects associated with cocaine-induced malnutrition. We find that transplacental cocaine exposure independently impairs fetal brain and body growth and results in behavioral deficits and permanent alterations in neocortical cytoarchitecture in exposed offspring.     

Conditioned increases in behavioral activity and accumbens dopamine levels produced by intravenous cocaine.

In vivo microdialysis, behavioral activity assessments, and a conditioned place preference (CPP) test were used to investigate dopaminergic correlates of cocaine-conditioned behaviors. Over 12 days, rats were given either intravenous cocaine (4.2 mg/kg) or saline (6 cocaine and 6 saline infusions) daily in distinctively different environments. The following day, rats were tested in the cocaine- and saline-paired environments; 48 hr later, CPP was determined. The cocaine-associated environment elicited greater nucleus accumbens dopamine (NAcc DA) levels, hyperactivity, and place preference, though the emergence of DA increases was not in synchrony with peak behavioral activation. Although conditioned behavioral effects after repeated cocaine are well documented, direct evidence of increased NAcc DA in response to a cocaine-paired environment has not been previously reported. Discrepancies with previous work are attributed to a number of methodological differences. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Correlated changes in focused attention and associative encoding following diazepam ingestion.

Forty-eight volunteers received an average of 0.18 mg/kg oral diazepam or placebo in a double-blind manner. Diazepam's effect on arousal and attention was assessed by subjective ratings of drowsiness, digit cancellation, and rehearsal speed. the drug's effect on recall , short-term memory capacity, and a computer modeling parameter representing the encoding of contextual and interitem associations was also assessed. Change in digit cancellation speed correlated with change in total recall and with change in the associative encoding parameter following diazepam ingestion. No other correlations involving change scores were significant in the diazepam condition. Although attention and learning are broadly impaired following diazepam ingestion, their shared decline involves only specific components on attention and learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Maturation-related changes in tolerance development to hexobarbital after short term treatment with diazepam in the rat

Male rats at six different ages received diazepam on a 4-day treatment schedule. Cross-tolerance to hexobarbital was tested several times during withdrawal period with an anaesthesia threshold technique. Pattern of cross-tolerance was different at different ages. Thus, age and maturation of the rat is a variable which must be considered in studies of tolerance to diazepam.     

Repeated injection of GBR 12909, but not cocaine or WIN 35,065-2, into the ventral tegmental area induces behavioral sensitization

A role for the mesolimbic dopamine system in the development of behavioral sensitization to psychostimulants, such as cocaine and amphetamine, is well established. Previous reports have suggested that the ventral tegmental area (VTA) is involved in the initiation of, while the nucleus accumbens is in involved in the expression of behavioral sensitization. This hypothesis is supported in part, by studies which demonstrated that behavioral sensitization could be induced by repeated intra-VTA, but not intra-accumbal, administration of amphetamine. The present studies were designed to determine whether repeated intra-VTA cocaine would similarly induce behavioral sensitization. Rats receiving four daily injections of cocaine (1.5, 5 or 15 nmol/side) into the VTA did not show a sensitized behavioral response when challenged with cocaine (15 mg/kg, ip) 1 week later. In contrast to this, repeated injection of the specific dopamine reuptake inhibitor, GBR 12909 (15 nmol/side) produced behavioral sensitization to a challenge injection of cocaine. Repeated injections of the cocaine analog WIN 35,065-2 did not induce behavioral sensitization to cocaine, suggesting that the local anesthetic properties of cocaine were not responsible for the inability of intra-VTA cocaine to induce sensitization. In summary, the data suggest that sensitization to cocaine may involve mechanisms different from amphetamine.