Differences In Behavioral Effects Research Articles

Optimizing 6‐Hydroxydopamine Concentrations for induction of a Parkinson’s Disease Like Behavior in Zebrafish

Parkinson’s disease is an increasing problem that affects the quality of life for over 10 million people worldwide. Affected individuals undergo worsening symptoms that begin with motor function impairment and can eventually result in death. Parkinson’s Disease is associated with the loss of Tyrosine Hydroxylase (TH) expressing dopaminergic neurons. TH is the rate limiting enzyme in catecholamine neurotransmitter synthesis including dopamine. Therefore, chemically induced animal models have focused on mitigation of movement abnormalities and loss of dopaminergic neurons as indicators for drug screening. We chose the 6‐hydroxydopamine (6‐OHDA) chemically induced Parkinson’s Disease model in zebrafish as a tool for drug screening. Previous work on this model had been conducted with varying drug concentrations and methodologies. All demonstrated reductions in TH expressing neurons; however, the behavioral assessments varied in both method, dose of OHDA (1‐750 μM 6OHDA), and whether behavioral abnormalities were observed. The objective of the current study is to determine the minimal 6‐OHDA dosage that is sufficient to induce a significant difference in behavioral effects while minimizing morphological toxicity. Zebrafish larvae were treated daily with 6‐OHDA with ascorbic acid from 2 to 5‐day post fertilization (dpf). We observed significant difference in behavior at ~20 μM 6‐OHDA, and developmental delays in swim bladder formation at 85 μM 6‐OHDA. The swim bladders were developed by 5 dpf when we assessed swim behavior; however, other signs of delay may still be present that would complicate results. Several studies focused on doses of 150 μM 6‐OHDA or higher; however, at these doses we observed severe morphological issues including edema, curved spines, and death. Future work will focus on the TH‐expressing neuron pathology as assessed by immunohistochemical and Western blotting methodologies.

Persuasive Message Pretesting Using Non-Behavioral Outcomes: Differences in Attitudinal and Intention Effects as Diagnostic of Differences in Behavioral Effects

Abstract Persuasive message designers would like to be able to pretest messages to see which will be more effective in influencing behavioral outcomes, but pretesting using behavioral measures is commonly not practical. Examination of within-study effect size comparisons from 317 studies of 22 message variations suggests that persuasive messages’ relative effectiveness is strikingly similar across attitudinal, intention, and behavioral outcomes—with messages’ relative persuasiveness with respect to intention outcomes especially indicative of relative persuasiveness with respect to behavioral outcomes. Intention measures thus provide a convenient and accurate means of persuasive message pretesting.

Sex difference in behavioral effects of the THC agonist CP55,940

Aims: Attentional biases (AB) interfere with decision making processes and AB to drug cues is a cardinal feature of addiction that may contribute to relapse. Thus it is critical to identify the neural correlates of AB for improving interventions. Cue responsivity and AB differ between males and females suggesting the neural correlates of AB to drug cues may also be sex-specific. Methods: We explored associations between AB for cannabis cues (CCs) and neural responses to CCs among males (n=24) and females (n=14) seeking treatment for cannabis use disorder (CUD). CUDs were exposed to CCs and comparison cues (500ms duration; 48 images of each cue type) presented in a quasi-random order in a BOLD fMRI fast event-related paradigm. Males and females did not differ in demographic or drug use characteristics. Male and female CUDs also completed a visual dot-probe AB task, which contained pictures of CCs and nondrug cues to examine whether sex influences AB and to investigate relationships between AB and neural responses to CCs. Results: CUDs showed an AB to CCs (22.8±4.7ms), which was not significantly different between males and females. Neural responses to CCs were strongest in the ventral striatum in females and the amygdala inmales.Males showed positive correlations between AB and increased CC-induced brain activity in visual cortex and bilateral parahippocampus whereas females showed positive correlations (all bilateral) in the insula, lateral orbitofrontal cortex, dorsolateral prefrontal cortex and middle temporal cortex. (T values range from 3 to 6, p=0.01). Conclusions: Results suggest that AB to CCs has different brain correlates for men and women. Thus, strategies to address AB may need to target sex-specific brain vulnerabilities for maximum impact on relapse. Financial support: PA DOH CURE.

Blood-gene expression reveals reduced circadian rhythmicity in individuals resistant to sleep deprivation.

To address whether changes in gene expression in blood cells with sleep loss are different in individuals resistant and sensitive to sleep deprivation. Blood draws every 4 h during a 3-day study: 24-h normal baseline, 38 h of continuous wakefulness and subsequent recovery sleep, for a total of 19 time-points per subject, with every 2-h psychomotor vigilance task (PVT) assessment when awake. Sleep laboratory. Fourteen subjects who were previously identified as behaviorally resistant (n = 7) or sensitive (n = 7) to sleep deprivation by PVT. Thirty-eight hours of continuous wakefulness. We found 4,481 unique genes with a significant 24-h diurnal rhythm during a normal sleep-wake cycle in blood (false discovery rate [FDR] < 5%). Biological pathways were enriched for biosynthetic processes during sleep. After accounting for circadian effects, two genes (SREBF1 and CPT1A, both involved in lipid metabolism) exhibited small, but significant, linear changes in expression with the duration of sleep deprivation (FDR < 5%). The main change with sleep deprivation was a reduction in the amplitude of the diurnal rhythm of expression of normally cycling probe sets. This reduction was noticeably higher in behaviorally resistant subjects than sensitive subjects, at any given P value. Furthermore, blood cell type enrichment analysis showed that the expression pattern difference between sensitive and resistant subjects is mainly found in cells of myeloid origin, such as monocytes. Individual differences in behavioral effects of sleep deprivation are associated with differences in diurnal amplitude of gene expression for genes that show circadian rhythmicity.

Forebrain glucocorticoid receptor gene deletion attenuates behavioral changes and antidepressant responsiveness during chronic stress

Stress is an important risk factor for mood disorders. Stress also stimulates the secretion of glucocorticoids, which have been found to influence mood. To determine the role of forebrain glucocorticoid receptors (GR) in behavioral responses to chronic stress, the present experiments compared behavioral effects of repeated social defeat in mice with forebrain GR deletion and in floxed GR littermate controls. Repeated defeat produced alterations in forced swim and tail suspension immobility in floxed GR mice that did not occur in mice with forebrain GR deletion. Defeat-induced changes in immobility in floxed GR mice were prevented by chronic antidepressant treatment, indicating that these behaviors were dysphoria-related. In contrast, although mice with forebrain GR deletion exhibited antidepressant-induced decreases in tail suspension immobility in the absence of stress, this response did not occur in mice with forebrain GR deletion after defeat. There were no marked differences in plasma corticosterone between genotypes, suggesting that behavioral differences depended on forebrain GR rather than on abnormal glucocorticoid secretion. Defeat-induced gene expression of the neuronal activity marker c-fos in the ventral hippocampus, paraventricular thalamus and lateral septum correlated with genotype-related differences in behavioral effects of defeat, whereas c-fos induction in the nucleus accumbens and central and basolateral amygdala correlated with genotype-related differences in behavioral responses to antidepressant treatment. The dependence of both negative (dysphoria-related) and positive (antidepressant-induced) behaviors on forebrain GR is consistent with the contradictory effects of glucocorticoids on mood, and implicates these or other forebrain regions in these effects.

Different behavioral effect dose–response profiles in mice exposed to two-carbon chlorinated hydrocarbons: Influence of structural and physical properties

The present study aimed to clarify whether dose–response profiles of acute behavioral effects of 1,2-dichloroethane (DCE), 1,1,1-trichloroethane (TCE), trichloroethylene (TRIC), and tetrachloroethylene (PERC) differ. A test battery involving 6 behavioral endpoints was applied to evaluate the effects of DCE, TCE, TRIC, and PERC in male ICR strain mice under the same experimental conditions. The behavioral effect dose–response profiles of these compounds differed. Regression analysis was used to evaluate the relationship between the dose–response profiles and structural and physical properties of the compounds. Dose–response profile differences correlated significantly with differences in specific structural and physical properties. These results suggest that differences in specific structural and physical properties of DCE, TCE, TRIC, and PERC are responsible for differences in behavioral effects that lead to a variety of dose–response profiles.

Cell behaviors regulated by guidance cues in collective migration of border cells

Border cells perform a collective, invasive, and directed migration during Drosophila melanogaster oogenesis. Two receptor tyrosine kinases (RTKs), the platelet-derived growth factor/vascular endothelial growth factor-related receptor (PVR) and the epidermal growth factor receptor (EGFR), are important for reading guidance cues, but how these cues steer migration is not well understood. During collective migration, front, back, and side extensions dynamically project from individual cells within the group. We find that guidance input from both RTKs affects the presence and size of these extensions, primarily by favoring the persistence of front extensions. Guidance cues also control the productivity of extensions, specifically rendering back extensions nonproductive. Early and late phases of border cell migration differ in efficiency of forward cluster movement, although motility of individual cells appears constant. This is caused by differences in behavioral effects of the RTKs: PVR dominantly induces large persistent front extensions and efficient streamlined group movement, whereas EGFR does not. Thus, guidance receptors steer movement of this cell group by differentially affecting multiple migration-related features.

Sex differences in analgesic, reinforcing, discriminative, and motoric effects of opioids.

This review summarizes evidence for sex differences in behavioral effects of opioids, primarily in rats. Whereas micro agonists have been found to be more potent and in some cases more efficacious in producing analgesia and sedation in males than females, females are more sensitive than males to reinforcing and locomotor stimulant effects of opioids. Sex differences in motoric effects of opioids may contribute to sex differences in other behavioral effects of opioids; for example, sex differences in rats' ability to discriminate morphine from saline can be attributed entirely to greater morphine-induced sedation in males. Chronic estradiol blunts females' sensitivity to morphine's analgesic and sedative effects, but enhances females' sensitivity to the reinforcing and locomotor stimulant effects of micro opioids. The neurobiological basis for sex differences in and estradiol modulation of behavioral effects of opioids includes brain opioid receptor density (greater in males and under low-estradiol conditions in females) and dopaminergic function (greater in females and under high-estradiol conditions). Given the significant and growing use of opioids by women, both medicinally and recreationally, understanding how female biology influences analgesic and other effects of opioids is crucial.

MDMA ( N-methyl-3,4-methylenedioxyamphetamine) and its stereoisomers: Similarities and differences in behavioral effects in an automated activity apparatus in mice

Racemic MDMA (0.3–30 mg/kg), S(+)-MDMA (0.3–30 mg/kg), R(−)-MDMA (0.3–50 mg/kg) and saline vehicle (10 ml/kg) were comprehensively evaluated in fully automated and computer-integrated activity chambers, which were designed for mice, and provided a detailed analysis of the frequency, location, and/or duration of 18 different activities. The results indicated that MDMA and its isomers produced stimulation of motor actions, with S(+)-MDMA and (±)-MDMA usually being more potent than R(−)-MDMA in measures such as movement (time, distance, velocity), margin distance, rotation (clockwise and counterclockwise), and retraced activities. Interestingly, racemic MDMA appeared to exert a greater than expected potency and/or an enhanced effect on measures such as movement episodes, center actions (entries and distance), clockwise rotations, and jumps; actions that might be explained by additive or synergistic (i.e. potentiation) effects of the stereoisomers. In other measures, the enantiomers displayed different effects: S(+)-MDMA produced a preference to induce counterclockwise (versus clockwise) rotations, and each isomer exerted a different profile of effect on vertical activities and jumps. Furthermore, each isomer of MDMA appeared to attenuate the effect of its opposite enantiomer on some behaviors; antagonism effects that were surmised from a lack of expected activities by racemic MDMA. S(+)-MDMA (but not R(−)-MDMA), for example, produced an increase in vertical entries (rearing) and a preference to increase counterclockwise (versus clockwise) rotations; (±)-MDMA also should have induced such effects but did not. Apparently, R(−)-MDMA, when combined with S(+)-MDMA to form (±)-MDMA, prevented the appearance of those increases (from control) in activities. Similarly, R(−)-MDMA (but not S(+)-MDMA) produced increases in episodes (i.e. jumps) and vertical distance that racemic MDMA also should have, but were not, exhibited. Evidently, the presence of S(+)-MDMA in the racemic mixture inhibited the appearance of those increases (from control) in behavior. Taken together, the various and complex effects of MDMA and its stereoisomers are noted and a strategy is suggested for future studies that stresses the importance of steric effects and interplay, probable interaction(s) with various neurotransmitters, and interaction(s) with the particular behavioral or biological event (or action) being measured.

Differences in behavioural effects of amphetamine and dopamine-related gene expression in wild-type and homozygous CCK 2 receptor deficient mice

Neuropeptide cholecystokinin (CCK) interacts with dopamine in the regulation of motor activity and motivations. Therefore, in CCK 2 receptor deficient mice the behavioural effects of repeated amphetamine administration and changes in dopamine-related gene expression were studied. Four-day amphetamine (1 mg/kg) treatment induced a significantly stronger motor sensitization in homozygous mice compared to their wild-type littermates. However, in the conditioned place preference test the action of amphetamine was more pronounced in wild-type animals. As opposed to wild-type mice, amphetamine (1–3 mg/kg) did not cause a significant conditioned place preference in homozygous mice. The expression of Tyhy gene was elevated in the mesolimbic structures and Drd2 gene was down-regulated in the mesencephalon of saline-treated homozygous mice in comparison with respective wild-type group. Four-day treatment with amphetamine induced a significant increase in the expression of Tyhy in the mesencephalon, striatum and mesolimbic structures of wild-type mice, whereas in homozygous mice a similar change was evident only in the mesencephalon. Also, the expression of Drd1 gene in the striatum and Drd2 gene in the mesolimbic structures of wild-type mice were up-regulated under the influence of amphetamine. In conclusion, the present study established differences in the behavioural effects of amphetamine in wild-type and homozygous mice. The increased tone of dopaminergic projections from the mesencephalon to mesolimbic structures is probably related to increased amphetamine-induced motor sensitization in homozygous mice. The lack of development of up-regulation of Drd1 and Drd2 genes after repeated treatment with amphetamine probably explains the reduced place conditioning in CCK 2 receptor deficient mice.

Sex differences in behavioral effects of cannabinoids

This review summarizes the existing literature on sex differences in the effects of cannabinoid drugs on behavior, primarily in the adult rodent. These preclinical studies, taken together with preliminary reports of sex differences in cannabinoid effects in humans, suggest that sex of subject may be an important modulating factor in a variety of cannabinoid effects. When sex differences are found, females are usually more sensitive than males to cannabinoids. Both pharmacokinetic and pharmacodynamic variables may contribute to sex differences in behavioral effects of cannabinoids. Given the significant therapeutic potential of cannabinoid agonists and antagonists — as well as their widespread recreational use — it will be important to determine the reliability and functional significance of, as well as mechanisms underlying sex differences in cannabinoid effects.

Effects of 4′-Chloro-3α-(diphenylmethoxy)-tropane on Mesostriatal, Mesocortical, and Mesolimbic Dopamine Transmission: Comparison with Effects of Cocaine

Increase in dopamine (DA) neurotransmission resulting from blockade of the DA transporter (DAT) after administration of cocaine is believed to play a major role in mediating its behavioral and reinforcing effects. Since it was hypothesized that drugs that block the DAT have cocaine-like behavioral effects, it was of interest to study in the present article the stimulant effects of cocaine on locomotor activity and on pattern of activation of DA neurotransmission in different DAergic terminal areas in rats and compare these effects with those of 4'-chloro-3alpha-(diphenylmethoxy)-tropane (4-Cl-BZT), a benztropine analog showing higher affinity for the DAT, but reduced behavioral effects compared with cocaine. Administration of cocaine resulted in a dose-dependent stimulation of locomotor activity and DA neurotransmission in the nucleus accumbens shell and core, dorsal caudate, and in the medial prefrontal cortex (PFCX) measured by microdialysis. At comparable doses, the effects of 4-Cl-BZT on DA levels in all brain areas except the PFCX were generally reduced compared with those of cocaine, as were the effects on locomotor activity. The differences in behavioral effects corresponded generally to differences between the drugs with regard to their stimulation of extracellular DA levels, although the mechanism(s) for the differences in extracellular DA may involve effects mediated by sites other than the DAT or differences in the efficiency of the two drugs in blocking DA uptake. Nonetheless, the present results suggest that the differences in behavioral effects between cocaine and 4-Cl-BZT are related to differences in their patterns of activation of DA transmission.

The influence of face similarity in the case of the perception of morphed self-face

The purpose of the study was to examine if differences in behavioral effects in terms of facial self-recognition, compared to other identity recognition (familiar, strange) exist. Morphed versions of three facial identities were used in the experiment. The subject's own face was morphed with an unknown identity. A face of a highly familar person and of a stranger were also morphed in the same manner. This morphing procedure was repeated six times for each identity, but with six different unknown faces, in which three of the unknown faces were rated as being similar and the other three as dissimilar. The reaction times and categorical boundaries were then measured. The major finding of the study was that there were significant delayed mean reaction times for the morphed imges of version "self versus similarly rated unknown faces" in contrast to the images of "self versus dissimilarly rated unknown faces" only. No significant differences were found in any of the other morphed versions. The authors interpret this result as being uniquely associated to the facial self-recognition and suggest that this association might be related to the "self effect."

Synthesis and biological evaluation of 2-substituted 3beta-tolyltropane derivatives at dopamine, serotonin, and norepinephrine transporters.

A series of eight 2-substituted 3-tolyltropane derivatives were synthesized, and the in vitro and in vivo biological activities as dopamine uptake inhibitors were determined. From the in vitro structure-activity data, it is apparent that a tolyl group in the 2-position, independent of the stereochemical attachment to the tropane ring system, provided compounds (9-12, 14) that exhibit high-affinity binding at the dopamine transporter (DAT). Although a slight stereochemical preference in binding affinity at the DAT was observed for the 2beta-(R)-alcohol 10 over the 2beta-(S)-isomer 11, no significant differences in behavioral effects were observed. Furthermore, despite a relatively low potency of 10 for the inhibition of dopamine uptake compared to its affinity for the DAT, its behavioral profile did not vary significantly from cocaine. These data indicate that a behavioral characterization of compounds is a critical feature of efforts to discover pharmacological treatments for cocaine abuse.

Dopamine D1and D2Receptor-Mediated Acute and Long-Lasting Behavioral Effects of Glial Cell Line-Derived Neurotrophic Factor Administered into the Striatum

To determine the differences in behavioral effects between intrastriatal and intracerebroventricular glial cell-derived neurotrophic factor (GDNF) administration, spontaneous locomotor activity was measured after intrastriatal or intracerebroventricular injection of GDNF (10 microg) in normal adult rats with implanted guide cannulae. In addition, the distribution of GDNF after intracerebral injection was studied immunohistochemically. Intrastriatal administration of GDNF significantly increased rearing behavior 3-4 h after injection. Increases in all three aspects of locomotor activity (motility, locomotion, and rearing) were most pronounced 3 days after intrastriatal injection, and they lasted for several days. This hyperactivity was blocked by the selective dopamine D1 receptor antagonist SCH22390 and by the selective D2 receptor antagonist raclopride at doses of the dopamine receptor antagonists, which by themselves did not affect spontaneous locomotor activity. These results suggest that GDNF has both acute and long-lasting pharmacological effects on dopamine neurons in adult animals and stimulates locomotor activity by activating both dopamine D1 and D2 receptors. On the other hand, intracerebroventricular administration of the same dose of GDNF failed to increase locomotor activity at any time during the test period (12 days). The immunohistochemical study demonstrated widespread distribution of GDNF in the entire body of the striatum within 24 h after intrastriatal injection. It also revealed deep penetration of GDNF from the ventricular space into the brain parenchyma after intracerebroventricular injection. GDNF-immunoreactive neuronal cell bodies were seen in the ipsilateral substantia nigra pars compacta most frequently 6 h after intrastriatal injection. The number of such cell bodies after intracerebroventricular administration, on the other hand, was much lower than that seen after intrastriatal administration. Taken together, these data suggest that intrastriatal administration of GDNF is an effective approach for affecting DA transmission. Long-lasting behavior effects are mediated via dopamine D1 and D2 receptors. Higher doses of GDNF would probably be needed using the intracerebroventricular route as compared to intraparenchymal delivery to exert effects on the nigrostriatal system in Parkinson's disease patients.

Cerebral microgyria, thalamic cell size and auditory temporal processing in male and female rats.

Induction of microgyria by freezing injury to the developing somatosensory cortex of neonatal rats causes a defect in fast auditory processing in males, but not in females. It was speculated that early damage to the cortex has sexually dimorphic cascading effects on other brain regions mediating auditory processing, which can lead to the observed behavioral deficits. In the current series of experiments, bilateral microgyri were induced by placement of a freezing probe on the skulls of newborn male and female rats, and these animals were tested in adulthood for auditory temporal processing. Control animals received sham surgery. The brains from these animals were embedded in celloidin, cut in the coronal plane and the following morphometric measures assessed: microgyric volume, medial geniculate nucleus (MGN) volume, cell number, and cell size, and, as a control, dorsal lateral geniculate nucleus (dLGN) volume, cell number and cell size. There were no sex differences in the cortical pathology of lesioned animals. However, microgyric males had more small and fewer large neurons in the MGN than their sham-operated counterparts, whereas there was no difference between lesioned and sham-operated females. There was no effect on dLGN cell size distribution in either sex. Microgyric males were significantly impaired in fast auditory temporal processing when compared to control males, whereas lesioned females exhibited no behavioral deficits. These results suggest that early injury to the cerebral cortex may have different effects on specific thalamic nuclei in males and females, with corresponding differences in behavioral effects.

Reply

Ian Gilron, M.D., F.R.C.P.(C), Pain Research Fellow, Departments of Neurology/Neurosurgery and Anaesthesia, McGill University.Terence J. Coderre, Ph.D., Director, Pain Mechanisms Laboratory, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, Quebec, Canada H2W 1R7.In Reply:-Goto et al. continue an interesting discussion regarding conflicting results among the cited studies. As they reiterate, evidence exists to support the dose dependency of barbiturates on nociceptive behavior. This phenomenon appears to be due to a dose-related progression starting from suppression of descending inhibitory systems (hyperalgesic effect) to suppression of spinal nociceptive mechanisms (analgesic effect). For this reason, differences in behavioral effects of GABAminergic anesthetics that have variable pharmacokinetic/pharmacodynamic (PK/PD) profiles must be interpreted with caution. Goto et al. suggest that, in our study, the lack of analgesic effect with pentobarbital may be due to the possibility that the dose used produced roughly equal suppression of both descending inhibitory and spinal nociceptive systems. Although this is a feasible hypothesis, it should be noted that the purpose of our study paradigm is to measure persistent pain during phase 2, which is thought to be an expression of spinal sensitization produced by noxious stimulation during phase 1. The timing and dosing of drugs used in our study was designed to maximize drug effect during phase 1, in an attempt to prevent spinal sensitization while allowing for anesthetic recovery, so as to eliminate or at least minimize residual drug effect during phase 2. With this in mind, phase 2 pain behavior is interpreted as how effectively the study drug prevented sensitization during phase 1 and less dependent on whether the drug dose was hypnotic or subhypnotic.Although flinch counting and weighted scores behavioral measurement have both been validated and widely used, Goto et al. emphasize the value of qualitative distinction between different pain behaviors in the rat formalin test. This is an interesting idea, because each of these behaviors may be an expression of diverse subjective sensations and may respond differentially to pharmacologic manipulations.Given the obvious difficulties in interpreting pharmacologic effects on experimental pain behavior, it is of vital importance that we enhance such behavioral studies with other concomitant measures, such as PK/PD analyses, electrophysiology, molecular biology, and receptor binding assays. Such strategies may provide additional information regarding specific mechanisms of drug action and further aid in clarifying equivocal behavioral findings.Ian Gilron, M.D., F.R.C.P.(C.), Pain Research Fellow, Departments of Neurology/Neurosurgery and Anaesthesia, McGill University.Terence J. Coderre, Ph.D., Director, Pain Mechanisms Laboratory, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, Quebec, Canada H2W 1R7.(Accepted for publication October 31, 1996.)

Behavioral consequences of neonatal injury of the neocortex

Several strains of autoimmune mice spontaneously develop molecular layer ectopias that are similar in appearance to those seen in humans and are caused by disturbances in neocortical neuronal migration. These mice also exhibit behavioral anomalies, some of which correlate with ectopias, others with the immunological disorder. In this study, we induced neocortical ectopias (via puncture wounds) and microgyria (via freezing lesions) in the neocortex of 1-day-old (newborn) mice without immune disorders in an attempt to further disentangle the effects of autoimmunity and of cortical malformation on behavior. In addition, we wished to compare the behavioral effects of small ectopias to larger microgyric lesions. DBA mice were assigned at birth to receive either a puncture wound or freezing lesion of either the left or right hemisphere. An independent group was subjected to sham surgery. In adulthood, these mice were given a battery of tests designed to measure lateralization and learning capacity. Lesioned mice (irrespective of hemisphere or type of damage) performed poorly when compared to sham-operated animals in discrimination learning, in a spatial Morris Maze Match-to-Sample task, and in a Lashley Type III maze. In shuttlebox avoidance conditioning, where immunological disorder has been shown to compromise behavioral performance in autoimmune mice, there was no difference between lesioned and sham animals. These results (1) support the dissociation between the effects of developmental neocortical anomalies and autoimmune disease on behavior (2) reveal similarities between spontaneous and induced neocortical malformations and (3) fail to support a difference in behavioral effects between ectopias and microgyria.

Pharmacogenetics of cocaine: II. Mesocorticolimbic and striatal dopamine and cocaine receptors in C57BL and DBA mice.

Studies were conducted to determine whether genetic differences in behavioural effects of cocaine in C57BL/6 and DBA/2 mice might be mediated by strain differences in dopamine and serotonin transporters and dopamine D1 and D2 receptors in specific brain regions. Binding characteristics of [3H]CFT, a cocaine analogue, in the presence of either GBR12909, a dopamine uptake blocker or fluoxetine, a serotonin uptake blocker and binding of [3H]-paroxetine, a specific serotonin uptake receptor antagonist, were evaluated. We observed regional differences in [3H]CFT binding parameters in the presence of GBR12909 or fluoxetine, but no strain differences by brain region were observed. There were no differences in [3H]paroxetine binding characteristics between corresponding brain regions from C57BL and DBA/2 mice. The D1 antagonist, [3H]SCH23390 and the D2 ligands [3H]sulpiride or [125I]epidepride were used to determine dopamine receptor characteristics. Regional differences were found in [3H]SCH23390 and [3H]sulpiride, with higher affinities and lower densities in frontal cortex compared to striatum; with no differences in [3H]SCH23390 binding in corresponding tissues from C57BL and DBA/2 brains. There were strain-related differences in [3H]sulpiride and in [3H]epidepride binding in striatal membranes with higher densities in C57BL than in DBA/2. Our findings suggest striatal D2 receptor differences are possibly involved in genetic differences in cocaine-related behaviours.

Acute effects of neuroleptics on unmedicated schizophrenic patients and controls

Acute administration of haloperidol (0.2 mg/kg) produced many more side effects in normal controls than in unmedicated schizophrenic patients. Prior to the neuroleptic challenge, both groups were on the peripheral monoamine oxidase inhibitor, debrisoquin, for at least 1 week, in order to enhance the relative contribution of CNS catecholamine metabolites to those measured in both plasma and urine. The patient group had higher plasma levels of methoxyhydroxyphenylglycol (MHPG) and homovanillic acid (HVA) and higher urinary MHPG output than controls, but there were no effects of haloperidol challenge, compared to placebo challenge. In both groups there were significant declines in plasma HVA levels from 8:30 am to 12 noon. These declines were unaffected by the haloperidol challenge. Explanations for the marked differences in behavioral effects of haloperidol on patients and controls include the possibility that dopamine receptor numbers were increased in the brains of the schizophrenic patients.