The 24th Annual Meeting of the Canadian College of Neuropsychopharmacology: Banff, Alberta, Canada, June 17–20, 2001

The 24th Annual Meeting of the Canadian College of Neuropsychopharmacology (CCNP) was held in Banff, Alberta, June 17–20, 2001. The meeting included contributions from the British Association for Psychopharmacology and the Japanese Society of Neuropsychopharmacology. This report summarizes the 2 plenary lectures, the 3 award lectures and the 7 symposia of this year's annual meeting.

Higher cortical function

Plenary lecture

Dr. Trevor Robbins (Department of Experimental Psychology, University of Cambridge, Cambridge, UK) gave the opening plenary lecture on “Neurotransmitters and higher cortical function.” He described an elegant series of studies, the objective of which was to delineate the roles of frontostriatal dopamine (DA), norepinephrine (NE), serotonin (5-HT) and acetylcholine (ACh) function in the regulation of complex behaviours, particularly working memory, attention and the initiation, inhibition and selection of behaviours appropriate to the environmental context.

Briefly, lesion and microdialysis studies conducted in rats suggest that NE plays an important role in attention and distractibility, DA in latency to respond and interest in appetitive stimuli, ACh in accuracy of responding, and 5-HT in impulse control and ability to inhibit premature responding.

Neurocognitive studies in humans and nonhuman primates support the same transmitter-specific associations. Based on tryptophan-depletion studies and observations in patients with diseases of frontostriatal circuits (e.g., Huntington's disease, Parkinson's disease, untreated attention-deficit hyperactivity disorder [ADHD], obsessive–compulsive disorder, schizophrenia, amphetamine abuse), 5-HT function in this circuit was suggested to regulate the ability to inhibit previously appropriate responses and change behavioural responses. In comparison, these behavioural perturbations (e.g., extradimensional shift deficits) are not seen in patients with temporal lobe lesions, Alzheimer's disease, treated ADHD or heroin dependence.

The role of DA was studied using functional neuroimaging. Working memory tasks increase regional cerebral blood flow in the dorsolateral prefrontal cortex (DLPFC). However, both methylphenidate and L-DOPA improve working memory performance but, intriguingly, decrease DLPFC activation during the task. It was suggested that DA enhances DLPFC efficiency such that less of the region needs to be activated. Finally, the orbitofrontal cortex (OFC) is implicated in the selection of appropriate reward-related behaviours. Participating in a gambling task (i.e., choosing between high-risk high-win versus low-risk low-reward options) activates the OFC, and patients with OFC lesions perform poorly on this task.

The genome and the brain

CCNP Innovations in Neuropsychopharmacology Award lecture

This year, the CCNP Innovations in Neuropsychopharmacology Award went to Dr. Harold Robertson (Department of Pharmacology, Dalhousie University, Halifax, NS), who summarized some of his work under the title “The genome and the brain: toward a neurobiology of brain repair.” He began by pointing out that just over a decade ago, textbooks stated that cells do not divide in the mature brain and that gene expression is determined at the last mitotic division. However, we now know that some cells in the central nervous system (CNS) are capable of division throughout life and that changes in gene expression play a role in gene function throughout life. One of the first significant reports of gene expression in the CNS, in 1987, demonstrated that seizure activity induces an increase in c-Fos protein-like immunoreactivity in granule cells of the rat dentate gyrus. Changes in flux through ion channels lead to changes in messengers. Within minutes, this leads to changes in the expression of immediate early genes (IEG) such as c-fos, which in turn, cause changes in the expression of late response genes, changes in protein synthesis and long-term changes in brain function. IEG expression is altered by many stimuli including pain, DA receptor antagonists and drugs such as cocaine and amphetamine. It is also involved in the regulation of circadian rhythms. However, although IEGs are useful for mapping changes in the brain, there are still questions about their function. Kindling activates c-fos and an antisense oligodeoxynucleotide to c-fos accelerates amygdala kindling, raising the possibility that c-fos expression is part of an attempt by the brain to suppress kindling.

Whereas studies using c-fos and the recently popular gene chip method look for specific changes, a nonbiased way to look at all changes in gene expression is to compare the mRNA displays of control and experimental animals. Genes that are differentially displayed can then be cloned and sequenced. Administration of kainic acid to rats, which causes stroke-like damage, resulted in the expression of a gene in the pyriform cortex only 3 hours after treatment. This gene was found to be a new member of the synaptotagmin family. A similar approach in a mouse model of Huntington's disease (HD) led to the discovery of a new member of the phosphodiesterase family (PDE 10a). Expression of this gene in mice with the HD gene disappears as the phenotype develops. A post-mortem study in humans confirmed that it is lost in HD patients also. Another gene that is expressed less in people with HD and in the mouse model of HD is for the cannabinoid CB₁ receptor.

Dr. Robertson finished by talking about minocycline, an antibiotic that also decreases caspases. Two siblings followed at Dalhousie University inherited the gene for HD; 1 developed severe HD, but the other, who was treated for 16 years with minocycline for severe acne, only has minimal signs of HD. Clinical trials of minocycline in patients with HD are being planned.

Drug abuse

CCNP Heinz Lehmann Award lecture

This year, the CCNP Heinz Lehmann Award went to Dr. Franco Vaccarino (Department of Psychiatry, University of Toronto, Toronto, Ont.), who spoke on “CCK modulation of mesolimbic DA function: a model for the opposing effects of stress on motivated behaviour.” Dr. Vaccarino described an innovative series of studies investigating associations between DA and its colocalized neuropeptide choleocystokinin (CCK). It was suggested that the differential release of these transmitters — possibly related to different cell firing rates — might account for opposing effects of stressors on appetitive motivation, reinforcement and anxiety.

During the past decade, Dr. Vaccarino has tested 3 related hypotheses: (1) DA and CCK might have opposite effects on goal-directed behaviour, (2) activating versus disruptive effects of stressors might be related to DA versus CCK, and (3) individual differences in response to rewards and stressors might be related to inherent differences in DA and CCK transmission.

In support of this model, Dr. Vaccarino's studies indicate that intra-nucleus accumbens (NAC) injections of CCK agonists and antagonists have behavioural effects that are the opposite of those typically produced by ligands for DA receptors. CCK agonists decrease willingness to work for rewards, such as amphetamine and electrical stimulation of the ventral tegmental area (VTA), whereas intra-NAC injections of a CCK antagonist potentiate amphetamine-induced locomotor activity and increase sugar ingestion.

A second hypothesis — that DA and CCK might mediate activating versus inhibiting effects of stressors — was tested by comparing the effects of low- and high-intensity stressors. This was based on evidence that low-intensity stressors might selectively elicit DA release, whereas high-intensity stressors might release both DA and CCK. His studies indicated that low levels of foot shock increased motivation and willingness to work for rewards, such as cocaine or sugar. As predicted by the model, though, above a certain intensity (≥ 2.0 mA), foot shock decreased willingness to work for cocaine or sugar. Additional studies suggest that CCK-induced anxiety might be mediated by effects in the amygdala, whereas effects on reinforcement and motivation might be mediated by effects in the NAC.

The third hypothesis was that individual differences in DA and CCK transmission are related to differential responses to rewards and stressors. Rats exhibiting high mesolimbic DA function were less anxious (i.e., on elevated plus maze and acoustic startle tests) and more active in novel environments and in response to amphetamine challenges, and they self-administered sugar and amphetamine more readily than those exhibiting low DA activity. Moreover, “low DA rats” could be made to behave like “high DA rats” with intra-NAC injections of CCK antagonists; that is, they self-administered more sugar and exhibited potentiated locomotor activity responses to amphetamine.

Together, these results suggest that varying predispositions to release DA and CCK under challenge conditions might be related to vulnerability to anxiety and psychostimulant drug self-administration.

Symposium — Dopamine and drug addiction: studies in rats, nonhuman primates and humans

Dr. Marco Leyton (Department of Psychiatry, McGill University, Montreal, Que.) opened the session with a brief summary of pivotal findings in the DA literature. In the mid-1970s, behavioural studies in rats demonstrated that DA lesions disrupted psychostimulant drug self-administration. During the 1980s, the dominant interpretation of these results was that DA mediated rewarding or pleasurable effects. By the 1990s, the use of tools with fine temporal resolution (e.g., electrophysiological studies of DA cell firing, voltammetry studies of extracellular DA) suggested that DA transmission correlated more closely with the expectation of receiving a reward than with reward, per se. Finally, it was noted that, in humans, neuroleptic drugs have not clearly decreased either the subjective effects or the self-administration of addictive drugs, either in the laboratory or in clinical trials. The primary objective of the symposium, therefore, was to discuss the role of DA, as assessed by studies using new methods and new measures.

Dr. Julie Staley (Department of Psychiatry, Yale University School of Medicine, New Haven, Conn.) talked about “In vitro and in vivo imaging of the DA synapse in human cocaine abusers.” She presented results from studies using post-mortem brain tissue and functional neuroimaging. Compared with post-mortem tissue from individuals with no history of psychopathology, those with a history of cocaine dependence who died after a cocaine overdose had elevated striatal DA transporters (DAT) and D₃ receptor densities and lower D₁ receptor densities. D₂ receptors and total tissue concentrations of DA and its metabolites homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were unchanged.

Functional neuroimaging studies with SPECT suggest that amphetamine-induced changes in synaptic DA levels are less pronounced in people with a history of cocaine dependence than in healthy controls. The possible mechanisms mediating this effect — decreased amphetamine-induced release of DA or reuptake blockade and increased DAT-mediated reuptake — were discussed.

Dr. Roberta Palmour (Department of Psychiatry, McGill University) spoke on “Dopamine in a vervet monkey model of alcohol abuse: a complex relationship.” Her work suggests that in vervet monkeys, as in humans, there is substantial individual variability in alcohol self-administration. Approximately 20% of vervet monkeys drink abusively, typically in intense binges, which lead to marked motor impairment and loss of consciousness. In these monkeys, there appears to be both pre-existing dopaminergic vulnerability traits and developmental changes that occur after repeated alcohol use.

Acute ethanol administration increases cerebrospinal fluid (CSF) concentration of HVA. In alcohol-naive monkeys, low CSF HVA responses to alcohol predict high levels of self-administration later in life. Alcohol self-administration can be altered by treatments that affect DA transmission. For example, acute phenylalanine and tyrosine depletion decreased both catecholamine synthesis (as assessed by decreased CSF concentrations of HVA and 3-methoxy-4-hydroxyphenylglycol) and alcohol self-administration. In comparison, buspirone increased both CSF HVA and self-administration, and the direct D₂ agonist, bromocriptine, decreased self-administration.

Dr. Anthony Phillips (Department of Psychiatry, University of British Columbia, Vancouver, BC) talked about “Factors related to relapse in drug-seeking behaviour: a preclinical perspective.” He reported studies of mechanisms that mediate relapse to psychostimulant drug self-administration. When provided with unlimited access to intravenous amphetamine, rats self-administer in binges, and these binges are separated by periods of abstinence. During the period of abstinence, a free “priming” injection of amphetamine neither increases dialysate concentrations of DA in the striatum nor reinstates self-administration. In comparison, electrical stimulation of the ventral subiculum/ventral hippocampus increases extracellular DA levels and elicits drug self-administration. The same effect is seen when animals have ceased self-administration due to extinction training. The effect is prevented by coadministration of a D₁ receptor antagonist and an NMDA antagonist, but neither treatment alone is effective. These observations raise the possibility that treatments targeting both D₁ receptors and NMDA binding sites might be more effective than neuroleptics alone.

Dr. Leyton's talk was titled “Dopaminergic mechanisms and substance abuse: studies in healthy volunteers.” He reported results from recent acute phenylalanine and tyrosine depletion (APTD) and positron emission tomography [¹¹C]raclopride studies. The results suggest that, in healthy humans, addictive substances across drug classes (e.g., d-amphetamine, ethanol) increase synaptic DA levels, with preferential effects in the ventral striatum and nucleus accumbens. Preliminary studies suggest that APTD decreases alcohol self-administration, subjective and behavioural effects of d-amphetamine and d-amphetamine-induced [¹¹C]raclopride displacement and DA release. By assessing which effects of APTD are prevented by the immediate DA precursor L-DOPA, it might be possible to distinguish between effects that are best attributed to DA versus NE. The data suggest that mood-elevating and excitatory effects of amphetamine might be best attributed to NE, whereas the reinforcing effects (e.g., the learned association between a behaviour and a reward) might be more closely related to DA. A role of NE in subjective effects of psychostimulants may account, in part, for the lack of clinical efficacy of neuroleptics.

Symposium — Endocannabinoids, cannabinoids and behaviour

The first speaker in this session, Dr. Charles A. Marsden (University of Nottingham, Nottingham, UK), spoke about “Cannabinoids, past, present and future.” Delta-9-tetrahydrocannabinol (THC) and other cannabinoids act on cannabinoid (CB) receptors, which are present throughout the body and are normally engaged by a family of endogenous lipids referred to as endocannabinoids (e.g., anandamide and 2-arachidonlyglycerol [2-AG]). Activation of the CB receptor inhibits adenylate cyclase though the action of a G-protein. CB₁ receptors are present in the brain and certain peripheral sites, whereas CB₂ receptors are peripheral and regulate immune function. The distribution of receptors in the brain reflects the known functions of cannabinoids. CB₁ receptors are present in the hippocampus and dentate gyrus (effects on memory and cognition), the basal ganglia (movement control and ataxia), the amygdala and periaqueductal grey (pain perception) and the cerebellum (motor function). Interestingly, low densities are found in the NAC and the VTA, which are involved in reward and dependence. CB agonists have marked effects on regional cerebral blood flow, as measured by functional magnetic resonance imaging in rats, in the VTA, periaqueductal grey and dentate gyrus; there is poor activation in the NAC and amygdala. Effects on the periaqueductal grey are presumably related to pain perception, whereas the effects on the VTA, where CB receptor density is low, would support an influence on reward systems.

Cannabinoids have several acute effects in humans. Impaired attention, memory and psychomotor function are usual, and anxiety and panic occurs in some naive users. There is also an increased risk of psychosis in vulnerable people. The existence of a cannabis dependence syndrome in humans remains controversial. In animals, activation of CB₁ receptors can cause reward in some circumstances and aversion in others, and CB antagonist administration can cause a withdrawal syndrome in animals previously treated with cannabinoids.

Dr. Richard J. Beninger (Queen's University, Kingston, Ont.) talked about “Cannabinoids and reward.” Some animal studies report that cannabinoids produce place preference, whereas others demonstrate place aversion. Sometimes, pre-exposure will change place aversion to place preference; however, reports of inverted U-shaped dose–response curves are common — a confusing picture overall. About one-third of the studies in monkeys and two-thirds of studies in rats have demonstrated self-administration of cannabinoids, usually only at low doses.

Consistent with this, electrophysiological studies have shown that cannabinoids can activate DA neurons, and intracerebral dialysis has shown enhanced DA release in the prefrontal cortex, NAC and striatum. Antagonists of CB receptors block the rewarding effect of food and place conditioning with cocaine and morphine. Conversely, opiate antagonists block the enhanced release of DA in the NAC caused by THC.

Dr. Daniele Piomelli (University of California, Irvine, Calif.) presented on “The endocannabinoid system as a target for neuropsychiatric medications.” Although delta-9-THC is the most important cannabinoid, about 400 others are present in cannabis plants. The situation in the brain is also complex. In addition to anandamide and 2-AG, another endocannabinoid, palmitylethanolamide, is present in the brain. It is analgesic, but does not bind to CB₁ or CB₂ receptors, suggesting the existence of another similar receptor. The endocannabinoids are cleaved from membrane precursors and act on the same neuron or presynaptically as a retrograde neurotransmitter. They are inactivated by facilitated diffusion into neurons or glia and then intracellular hydrolysis. Uptake inhibitors such as AM404 may have therapeutic potential.

Anandamide may act in the negative feedback of dopaminergic function — DA causes release of anandamide, which then antagonizes DA function. One report suggests that anandamide, but not 2-AG, is elevated in the CSF of patients with schizophrenia, and on treatment with antipsychotic drugs, anandamide levels return to normal. The elevated anandamide levels may be an attempt to downregulate dopaminergic function.

The final speaker, Dr. Judy A. Pratt (University of Strathclyde, Glasgow), talked about the “Psychopharmacology of cannabinoids: from neural circuits to gene expression.” She pointed out that, as with other dependence-producing drugs, cannabinoids increase DA release but can sometimes be aversive. She suggested that distinct neural circuits are recruited after low and high doses of THC. Changes in neural activity in rat brain were mapped using 2-deoxyglucose. In several areas, a low dose of THC caused a small increase in glucose utilization, but a high dose decreased glucose utilization. This was true for areas involved in sensory processing (medial geniculate, superior colliculus), sensory-motor function (substantia nigra, ventromedial thalamus, somatosensory cortex) and memory (hippocampus). A high dose of THC (associated with a decrease in open field activity), but not a low dose, induced immediate early gene (IEG) expression in the caudate and putamen. Moreover, repeated administration of a low dose of THC (motor stimulatory), which may be more relevant to addictive processes, decreased mRNA for the glutamate AMPA receptor GluR1 subunit in the prefrontal cortex, but not in the hippocampus. The functional significance of this is not yet known, however.

Overall, the symposium produced an interesting picture of the similarities and differences between different doses of THC and between THC and other drugs of abuse. The current picture is confusing, but there are a variety of interesting leads for future research.

Symposium — Psychopharmacology of ecstasy

The first speaker in the symposium on ecstasy, Dr. Una McCann (Department of Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, Md.), reviewed some of the data on the neurotoxicity of the drug. In squirrel monkeys, there is a chemical axotomy of the 5-HT neurons that leaves the cell bodies intact. With high doses of ecstasy, the depletion of 5-HT terminals can be as high as 90%. The axons seem to regenerate somewhat, although not to more distant terminal areas such as the cortex, where deficits are seen even 7 years after treatment. To date, all animal species studied have shown a neurotoxic effect of ecstasy, and neurotoxic doses in squirrel monkeys approach those used by humans. In studies on humans who have used ecstasy at least 25 times, levels of the 5-HT metabolite 5-hydroxyindoleacetic acid in CSF are markedly low, although levels of the DA and NE metabolites are unchanged. Levels of the 5-HT transporter, as assessed by positron emission tomography, were low in the brains of ecstasy users, and the loss of the transporter was related to the number of times the subject reported using ecstasy. Although these studies are consistent with the animal studies, they are limited by the retrospective reports of drug use, polydrug use by many ecstasy users and the possibility that the deficits may pre-exist ecstasy use.

Dr. Andy Parrott (Department of Psychology, University of East London, UK) spoke on “Cognitive, psychobiological and psychiatric deficits in recreational ecstasy (MDMA) users: neuropharmacological implications.” Ecstasy users have memory deficits, specifically in immediate and delayed word recall, but performance in several other cognitive tests is unimpaired. Tests done on ecstasy users as they enter clubs and during their time in the club demonstrate that the memory impairments present before they enter a club are present in the club when they are taking the drug. On the other hand, impairments in visual scanning are present only while taking ecstasy in the club. The memory deficits are not explained by polydrug use, cannabis use or merely attending raves without using drugs. Cannabis causes short-term memory deficits, but the deficits with ecstasy are long lasting. Studies on other problems in ecstasy users are not entirely consistent, but ecstasy use does seem to be associated with obsessionality, anxiety, hostility, paranoid ideation, psychoticism and eating disorders.

Dr. Barbara Sahakian (Department of Psychiatry, University of Cambridge) continued on a similar theme, talking about “Cognitive dysfunction in amphetamine, ecstasy and opiate abusers.” Ecstasy abusers did a test battery designed to detect lesions in different brain areas. Impairment of pattern recognition suggested temporal lobe damage, whereas impairments in a spatial working memory task and in search strategies indicated a frontal and temporal pattern. Heroin and amphetamine users, like ecstasy users, show impairments of pattern recognition (temporal lobe). In the Wisconsin Card Sort Test, amphetamine users have problems with problem solving and shifting cognitive sets, whereas heroin users demonstrate an inability to generalize. In a decision-making task, amphetamine users, but not opiate users, are impaired, suggesting orbitofrontal cortex damage. A similar deficit can be elicited in healthy subjects using acute tryptophan depletion, which lowers brain 5-HT levels. Some of the cognitive impairments in drug abusers may reduce their ability to participate in rehabilitation programs.

Dr. Kathleen Hegadoren (Faculty of Nursing, University of Alberta, Edmonton, Alta.) closed the symposium with her talk on “3,4-Methylenedioxymethamphetamine (MDMA): defining the neuropsychopharmacological risk to humans.” She started by emphasizing the complexity of ecstasy use in humans, given that a wide range of doses and drug combinations are used. Studies on tablets sold as “ecstasy” show that they do not all contain the main putative active ingredient MDMA. A common component of ecstasy tablets is dextromethorphan. Furthermore, a variety of other amphetamine analogs have effects that overlap with those of ecstasy. The acute effects of ecstasy include increases in tactile sensations, mood, desire for social contact, motor activity and temperature, as well as neuroendocrine effects. After-effects, which can occur up to 5 days after use, include decreased mood and appetite, restlessness, muscle aches, generalized fatigue and disturbances in sleep and concentration. Some users take fluoxetine to overcome lowered mood. The acute toxicity of ecstasy is enhanced by the high ambient temperatures at raves, where hyperthermia and dehydration can occur. In animals, controlling ambient temperatures has a protective effect. Other acute toxic effects include blood pressure instability, rhabdomyolysis and disseminated intravascular coagulopathy, all of which tend to be resistant to supportive therapies. Psychiatric sequelae include panic disorder and generalized anxiety disorder, depression and suicide, and paranoia. Although the abuse potential of ecstasy is low in the young adult experimenter, it is moderate in the socially unsure and high when ecstasy is used with other drugs.

Schizophrenia

Plenary lecture

Dr. Pat Levitt (Department of Neurobiology, University of Pittsburgh, Pittsburgh, Pa.) gave a lecture entitled “Gene profiling of neuropsychiatric diseases: Is schizophrenia a disease of the synapse?” He began by reviewing some rather robust findings in schizophrenia research, namely, a reduction in grey matter and cortical thickness and increased cell packing density in the face of normal cell numbers. He then presented data from his studies on gene expression profiling in the DLPFC of post-mortem brains of normals and those who were diagnosed with schizophrenia. Using cDNA microarrays (gene chip) containing 8 000–10 000 known genes, he observed significant decreases in a number of genes related to presynaptic function (e.g., synapsin, N-ethymaleimide sensitive factor [NSF], regulator of G-protein signalling 4 [RGS4]). Although the pattern of changes in presynaptic genes varied across subjects, most marked reductions were seen in NSF and RGS4 genes; these were also replicated by further in situ hybridization studies. Monkey studies showed that these genes are not altered by haloperidol, suggesting that the changes seen in schizophrenia are unlikely to be due to medication history. RGS4, a GTPase-activating protein associated with Gi, Go and Gq, regulates responsiveness of neurons to signals from G-protein-coupled receptors. Thus, the findings suggest a fundamental problem of synaptic transmission in schizophrenia. Whether these gene changes reflect primary genetic abnormalities or molecular adaptations in the disease is unclear at present.

Levitt concluded the talk by advancing the hypothesis that schizophrenia is a disorder of the synapse, with a developmental origin. He proposed that impaired mechanics of synaptic transmission in specific neural circuits during childhood or adolescence might cause altered synapse formation, pruning or both. The distinct patterns of clinical expression and course of the disease may reflect the heterogeneity of the gene defects and molecular adaptations.

CCNP Young Investigator Award lecture

This year the CCNP Young Investigator Award went to Dr. Ridha Joober (Department of Psychiatry, McGill University) who spoke on “Genetics of schizophrenia: from animal models to clinical studies.” He described genetic association studies in schizophrenia and the use of recombinant congenic lines of mice to search for genes responsible for behavioural traits relevant to schizophrenia. Joober first highlighted the problems associated with studying the genetics of complex disorders, including the heterogeneity of symptoms, lack of diagnostic tests and complex inheritance patterns. His own studies have used relatively homogeneous phenotypes within schizophrenia such as patients who are neuroleptic responders (R) and those who are nonresponders (NR). Genetic association studies in these subgroups reveal the possible involvement of several genes. For example, NR patients show 5-HT_2A receptor allele 2 and they have increased frequency of homozygosity with respect to the D₃ receptor gene. Further, the methylenetetrahydrofolate reductase gene presents with increased frequency in the genotype valine/ valine in the responders. The shorter allele of a CAG repeats containing the gene GT1 shows an association with the responders as well as with pattern of symptom severity. Further, dopamine β -hydroxylase and dopamine transporter 1 genes do not seem to be associated with schizophrenia, but low activity of the catechol-O-methyltransferase gene was found to be associated with more perseverative errors in patients. Mapping quantitative trait loci (QTL) in congenic mice shows several loci associated with prepulse inhibition of startle (PPI). One of these loci contains a gene for a G-protein-coupled receptor kinase. As PPI is considered to be a stable trait in schizophrenia, QTL mapping may be a profitable area of research in the quest to identify schizophrenia gene(s).

Symposium — New findings and new antipsychotics in schizophrenia

Dr. Donald Addington (Department of Psychiatry, University of Calgary, Calgary, Alta.) presented a review of published studies and meta-analyses examining the impact of new atypical antipsychotic drugs (e.g., olanzapine, risperidone, quetiapine, ziprasidone and zotepine) on the symptoms and course of schizophrenia. Data from the large meta-analyses of Leucht et al (1999) and of Geddes et al (2000) were presented. Although the effect sizes were small, treatment with new antipsychotics resulted in better outcomes for both positive and negative symptoms. Addington also pointed out that the advantages of atypical antipsychotics are seen when compared with placebo or high doses of haloperidol, a typical antipsychotic; however, these advantages tend to disappear when compared with a low dose (< 12 mg/day) of haloperidol. Newer antipsychotics also show benefits in treating neurocognitive abnormalities and depressive symptoms in schizophrenia, but further studies are needed. He also noted that the assessment of the course of schizophrenia, in particular episodes of relapse, is another underinvestigated area of research, though recent data support better efficacy of the new antipsychotics vis-à-vis placebo or haloperidol.

Dr. Lakshmi Voruganti (Department of Psychiatry, University of Western Ontario, London, Ont.) addressed the mechanisms of unpleasant subjective experiences of patients taking antipsychotic medications. The unpleasant experiences, termed neuroleptic dysphoria, are partly responsible for the low rates of treatment compliance with typical antipsychotics. He noted that, compared with typical antipsychotics, the novel antipsychotic drugs, especially the ones with 5-HT and DA-blocking properties, have improved subjective tolerability. He advanced the hypothesis that DA blockade causes dysphoria, and that dysphoria is not universal with all antipsychotic drugs, with variation in DA activity determining subjective responses. He studied 12 drug-free patients with schizophrenia, half with and half without a history of dysphoria, for DA activity and subjective experiences after α -methyl-p-tyrosine (AMPT, an inhibitor of catecholamine synthesis) ingestion. The dysphoric group showed little reduction in DA activity with AMPT and a larger increase in dysphoria than the nondysphoric group. The nondysphoric group showed greater DA reductions, suggesting that DA activity is inversely correlated with dysphoria.

Dr. George Awad (Department of Psychiatry, University of Toronto) presented data that showed the superiority of new antipsychotics (e.g., risperidone, olanzapine, quetiapine) in terms of subjective tolerability, frequency of neuroleptic dysphoria and impact on quality of life. Dr. Awad observed marked differences between patients taking conventional and atypical antipsychotics on the Drug Attitude Inventory (DAI) scale he developed. When patients switched from conventional antipsychotics to the atypicals, improved dysphoric response, DAI and quality of life were noted.

Dr. Ruth Dickson (Department of Psychiatry, University of Calgary) discussed the impact of new antipsychotics on health economics. She began by noting that the economic burden of schizophrenia in Canada stood at $2.35 billion in 1996, with approximately $1.1 billion in direct medical costs and another $1.2 billion in lost productivity. Indirect costs of schizophrenia (e.g., distress to family, caregivers, quality of life) are difficult to quantify. Interestingly, the cost of medications is only $48 million (i.e., 2% of the total or 4% of the direct cost of the disease). On a pill-by-pill basis, the new antipsychotics have higher acquisition costs than older drugs, but when considered in relation to the number of days spent in the hospital, the new drugs save money. For example, hospital days of patients taking clozapine or risperidone are 38% lower than for those taking typical antipsychotics. She concluded by saying that atypical drugs can reduce the cost of hospitalization and indirect costs of schizophrenia.

Mood disorders

Symposium — Neurosteroids, sigma ligands and mood

Dr. Rémi Quirion (Douglas Hospital Research Centre, Montreal, Que.) presented an overview of the field of sigma receptors. He discussed the heterogeneity of sigma receptor subtypes and their distribution in the brain. The availability of newer, more specific ligands is useful in defining the roles of specific sigma receptors. The possible usefulness of sigma ligands in mood disorders was also highlighted.

Dr. Masashi Sasa (Department of Pharmacology, Hiroshima University, Hiroshima, Japan) presented his studies on the effects of a novel sigma ligand OPC-24439 on neuronal activity in the CA1 area of the hippocampus. OPC-24439 inhibited the population spike induced by stimulation of scheffer collaterals in a concentration-dependent manner, and this inhibition was antagonized by haloperidol. OPC-24439 also inhibited spontaneous firing and scheffer collateral-induced excitatory postsynaptic potentials of CA1 neurons without affecting the resting membrane potential. Depolarization-induced firing was also inhibited by OPC-24439, but glutamate-induced depolarization was unaffected. His results suggest that OPC-24439 elevates the threshold for opening NA channels to subsequently reduce neurotransmitter release from nerve terminals, thereby inhibiting neuronal activities in the CA1 area.

Dr. Guy Debonnel (Department of Psychiatry, McGill University) presented data suggesting important regulation of serotonergic transmission by sigma ligands and neurosteroids. Short- and long-term administration of the selective sigma1 ligands 4-IBP and (+)-pentazocine dose-dependently increased the firing of 5-HT neurons in the dorsal raphe nucleus (DRN). These effects were blocked by NE-100, a selective sigma1 antagonist. Neurosteroids represent potential endogenous sigma1 ligand(s). In pregnancy day 17, rats show an increase in firing activity of serotonergic neurons in the DRN, which parallels the rise in progesterone, not estrogen. A metabolite of progesterone, 5-β -pregnane-3,20-dione increased the firing rate after 7 days of treatment. This was not blocked by NE-100 and therefore may not be mediated by sigma receptors. His studies suggest that sigma ligands and neurosteroids could have antidepressant effects through atypical mechanisms.

Dr. Toshitaka Nabeshima (Department of Neuropsychopharmacology, Nagoya University, Nagoya City, Japan) discussed the roles of neuroactive steroids, in particular, dehydroepiandrosterone (DHEAS) and sigma ligands on stress responses in animals. DHEAS has antidepressant effects in the forced swimming test. The sigma ligands (+)-SKF 10047 and dextromorphan attenuated the conditioned fear response in mice (blocked by NE-100), whereas (+)-pentazocine and DTG had no effect. Similarly, the conditioned fear response was attenuated by DHEAS and PREGS in stressed mice, which was blocked by NE-100 or progesterone (sigma1 antagonists). SKF and DHEAS showed additive effects when combined. Blocking progesterone synthesis with trilostane attenuated the conditioned fear response. DHEAS also prevented apoptosis induced by conditioned fear. Thus, DHEAS may be a novel therapeutic agent in at least some mood disorders.

The future

Symposium — CCNP Travel Awardees

The symposium “CCNP Travel Awardees” consisted of 6 short talks from research trainees who had submitted the best abstracts.

The first speaker was Lana Depatie (Douglas Hospital Research Centre, Montreal) whose talk was entitled “Nicotine improves behavioural risk markers of schizophrenia.” She gave nicotine to patients with schizophrenia and controls and found it improved attention in patients but not controls and improved oculomotor (pursuit and antisaccade) performance in both patients and controls. This is consistent with the idea that nicotinic ACh function plays a role in the pathophysiology of some symptoms of schizophrenia.

Lenka Zedkova (Department of Psychiatry, University of Alberta) studied “Serum cortisol and flumazenil-induced panic.” She looked at panic symptoms and serum cortisol levels in response to the benzodiazepine antagonist flumazenil in patients with panic disorder, and with depression and in healthy controls. Panic patients exhibited a higher frequency of flumazenil-induced panic attacks. Flumazenil, relative to placebo, did not increase serum cortisol in any of the groups. These data support the greater sensitivity of patients with panic disorder to flumazenil. However, given that a reduction in GABA function would be expected to activate the HPA axis, the investigators question whether flumazenil induces panic by acting as a benzodiazepine inverse agonist.

Michele Ulrich (Department of Psychiatry, University of Alberta) talked on “Effects of dextroamphetamine, lithium chloride, sodium valproate and carbamazepine on platelet [Ca²⁺].” Giving amphetamine to healthy volunteers had no effect on basal or agonist-induced platelet [Ca²⁺]. However, amphetamine, lithium, valproate and carbamazepine added to platelets in vitro increased basal [Ca²⁺] concentrations, and thrombin and 5-HT-induced increases of platelet [Ca²⁺] concentrations were enhanced by giving carbamazepine in vitro. Thus, mood stabilizers can increase intracellular calcium concentrations.

Ariel Ase (Département de physiologie, Université de Montréal) talked about “Changes in density of 5-HT transporter (5-HTT) in the brain of 5-HT_1A and 5-HT_1B knockout (KO) mice and of 5-HT innervation in the 5-HT_1B knockout.” In 5-HT_1A KO mice, 5-HT_1B receptors were unchanged, and in 5-HT_1B KO mice 5-HT_1A receptors were unchanged. 5-HTT was low in some areas in both, but was increased in the ventral hippocampus and amygdalo-hippocampal nucleus of the 5-HT_1B KO. Measurements of axonal length and number of axonal varicosities revealed that increases but not decreases in the 5-HTT were associated with increased 5-HT innervation. Thus, 5-HT_1B receptors may have negative effects on 5-HT neuron growth.

Steven Szabo (Department of Psychiatry, McGill University) continued on the theme of 5-HT receptors and spoke on “Serotonin receptor effects on NE neuron firing are mediated though excitatory amino acid and GABA_A receptors.” A complex series of experiments in the rat demonstrated that a 5-HT_1A receptor antagonist attenuates firing of NE neurons by blocking inhibitory 5-HT_1A receptors on glutamate neurons, thereby enhancing glutamate release and activating kainate receptors on 5-HT terminals. The ensuing increased 5-HT release then acts on excitatory 5-HT_2A receptors on GABA neurons that are ultimately responsible for the GABA_A-mediated inhibition of NE neurons.

Glen Wunderlich (Department of Psychology, University of Toronto) gave a talk entitled “Novelty-induced locomotion is attenuated by nucleus accumbens CCK_A receptor antagonism only in rats previously exposed to chronic amphetamine.” He demonstrated that a CCK_A receptor antagonist injected into the nucleus accumbens of rats attenuated the locomotor response to a novel environment. This effect was seen in animals previously treated with amphetamine, which sensitizes them to the novel environment, but not in amphetamine naive animals. These results suggest that repeated stimulant treatment augments the contribution of endogenous CCK to mesolimbic DA-mediated behaviours.

David Bush (Department of Psychology, University of Toronto) gave a talk entitled “Individual differences in anxiety on the elevated plus maze are predictive of progressive ratio self-administration of intravenous cocaine.” Rats differ greatly in their propensity to self-administer cocaine. Rats were screened on the elevated plus maze because cocaine can induce anxiety. High explorers (low anxiety) showed a greater propensity than low explorers (high anxiety) to self-administer cocaine. Rats who liked sugar feeding more also showed less anxiety and a greater propensity to self-administer cocaine. Thus, high levels of anxiety may suppress the rewarding effects of cocaine.

Overall, the talks were characterized by sophistication in presentation skills and experimental approaches used and a wide range of research topics. The future of the CCNP is obviously secure.