- Email: [email protected]
S.04.07 Could nicotine potentiate the beneficial effects of levodopa in the 6-OHDA rat model? A behavioural study
S162
S.04. Hot Topics 1
S.04.05 Effects of repeated treatment of phencyclidine in cognition, emotional activity and gene expression in C57BL/6J mice S. Beraki1 ° , R. Diaz-Heijtz1 , F. Tai1 , S.O. Ogren1 . 1 Karolinska Institutet, Department of Neuroscience, Stockholm, Sweden A number of studies indicate that glutamatergic NMDAneurotransmission is disturbed in schizophrenia. This hypothesis is partly based on the findings with the NMDA-receptor antagonist phencyclidine (PCP), which reproduces a schizophrenia-like syndrome in both humans and rodents (Javitt and Zukin, 1991). This study investigated whether repeated administration of low doses of PCP could produce long-term effects on cognitive and social behavior, related to alterations in gene expression of two genes, Arc and spinophilin. These genes are involved in neuronal plasticity and learning. Adult male C57Bl/6J mice received daily s.c. doses of PCP (0.5−2.0 mg/kg) or saline for 7 days and testing was performed 24 h after the last day of treatment. Only the 2.0 mg/kg dose of PCP produced a consistent impairment in spatial learning and working-memory performed in the watermaze task without any apparent sensorimotor deficits. The PCP-treated mice spent less time in active social interaction but increased non-social behavior when examined 24 h after the last treatment. PCP-treatment also suppressed rearing and sniffing substrate and induced an increase in aggressive behavior. The mRNA level of Arc was upregulated in the hippocampus and retrosplenial agranular cortex while spinophilin was downregulated in striatum by repeated treatment of PCP. These results demonstrate that repeated treatment with low doses of PCP in mice can produce a prolonged impairment in spatial learning, long-term, and working memory. Repeated PCP treatment also affects social interaction and emotional behavior. Furthermore, these effects were associated with altered gene expression in the corticohippocampal pathway and in the striatum. References [1] Javitt, D.C. Zukin, S.R., 1991. Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 148, 1301–1308.
S.04.06 A role for the opioid system in endocannabinoid-mediated fear-conditioned analgesia in rats R.K. Butler1 ° , K. Rea1 , Y. Lang1 , D.P. Finn1 . 1 National University of Ireland Galway, Department of Pharmacology and Therapeutics NCBES Neuroscience Cluster and Centre for Pain Research, Galway, Ireland The opioid (Helmstetter and Fanselow, 1987) and endocannabinoid (Finn et al., 2004) systems independently mediate analgesia expressed upon re-exposure to a contextually aversive stimulus (fear-conditioned analgesia; FCA) and activate the mitogenactivated protein kinase (MAPK) pathway. However, an interaction between the opioid and endocannabinoid systems during FCA has not been investigated at the behavioural or molecular level. Here we investigated the effects of pharmacological blockade of mu-opioid, CB1 and CB2 receptors on FCA in the presence or absence of the fatty acid amide hydrolase (enzyme which degrades the endocannabinoid anandamide) inhibitor, URB597. FCA was modelled in rats as described previously (Finn et al., 2004; Roche et al., 2007) with Western blotting for phospho-ERK1/2 carried
out on amygdaloid tissue. URB597 (0.3 mg/kg. i.p) enhanced expression of FCA. mu-opioid receptor blockade with naloxone attenuated FCA and the URB597-induced enhancement of FCA. SR141716A (CB1 antagonist) and SR144528 (CB2 antagonist) also attenuated the URB597-mediated enhancement of FCA. Additional results demonstrated an inverse correlation between duration of pain behaviours and the duration of fear behaviours. Expression of FCA was associated with increased pERK2 expression in the amygdala, an effect blocked by naloxone, SR141716A, and SR144528. Furthermore, URB597-mediated enhancement of FCA was associated with reduced pERK1 and pERK2 in the amygdala. These data suggest that endocannabinoid-mediated enhancement of FCA requires a functionally active mu-opioid receptor. Both pharmacological enhancement (with URB597) and attenuation (with naloxone) of this form of endogenous analgesia were associated with reduced phosphorylation of ERK1/2 in the amygdaloid complex. References [1] Finn, D.P., Beckett, S.R., Richardson, D., Kendall, D.A., Marsden, C.A., Chapman, V., 2004, Evidence for differential modulation of conditioned aversion and fear-conditioned analgesia by CB1 receptors. Eur J Neurosci, 20, 848−52. [2] Helmstetter, F.J., Fanselow, M.S., 1987, Effects of naltrexone on learning and performance of conditional fear-induced freezing and opioid analgesia. Physiol Behav 39, 501−5. [3] Roche, M., O’Connor, E., Diskin, C., Finn, D.P., 2007, The effect of CB(1) receptor antagonism in the right basolateral amygdala on conditioned fear and associated analgesia in rats. Eur J Neurosci 26, 2643−53.
S.04.07 Could nicotine potentiate the beneficial effects of levodopa in the 6-OHDA rat model? A behavioural study J.P. Guilloux1 ° , R. Massart1 , A.N. Samaha2 , V. Mignon1 , 1 Centre de Psychiatrie et de J.M. Arrang1 , J. Diaz3 . Neurosciences – Broca – Sainte-Anne, INSERM U894 – Laboratoire de Neurobiologie et Pharmacologie Mol´eculaire, Paris, France; 2 Centre for Addiction and Mental Health, Schizophrenia Program, Toronto, Canada; 3 Facult´e de Pharmacie Universit´e Descartes Paris5, UMRs 573 INSERM, Paris, France Epidemiological studies found that Parkinson’s disease (PD) is less prevalent in smokers suggesting a neuroprotective effect of nicotine. Furthermore, nicotine administration seems to protect against toxin-induced striatal dopamine depletion in various animal models of PD (Visanji et al., 2006, Quik et al., 2006). However, a few studies have evaluated the potential therapeutic effects on motor impairment of nicotine given alone or in combination with levodopa (treatment of reference of PD). Thus, we observe if nicotine can exert a beneficial effect on motor impairment, after lesion of the nigrostriatal tract in the unilateral 6-OHDA-lesion model of PD in rat. Lesioned rats were administered a low dose of levodopa (3 mg/kg/d, i.p.), or nicotine (1 mg/kg/day, s.c. using osmotic minipumps) or their co-administration for 14 days. Motor deficits and effects of treatment were assessed using the “Forelimb Stepping Test” and “Spontaneous Limb-Use Asymmetry Test”. In the Forelimb Stepping Test, DA-denervation caused a significant impairment in the performance of the contralateral limb (p < 0.001). A chronic treatment of nicotine or levodopa or coadministration progressively increase the number of adjusting steps of the impaired limb 14 days after the onset of treatment
S.05. TEM symposium – Cognitive impairment in affective disorders: a potential treatment target? (p < 0.001). In the Spontaneous Limb-Use Asymmetry Test, nicotine or levodopa given alone increase the number of contacts of the impaired limb with the cylinder (p < 0.05). Furthermore, nicotine potentiate the effects of levodopa in this test (p < 0.05). These overall results show that nicotine display anti-parkinsonian properties in the unilateral 6-OHDA-lesion rat model of Parkinson when given alone and could potentiate the effects of a low dose of levodopa. References [1] Quik, M., Parameswaran, N., McCallum, S.E., Bordia, T., Bao, S., McCormack, A., Kim, A., Tyndale, R.F., Langston, J.W., Di Monte, D.A., 2006, Chronic oral nicotine treatment protects against striatal degeneration in MPTP-treated primates. J Neurochem 98, 1866−75. [2] Visanji, N.P., O’Neill, M.J., Duty, S., 2006, Nicotine, but neither the alpha4beta2 ligand RJR2403 nor an alpha7 nAChR subtype selective agonist, protects against a partial 6-hydroxydopamine lesion of the rat median forebrain bundle. Neuropharmacology 51, 506−16.
S.04.08 Adolescent cannabinoid exposure induces sex dependent alterations in adulthood: behavioural and biochemical evidences N. Realini1 ° , D. Braida2 , S. Guidi3 , V. Capurro2 , T. Rubino1 , R. Bartesaghi3 , D. Parolaro1 . 1 University of Insubria, Dep.of Funct. and Struct. Biol., Busto Arsizio (Varese), Italy; 2 University of Milan, Dep.of Pharmacology, Milan, Italy; 3 University of Bologna, Dep.of Human and General Physiology, Bologna, Italy Marijuana is the illicit drugs most frequently used by human adolescents [1]. This work studied in rats the long-term consequences of adolescent consumption of D9 tetrahydrocannabinol (THC) on emotional and cognitive parameters. Adolescent male and female rats (35−45 PND) have been treated with increasing doses of THC for 11 days and left undisturbed until their adulthood (75 PND) when the behavioral and neurochemical assays were performed. The emotional profile was altered only in THC pretreated female rats. These animals showed a significant “behavioral despair” (forced swim test) paralleled by anhedonia (sucrose preference) and supported by biochemical parameters of depression, namely CREB alteration in the prefrontal cortex (PfCtx), hippocampus (Hippo) and nucleus accumbens (NAc). Neurocognitive functions were altered both in female and male pretreated rats, where we observed deficit in spatial memory (radial maze). To correlate memory impairment to altered neuroplasticity, level of proteins involved in synaptic plasticity was investigated in the most relevant areas for learning and memory, Hippo and PfCtx. In males we found significant reduction in pre- and post-synaptic protein expression ( ↓ 23%VAMP2, ↓ 41%PSD95) and in the astroglial marker GFAP ( ↓ 21%) in the Hippo, whereas females exhibited alterations specifically in the PfCtx ( ↓ 20%synaptophysin, ↓ 50%PSD95). Moreover THC pretreated male rats had a significant decrease in spine density and lower total dendritic length and number than vehicle group in the granule cells of the dentate gyrus. The present results suggest that cannabis consumption during adolescence may induce long term and gender dependent behavioral effects coupled with alteration in neurochemical markers and synaptic plasticity. References [1] Viveros M.P., Llorente R., Moreno E., Marco E.M., 2005. Behavioural and neuroendocrine effects of cannabinoids in critical developmental periods. Behav Pharmacol 16: 353–362.
S163
S.05. TEM symposium – Cognitive impairment in affective disorders: a potential treatment target? S.05.01 Cognitive impairment in affective disorders – what are the key issues? I.N. Ferrier1 ° . 1 University of Newcastle, Dept. of Psychiatry, Newcastle upon Tyne, United Kingdom In Bipolar Disorder, neurocognitive deficits occur in patients during euthymia across a number of domains. The key questions are: 1. Are impairments genuinely widespread or is there a core deficit which is expressed in different domains? 2. Do the deficits originate from a distinct regional pathology or relate to a distributed network? 3. What is the relationship between with the deficits in schizophrenia and what is the impact of a psychosis within Bipolar Disorder on this relationship? 4. The deficits worsen with number of episodes – what is the mechanism of this effect? 5. What is the relationship between impairments in Bipolar patients and those at risk of the disorder? 6. 6. What is the impact of medication? In Unipolar Depression, the key distinction is between the cognitive change found in late onset depression and that found in adult onset depression. In the former, the cognitive deficits are associated with pathology in grey and white matter and are a marker of that process and its prognosis. In adult depression, cognitive change can be found after the resolution of mood symptoms but this usually becomes a small feature in those who have made a good recovery. The above questions also relate to Unipolar Disorder but there are additional questions, eg what is the relationship between neuropsychological deficits and dysfunctional attitudes and negative cognitions. It is also not yet clear what the impact of these cognitive deficits are in functional terms and also how they impact on treatment concordance and results with psychoeducation and psychotherapy. References [1] Robinson, L.J., Thompson, J.M., Gallagher, P., Goswami, U., Young, A.H., Ferrier, I.N., Moore, P.B., 2006, A meta-analysis of cognitive deficits in euthymic patients with bipolar disorder. J Affect Disord 93, 105–115. [2] Porter, R.J., Bourke, C., Gallagher, P., 2007, Neuropsychological impairment in major depression: its nature, origin and clinical significance. Aust NZ J Psychiatry 41, 115–128.
S.05.02 Bipolar Disorder: neurodevelopmental or neurodegenerative A. Martinez-Aran1 ° . 1 Hospital Clinic, Bipolar Disorders Program IDIBAPS CIBERSAM, Barcelona, Spain Evidence for cognitive impairment prior to illness onset in bipolar disorder is still scant. In general, data suggest that bipolar disorder is not associated with premorbid intellectual decline as would be expected in a neurodevelopmental illness. On the other hand, if neurocognitive deficits are present in unaffected family members of bipolar disorder, it is possible that these deficits are genetic in origin, suggesting possible neurodevelopmental processes. Several differently designed studies have
S.04. Hot Topics 1
S.04.05 Effects of repeated treatment of phencyclidine in cognition, emotional activity and gene expression in C57BL/6J mice S. Beraki1 ° , R. Diaz-Heijtz1 , F. Tai1 , S.O. Ogren1 . 1 Karolinska Institutet, Department of Neuroscience, Stockholm, Sweden A number of studies indicate that glutamatergic NMDAneurotransmission is disturbed in schizophrenia. This hypothesis is partly based on the findings with the NMDA-receptor antagonist phencyclidine (PCP), which reproduces a schizophrenia-like syndrome in both humans and rodents (Javitt and Zukin, 1991). This study investigated whether repeated administration of low doses of PCP could produce long-term effects on cognitive and social behavior, related to alterations in gene expression of two genes, Arc and spinophilin. These genes are involved in neuronal plasticity and learning. Adult male C57Bl/6J mice received daily s.c. doses of PCP (0.5−2.0 mg/kg) or saline for 7 days and testing was performed 24 h after the last day of treatment. Only the 2.0 mg/kg dose of PCP produced a consistent impairment in spatial learning and working-memory performed in the watermaze task without any apparent sensorimotor deficits. The PCP-treated mice spent less time in active social interaction but increased non-social behavior when examined 24 h after the last treatment. PCP-treatment also suppressed rearing and sniffing substrate and induced an increase in aggressive behavior. The mRNA level of Arc was upregulated in the hippocampus and retrosplenial agranular cortex while spinophilin was downregulated in striatum by repeated treatment of PCP. These results demonstrate that repeated treatment with low doses of PCP in mice can produce a prolonged impairment in spatial learning, long-term, and working memory. Repeated PCP treatment also affects social interaction and emotional behavior. Furthermore, these effects were associated with altered gene expression in the corticohippocampal pathway and in the striatum. References [1] Javitt, D.C. Zukin, S.R., 1991. Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 148, 1301–1308.
S.04.06 A role for the opioid system in endocannabinoid-mediated fear-conditioned analgesia in rats R.K. Butler1 ° , K. Rea1 , Y. Lang1 , D.P. Finn1 . 1 National University of Ireland Galway, Department of Pharmacology and Therapeutics NCBES Neuroscience Cluster and Centre for Pain Research, Galway, Ireland The opioid (Helmstetter and Fanselow, 1987) and endocannabinoid (Finn et al., 2004) systems independently mediate analgesia expressed upon re-exposure to a contextually aversive stimulus (fear-conditioned analgesia; FCA) and activate the mitogenactivated protein kinase (MAPK) pathway. However, an interaction between the opioid and endocannabinoid systems during FCA has not been investigated at the behavioural or molecular level. Here we investigated the effects of pharmacological blockade of mu-opioid, CB1 and CB2 receptors on FCA in the presence or absence of the fatty acid amide hydrolase (enzyme which degrades the endocannabinoid anandamide) inhibitor, URB597. FCA was modelled in rats as described previously (Finn et al., 2004; Roche et al., 2007) with Western blotting for phospho-ERK1/2 carried
out on amygdaloid tissue. URB597 (0.3 mg/kg. i.p) enhanced expression of FCA. mu-opioid receptor blockade with naloxone attenuated FCA and the URB597-induced enhancement of FCA. SR141716A (CB1 antagonist) and SR144528 (CB2 antagonist) also attenuated the URB597-mediated enhancement of FCA. Additional results demonstrated an inverse correlation between duration of pain behaviours and the duration of fear behaviours. Expression of FCA was associated with increased pERK2 expression in the amygdala, an effect blocked by naloxone, SR141716A, and SR144528. Furthermore, URB597-mediated enhancement of FCA was associated with reduced pERK1 and pERK2 in the amygdala. These data suggest that endocannabinoid-mediated enhancement of FCA requires a functionally active mu-opioid receptor. Both pharmacological enhancement (with URB597) and attenuation (with naloxone) of this form of endogenous analgesia were associated with reduced phosphorylation of ERK1/2 in the amygdaloid complex. References [1] Finn, D.P., Beckett, S.R., Richardson, D., Kendall, D.A., Marsden, C.A., Chapman, V., 2004, Evidence for differential modulation of conditioned aversion and fear-conditioned analgesia by CB1 receptors. Eur J Neurosci, 20, 848−52. [2] Helmstetter, F.J., Fanselow, M.S., 1987, Effects of naltrexone on learning and performance of conditional fear-induced freezing and opioid analgesia. Physiol Behav 39, 501−5. [3] Roche, M., O’Connor, E., Diskin, C., Finn, D.P., 2007, The effect of CB(1) receptor antagonism in the right basolateral amygdala on conditioned fear and associated analgesia in rats. Eur J Neurosci 26, 2643−53.
S.04.07 Could nicotine potentiate the beneficial effects of levodopa in the 6-OHDA rat model? A behavioural study J.P. Guilloux1 ° , R. Massart1 , A.N. Samaha2 , V. Mignon1 , 1 Centre de Psychiatrie et de J.M. Arrang1 , J. Diaz3 . Neurosciences – Broca – Sainte-Anne, INSERM U894 – Laboratoire de Neurobiologie et Pharmacologie Mol´eculaire, Paris, France; 2 Centre for Addiction and Mental Health, Schizophrenia Program, Toronto, Canada; 3 Facult´e de Pharmacie Universit´e Descartes Paris5, UMRs 573 INSERM, Paris, France Epidemiological studies found that Parkinson’s disease (PD) is less prevalent in smokers suggesting a neuroprotective effect of nicotine. Furthermore, nicotine administration seems to protect against toxin-induced striatal dopamine depletion in various animal models of PD (Visanji et al., 2006, Quik et al., 2006). However, a few studies have evaluated the potential therapeutic effects on motor impairment of nicotine given alone or in combination with levodopa (treatment of reference of PD). Thus, we observe if nicotine can exert a beneficial effect on motor impairment, after lesion of the nigrostriatal tract in the unilateral 6-OHDA-lesion model of PD in rat. Lesioned rats were administered a low dose of levodopa (3 mg/kg/d, i.p.), or nicotine (1 mg/kg/day, s.c. using osmotic minipumps) or their co-administration for 14 days. Motor deficits and effects of treatment were assessed using the “Forelimb Stepping Test” and “Spontaneous Limb-Use Asymmetry Test”. In the Forelimb Stepping Test, DA-denervation caused a significant impairment in the performance of the contralateral limb (p < 0.001). A chronic treatment of nicotine or levodopa or coadministration progressively increase the number of adjusting steps of the impaired limb 14 days after the onset of treatment
S.05. TEM symposium – Cognitive impairment in affective disorders: a potential treatment target? (p < 0.001). In the Spontaneous Limb-Use Asymmetry Test, nicotine or levodopa given alone increase the number of contacts of the impaired limb with the cylinder (p < 0.05). Furthermore, nicotine potentiate the effects of levodopa in this test (p < 0.05). These overall results show that nicotine display anti-parkinsonian properties in the unilateral 6-OHDA-lesion rat model of Parkinson when given alone and could potentiate the effects of a low dose of levodopa. References [1] Quik, M., Parameswaran, N., McCallum, S.E., Bordia, T., Bao, S., McCormack, A., Kim, A., Tyndale, R.F., Langston, J.W., Di Monte, D.A., 2006, Chronic oral nicotine treatment protects against striatal degeneration in MPTP-treated primates. J Neurochem 98, 1866−75. [2] Visanji, N.P., O’Neill, M.J., Duty, S., 2006, Nicotine, but neither the alpha4beta2 ligand RJR2403 nor an alpha7 nAChR subtype selective agonist, protects against a partial 6-hydroxydopamine lesion of the rat median forebrain bundle. Neuropharmacology 51, 506−16.
S.04.08 Adolescent cannabinoid exposure induces sex dependent alterations in adulthood: behavioural and biochemical evidences N. Realini1 ° , D. Braida2 , S. Guidi3 , V. Capurro2 , T. Rubino1 , R. Bartesaghi3 , D. Parolaro1 . 1 University of Insubria, Dep.of Funct. and Struct. Biol., Busto Arsizio (Varese), Italy; 2 University of Milan, Dep.of Pharmacology, Milan, Italy; 3 University of Bologna, Dep.of Human and General Physiology, Bologna, Italy Marijuana is the illicit drugs most frequently used by human adolescents [1]. This work studied in rats the long-term consequences of adolescent consumption of D9 tetrahydrocannabinol (THC) on emotional and cognitive parameters. Adolescent male and female rats (35−45 PND) have been treated with increasing doses of THC for 11 days and left undisturbed until their adulthood (75 PND) when the behavioral and neurochemical assays were performed. The emotional profile was altered only in THC pretreated female rats. These animals showed a significant “behavioral despair” (forced swim test) paralleled by anhedonia (sucrose preference) and supported by biochemical parameters of depression, namely CREB alteration in the prefrontal cortex (PfCtx), hippocampus (Hippo) and nucleus accumbens (NAc). Neurocognitive functions were altered both in female and male pretreated rats, where we observed deficit in spatial memory (radial maze). To correlate memory impairment to altered neuroplasticity, level of proteins involved in synaptic plasticity was investigated in the most relevant areas for learning and memory, Hippo and PfCtx. In males we found significant reduction in pre- and post-synaptic protein expression ( ↓ 23%VAMP2, ↓ 41%PSD95) and in the astroglial marker GFAP ( ↓ 21%) in the Hippo, whereas females exhibited alterations specifically in the PfCtx ( ↓ 20%synaptophysin, ↓ 50%PSD95). Moreover THC pretreated male rats had a significant decrease in spine density and lower total dendritic length and number than vehicle group in the granule cells of the dentate gyrus. The present results suggest that cannabis consumption during adolescence may induce long term and gender dependent behavioral effects coupled with alteration in neurochemical markers and synaptic plasticity. References [1] Viveros M.P., Llorente R., Moreno E., Marco E.M., 2005. Behavioural and neuroendocrine effects of cannabinoids in critical developmental periods. Behav Pharmacol 16: 353–362.
S163
S.05. TEM symposium – Cognitive impairment in affective disorders: a potential treatment target? S.05.01 Cognitive impairment in affective disorders – what are the key issues? I.N. Ferrier1 ° . 1 University of Newcastle, Dept. of Psychiatry, Newcastle upon Tyne, United Kingdom In Bipolar Disorder, neurocognitive deficits occur in patients during euthymia across a number of domains. The key questions are: 1. Are impairments genuinely widespread or is there a core deficit which is expressed in different domains? 2. Do the deficits originate from a distinct regional pathology or relate to a distributed network? 3. What is the relationship between with the deficits in schizophrenia and what is the impact of a psychosis within Bipolar Disorder on this relationship? 4. The deficits worsen with number of episodes – what is the mechanism of this effect? 5. What is the relationship between impairments in Bipolar patients and those at risk of the disorder? 6. 6. What is the impact of medication? In Unipolar Depression, the key distinction is between the cognitive change found in late onset depression and that found in adult onset depression. In the former, the cognitive deficits are associated with pathology in grey and white matter and are a marker of that process and its prognosis. In adult depression, cognitive change can be found after the resolution of mood symptoms but this usually becomes a small feature in those who have made a good recovery. The above questions also relate to Unipolar Disorder but there are additional questions, eg what is the relationship between neuropsychological deficits and dysfunctional attitudes and negative cognitions. It is also not yet clear what the impact of these cognitive deficits are in functional terms and also how they impact on treatment concordance and results with psychoeducation and psychotherapy. References [1] Robinson, L.J., Thompson, J.M., Gallagher, P., Goswami, U., Young, A.H., Ferrier, I.N., Moore, P.B., 2006, A meta-analysis of cognitive deficits in euthymic patients with bipolar disorder. J Affect Disord 93, 105–115. [2] Porter, R.J., Bourke, C., Gallagher, P., 2007, Neuropsychological impairment in major depression: its nature, origin and clinical significance. Aust NZ J Psychiatry 41, 115–128.
S.05.02 Bipolar Disorder: neurodevelopmental or neurodegenerative A. Martinez-Aran1 ° . 1 Hospital Clinic, Bipolar Disorders Program IDIBAPS CIBERSAM, Barcelona, Spain Evidence for cognitive impairment prior to illness onset in bipolar disorder is still scant. In general, data suggest that bipolar disorder is not associated with premorbid intellectual decline as would be expected in a neurodevelopmental illness. On the other hand, if neurocognitive deficits are present in unaffected family members of bipolar disorder, it is possible that these deficits are genetic in origin, suggesting possible neurodevelopmental processes. Several differently designed studies have