Inhibition of glycogen synthase kinase-3 by SB 216763 affects acquisition at lower doses than expression of amphetamine-conditioned place preference in rats.

Dopamine (DA) drives incentive learning, whereby neutral stimuli acquire the ability to elicit responses. DA influences the signaling molecule glycogen synthase kinase-3 (GSK3). Inhibition of GSK3 attenuates the development of behavioral sensitization to stimulant drugs and conditioned place preference (CPP), a measure of incentive learning. We examined the role of GSK3 in the nucleus accumbens (NAc) of rats in CPP produced by amphetamine (1.5 mg/kg, i.p. or 20.0 µg/0.5 µl/side intra-NAc) by administering the inhibitor SB 216763 (1.0, 2.0, and 2.5 mg/kg, i.p. or 0.03, 0.30, 3.00, and 5.00 µg/0.5 µl/side intra-NAc) during acquisition or expression. We hypothesized a dose-dependent effect of SB 216763 and that acquisition would be affected by smaller doses than expression. For the systemic groups, 1.0 mg/kg of SB 216763 did not block CPP; 2.0 mg/kg administered in acquisition but not expression blocked CPP; and 2.5 mg/kg administered in either phase blocked CPP. For the central groups, 0.03 µg/0.5 µl/side of SB 216763 prevented acquisition but not expression, whereas larger doses administered in either phase blocked CPP. Thus, systemic or NAc inhibition of GSK3 by SB 216763 during acquisition or expression blocks amphetamine-produced CPP and acquisition is sensitive to lower doses than expression.

Spiroperidol, but not eticlopride or aripiprazole, produces gradual increases in descent latencies in the bar test in rats.

Rats repeatedly exposed to the bar test following injections with a dopamine D2-like receptor antagonist such as haloperidol show increased descent latencies, suggesting that contextual stimuli may lose their ability to elicit approach and other responses. Here, we showed that rats took progressively longer to initiate descent from a horizontal bar across sessions following daily intraperitoneal treatment (paired group) with the D2-like receptor antagonist, spiroperidol (0.125 and 0.25 mg/kg), but not in the control group that received 0.25 mg/kg in their home cage and testing following saline. When both groups were tested following an injection of spiroperidol or following saline, a sensitized and a conditioned increase in descent latency, respectively, were observed in the paired but not in the unpaired group. No evidence of sensitization or conditioning was found with the substituted benzamide compound, eticlopride (0.15-0.5 mg/kg), or the D2-like receptor partial agonist, aripiprazole (0.25-0.5 mg/kg). The different effects of these agents on learning may be related to different region-specific affinities for dopamine receptors or differences in receptor dissociation profiles. We suggest that the behavioural changes observed in spiroperidol-treated rats may reflect inverse incentive learning.

8-pCPT, an Epac activator, impairs conditioned place preference based on nucleus accumbens amphetamine in rats.

OBJECTIVES: Dopamine receptor-mediated 3',5'-cyclic adenosine monophosphate (cAMP)-dependent intracellular signalling is important for reward-related learning. cAMP activates cAMP-dependent protein kinase (PKA) and exchange protein directly activated by cAMP (Epac). We tested the hypothesis that reward-related learning may be mediated by Epac. METHODS: We evaluated conditioned place preference (CPP) on the basis of nucleus accumbens (NAc) injections of amphetamine (20 µg/0.5 µl/side) plus Sp-adenosine 3',5'-cyclic monophosphorothioate triethylamanine (Sp-cAMPS) (0.1, 1.0, 10, 15, 20 µg/0.5 µl/side), an activator of both PKA and Epac, or amphetamine (20 µg) plus 8-(4-chlorophenylthio)-2'-O-methyladenosine-3',5'-cyclic monophosphate (8-pCPT) (0.73, 1.27, 1.45, 2.89, 5.78, 11.56 µg/0.5 µl/side), an activator of Epac. RESULTS: In agreement with previous results, Sp-cAMPS dose-dependently impaired CPP. 8-pCPT impaired CPP at one dose (1.45 µg/0.5 µl/side) and we replicated this effect three times. CONCLUSION: The results implicate Epac in the acquisition of reward-related learning.

Haloperidol conditioned catalepsy in rats: a possible role for D1-like receptors.

Decreases in brain dopamine (DA) lead to catalepsy, quantified by the time a rat remains with its forepaws resting on a suspended horizontal bar. Low doses of the DA D2 receptor-preferring antagonist haloperidol repeatedly injected in a particular environment lead to gradual day-to-day increases in catalepsy (catalepsy sensitization) and subsequent testing following an injection of saline reveal conditioned catalepsy. We tested the hypothesis that D1-like and D2 receptors play different roles in catalepsy sensitization and in acquisition and expression of conditioned catalepsy. Rats were repeatedly treated with the DA D1-like receptor antagonist SCH 23990 (0.05, 0.1 and 0.25 mg/kg i.p.), the D2 receptor-preferring antagonist haloperidol (0.1, 0.25 and 0.5 mg/kg i.p.) or a combination of the two drugs and tested for catalepsy each day in the same environment. Following 10 drug treatment days, rats were injected with saline and tested for conditioned catalepsy in the previously drug-paired environment. Haloperidol did not elicit cataleptic responses in the initial session; however, rats developed sensitization with repeated testing. Significant catalepsy sensitization was not observed in rats repeatedly tested with SCH 23390. When rats were injected and tested with saline following haloperidol sensitization they exhibited conditioned catalepsy in the test environment; conditioned catalepsy was not seen following SCH 23390. Rats treated with 0.05 mg/kg SCH 23390+0.25 mg/kg haloperidol showed catalepsy sensitization but failed to show conditioned catalepsy. Conversely, SCH 23390 (0.05 mg/kg) given on the test day after sensitization to haloperidol (0.25 mg/kg) failed to block conditioned catalepsy. Repeated antagonism of D2 receptors leads to catalepsy sensitization with repeated testing in a specific environment. Conditioned catalepsy requires intact D1-like receptor function during sensitization sessions but not during test sessions. In conclusion, repeated antagonism of D2, but not D1-like receptors leads to catalepsy sensitization with repeated testing in a specific environment. Conditioned catalepsy requires functional D1-like receptors during sensitization sessions but not during test sessions.

Comparison of nafadotride, CNQX, and haloperidol on acquisition versus expression of amphetamine-conditioned place preference in rats.

Neurotransmission at dopamine (DA) and glutamate synapses has been implicated in conditioning place preference (CPP) in rats, but different receptor subtypes may be differentially involved in acquisition and expression. A balanced CPP was used to study the role of DA D2 and D3 and glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors in acquisition and expression of amphetamine (2.0 mg/kg) CPP. We tested the DA D3 receptor-preferring antagonist nafadotride, the AMPA/kainate glutamate-receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione disodium salt (CNQX), and the DA D2 receptor-preferring antagonist haloperidol. The results revealed that nafadotride (0.5 mg/kg) and CNQX (0.05 mg/kg) blocked the expression of amphetamine CPP at a dose that failed to block acquisition. In contrast, haloperidol (0.1 mg/kg) blocked the acquisition of CPP at a dose that failed to block expression. Cotreatment with subthreshold doses of nafadotride (0.1 mg/kg) and CNQX (0.01 mg/kg) before the test session failed to block the expression of CPP. The results suggest that AMPA/kainate and DA D3 receptors are more strongly involved in the expression of amphetamine CPP and D2 receptors are more strongly involved in the acquisition of amphetamine CPP.

Animal behaviour: chimpanzee choice and prosociality.

Silk et al. report that adult chimpanzees show no difference in their choices in a situation where one choice benefits a familiar conspecific and the other does not. From this, they conclude that chimpanzees are indifferent to the welfare of unrelated group members. But without additional data confirming that chimpanzees do choose differently in circumstances in which a difference would be expected, the authors cannot conclude that there is no difference in their scenario. How chimpanzees react to the welfare of unrelated group members remains an open question.

People newly in love are more responsive to positive feedback.

Passionate love is associated with increased activity in dopamine-rich regions of the brain. Increased dopamine in these regions is associated with a greater tendency to learn from reward in trial-and-error learning tasks. This study examined the prediction that individuals who were newly in love would be better at responding to reward (positive feedback). In test trials, people who were newly in love selected positive outcomes significantly more often than their single (not in love) counterparts but were no better at the task overall. This suggests that people who are newly in love show a bias toward responding to positive feedback, which may reflect a general bias towards reward-seeking.

Dissociable effects of ultralow-dose naltrexone on tolerance to the antinociceptive and cataleptic effects of morphine.

Ultralow-dose opioid antagonists augment the antinociceptive effect of morphine and block the development of tolerance to repeated morphine injections in rodents, but the effects are not reliably reproduced in humans. One explanation for this discrepancy is that preclinical studies of ultralow-dose antagonism in rodents generally use reflex-withdrawal tests of antinociception, which may be affected by cataleptic effects of morphine. We tested this hypothesis by examining whether ultralow-dose naltrexone alters the cataleptic effect of morphine or the development of tolerance to morphine-induced catalepsy. Rats (N=56) were randomly assigned to saline, morphine (10 mg/kg), cotreatments of morphine plus naltrexone (molar ratios of 1,000,000 : 1; 500,000 : 1; 100,000 : 1), or naltrexone-alone groups. Rats were injected with drug for 7 consecutive days; on each day, catalepsy and antinociception were assessed 30 and 60 min postinjection, using the bar and tail-flick tests, respectively. Ultralow-dose naltrexone (500,000 : 1) extended the antinociceptive effect of morphine within a session and attenuated the development of tolerance to the antinociceptive effect of morphine across sessions. Naltrexone alone had no effect on either test. These data show that the paradoxical effect of ultralow-dose naltrexone on antinociception is not the product of morphine-induced catalepsy, pointing to an important role for agonist-antagonist combinations in the clinical treatment of pain.

Subchronic phencyclidine in rats: alterations in locomotor activity, maze performance, and GABA(A) receptor binding.

Phencyclidine (PCP), an antagonist at the N-methyl-D-aspartate subtype of ionotropic glutamatergic receptors, decreases gamma-aminobutyric acid (GABA)ergic inhibition, suggesting that changes in GABAergic receptor function underlie behavioral and cognitive deficits resulting from repeated administration of PCP. To test this hypothesis, male Sprague-Dawley rats treated with PCP (4.5 mg/kg, intraperitoneal, twice a day for 7 consecutive days) or saline were tested in behavioral and cognitive tasks 7 days after injections. The PCP group showed increased amphetamine (1.5 mg/kg)-stimulated locomotor activity, and exhibited a greater number of errors in the double Y-maze memory task, when compared with controls. Subchronic PCP treatment increased [H]muscimol-binding sites and decreased affinity for [H]muscimol binding in frontal cortex, hippocampus, and striatum in comparison with controls. There were no changes in the expression of glutamic acid decarboxylase or the GABA membrane transporter protein. These data show that subchronic PCP administration induces an impaired performance of a previously learned task and an enhanced response to amphetamine in the rat. The observed changes in GABAA receptors in the rat brain are consistent with the notion that alterations in GABAergic receptor function contribute to the behavioral and cognitive impairments associated with repeated exposure to PCP.

Subchronic MK-801 behavioural deficits in rats: partial reversal by the novel nitrate GT 1061.

Cognitive deficits are a core feature of schizophrenia that may be linked to abnormalities in GABA and nitric oxide (NO). Subchronic treatment with glutamate receptor antagonists produces similar deficits, providing a useful model to examine potential therapeutics. The present study investigated the effects of subchronic MK-801 (intraperitoneally; 0.5 mg/kg twice daily for 7 days) on amphetamine-induced locomotor activity and reversal learning in the water maze in rats, and the ability of the novel compound GT 1061 (4-methyl-5-(2-nitroxyethyl) thiazole HCl), containing dual pharmacophores producing NO- and GABA-mimetic activity, to ameliorate these effects. MK-801 enhanced locomotor responses to amphetamine. GT 1061 (0.1; not 0.0001, 0.001, 0.01, 1.0 mg/kg) further enhanced locomotion; the pro-GABA drug chlormethiazole (0.1, 1.0 mg/kg) had no significant effect. In saline-pretreated rats GT 1061 (0.1; not 0.0001, 0.001 mg/kg) increased amphetamine-induced locomotion; chlormethiazole (0.1, 1.0 mg/kg) had no effect. In the water maze, MK-801 impaired reversal learning after platform relocation. GT 1061 (0.001, 0.01, 0.1; not 0.0001 or 1.0 mg/kg) attenuated this impairment; chlormethiazole had no significant effect. These ameliorative effects of GT 1061 may be linked to the activation of NO- and GABA-dependent signaling and suggests a new direction for treating cognitive dysfunction in schizophrenia.

Differential effects of dopamine and AMPA receptor antagonists on the expression of conditioned avoidance responding in rats.

AMPA receptor antagonists disrupt avoidance responding, but their day-to-day effect on this behavior has not been elucidated. This study compared the multisession effect of the AMPA/kainate receptor antagonist CNQX with that of the typical antipsychotic haloperidol on the expression of avoidance responding. Rats (N = 199) were trained to move to safety on presentation of a tone in one-way active conditioned avoidance and were tested across 5 sessions. Intracerebroventricular (icv) injection of CNQX (20-min injection-test interval) produced a dose-dependent, immediate block of avoidance responding, compared with the extinction-like decline of avoidance responding produced by haloperidol (intraperitoneal [ip], 60-min injection-test interval; icv, 60 but not 20-min injection-test interval). Previous exposure to CNQX significantly reduced its efficacy, illustrating that its effects may not be specific to the conditioned safety-related stimuli that control responding in conditioned avoidance, as proposed for antidopaminergic compounds. The new multisession profile of disrupted avoidance responding illustrated by CNQX suggests different roles for glutamatergic and dopaminergic neurotransmission in conditioned avoidance responding. Results are consistent with a role for AMPA receptors in maintaining the expression of learning.

Role of dopamine D3 receptors in the expression of conditioned fear in rats.

There has been considerable interest in the role of dopamine D(3) receptors in appetitive conditioning but few studies have examined their role in aversive conditioning. The present study examined the effect of the dopamine D(3) receptor-preferring partial agonist BP 897 (1-(4-(2-naphthoyl-amino)butyl)-4-(2-methoxyhenyl)-1A-piperazine hydrochloride) and the selective dopamine D(3) receptor antagonist SB-277011A (trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]syclohexyl]4-quinolininecarboxamide]) on the expression and acquisition of fear conditioning. Rats (N=143) received 3 conditioned stimulus-shock pairings and then received 15 conditioned stimulus-alone presentations (3 per day) while lever pressing for food. Response suppression was taken as the behavioral measure of fear. Rats showed strong suppression to the conditioned stimulus after it had been paired with shock and suppression progressively weakened over conditioned stimulus-alone presentations. In experiment 1, rats that received BP 897 (1.0, 2.0 mg/kg i.p.) or SB-277011A (10.0 mg/kg i.p.) prior to conditioned stimulus-alone presentation sessions showed reduced suppression to the conditioned stimulus as compared to rats that received vehicle or lower doses of drug (0, 0.1 mg/kg BP 897; 0, 0.5, 5.0 mg/kg SB-277011A). Injections of BP 897 (1.0, 2.0 mg/kg) or SB-277011A (10.0 mg/kg) prior to conditioned stimulus-shock pairings did not significantly affect subsequent response suppression. Thus, BP 897 and SB-277011A dose-dependently attenuated the expression but not the acquisition of conditioned fear. These findings suggest that BP 897 and SB-277011A reduce the control of responding by aversively conditioned stimuli.

Schizopsychotic symptom-profiles and biomarkers: beacons in diagnostic labyrinths.

Several avenues of investigation through which the 'labyrinths' of schizopsychotic diagnosis may be examined, are offered by the consideration of the 'beacons' of symptom-profiles and biomarkers. Neurodevelopmental issues and risk assessment, neurocognitive factors of predictive necessity, supersensitivity in neurotransmitter systems, the implications of prodromal expressions of the disorder, functional dysconnectivity arising from prefrontal to diverse regional patterns and circuits with a neurodevelopmental origin, and heritable gene characteristics are viewed against the backdrop of the schizophrenia spectrum disorders. The associations between adolescent-adult use of cannabis, on the one hand, and, alternatively, the prevalence of chromosomal abnormalities, e.g., GRIK4 and NPAS3, and mental retardation, on the other hand, with the symptom-profiles of schizopsychosis provide further evidence of emerging biomarkers of biological inheritance factors. The involvement of dopamine D1 and D2 receptors, particularly in prefrontal region, with regard to functional integrity of cognitive systems is reviewed. It would appear that considerations of these disorders imply that one essential hub around which much of the neuropathology revolves may be observed in the various expressions of the cognitive and structural insufficiency.

Affective status in relation to impulsive, motor and motivational symptoms: personality, development and physical exercise.

The contributions of impulsive and risk-taking behaviour in depressive and bipolar disorders, motivational and motor behaviours in anhedonic and substance addictive states, and the factors, particularly distress and trauma, underlying the development of neuropathology in affective status are described from clinical, epidemiological and laboratory perspectives. In order to distinguish one case factor for biopsychological substrates of health, an array of self-reported characteristics, e.g., positive or negative affect, stress or energy, optimism, etc., that may be predictive or counterpredictive for the propensity for physical exercise and activity were analysed using a linear regression in twelve different studies. Several individual characteristics were found to be markedly and significantly predictive of the exercise propensity, i.e., positive affect, energy, health-seeking behaviour and character, while optimism was of lesser, though significant, importance. Several individual characteristics were found to be significantly counterpredictive: expression of BDI- and HAD-depression, major sleep problems and lack/negligence of health-seeking behaviour. The consequences of physical activity and exercise for both affective well-being, cognitive mobility and neurogenesis is noted, particularly with regard to developmental assets for younger individuals. Affective disorder states may be studied through analyses of personal characteristics that unfold predispositions for symptoms-profiles and biomarkers derived from properties of dysfunction, such as impulsiveness, temperament dimensions, anhedonia and 'over-sensitivity', whether interpersonal or to reward.

Cognitive symptoms facilitatory for diagnoses in neuropsychiatric disorders: executive functions and locus of control.

Cognitive symptoms, considered in conjunction both with their regional brain and biomarkers as well as affective, attributional and neurodevelopmental components, demonstrate ever-increasing complexity to facilitate conceptualization yet, unavoidably, bedevil diagnosis in neuropsychiatry even before considerations of the enigmatic processes in memory, such as executive function and working memory, are drawn into the myriads of equations that await remedial interpretations. Prefrontal and limbic regions of the brain are involved in a diversity of expressions of cognition, normal or dysfunctional, at synaptic, intracellular and molecular levels that mobilize a concatenation of signaling entities. Serotoninergic neurotransission at prefrontal regions directs cognitive-affective entities that mediate decision-making and goal-directed behaviour. Clinical, non-clinical and basic studies challenge attempts to consolidate the multitude of evidence in order to obtain therapeutic notions to alleviate the disordered status of the diagnosed and yet-to-be diagnosed individuals. Locus of control, a concept of some utility in health-seeking procedures, is examined in three self-report studies from the perspective of a cognitive-emotional situation through observations of ordinary, 'healthy' young and middle-aged individuals, to assess the predictors of internal and external locus of control. A notion based on high level executive functioning in the dorsolateral prefrontal cortex (DLPFC) in individuals characterised by internal locus of control is contrasted with a hypofunctional executive DLPFC, characterising individuals that express an external locus of control, is discussed.

Nucleus accumbens PKA inhibition blocks acquisition but enhances expression of amphetamine-produced conditioned activity in rats.

RATIONALE: The nucleus accumbens (NAc) plays a central role in dopamine-produced reward-related learning. In previous studies, the cyclic adenosine monophosphate-dependent protein kinase (PKA) inhibitor Rp-Cyclic 3',5'-hydrogen phosphorothioate adenosine triethylammonium salt (Rp-cAMPS) blocked the acquisition but not expression of NAc reward-related learning for natural rewards and the acquisition of psychostimulant drug conditioning. OBJECTIVES: The current study assessed the role of PKA in the expression of NAc amphetamine (amph)-produced conditioning using conditioned activity (CA). MATERIALS AND METHODS: After 5 days of habituation, a test environment was paired with bilateral NAc injections of amph (0.0 or 25.0 micro g) and the PKA inhibitor Rp-cAMPS (0.0, 5.0, 10.0, or 20.0 micro g) over three 60-min conditioning sessions separated by 48 h. To test for effects on expression, some groups received vehicle or amph alone before conditioning sessions and were injected with 0.0, 0.25, 5.0, or 20.0 mug of Rp-cAMPS before the single 60-min test session. RESULTS: Amph produced acute increases in locomotion and robust CA. Rp-cAMPS impaired the acquisition of amph-produced CA but not its expression; in fact, it enhanced expression. CONCLUSIONS: Results show that PKA inhibition blocks the acquisition but not the expression of amph-produced conditioning.

Schizophrenic patients treated with clozapine or olanzapine perform better on theory of mind tasks than those treated with risperidone or typical antipsychotic medications.

Theory of mind (ToM), the ability to attribute mental states to others, is associated with medial prefrontal cortical (mPFC) activity and is impaired in schizophrenia. Olanzapine or clozapine but not typical antipsychotics or risperidone preferentially affect c-fos expression in mPFC in animals. We tested the hypothesis that schizophrenic patients treated with different antipsychotics would perform differently on ToM tasks. Groups receiving Typicals (n=23), Clozapine (n=18), Olanzapine (n=20) or Risperidone (n=23) and a Control group of healthy volunteers (n=24) were matched for age, gender, handedness and education. ToM functioning was assessed with picture sequence, second-order belief and faux-pas tests. Schizophrenic groups performed similarly to controls on non-ToM conditions. The Olanzapine and Clozapine groups performed similarly to Controls on ToM tasks. The Typicals and Risperidone groups performed worse than the other groups on ToM tasks. We concluded that ToM performance of schizophrenic patients is influenced by the antipsychotic they are taking. Our results suggest that olanzapine or clozapine but not typicals or risperidone may improve or protect ToM ability.

Comorbidity of substance abuse with other psychiatric disorders.

Substance abuse is a frequent comorbid condition with other psychiatric disorders including schizophrenia and depression. These disorders may share a common substrate at the neurotransmitter or neurocircuit level. One candidate is hypofunction of the glutamate system. Several lines of evidence suggest that N-methyl-D-aspartate (NMDA) receptors may hypofunction in schizophrenia. Thus, NMDA receptor antagonists are schizophrenogenic; postmortem and imaging results point to reduced NMDA receptor function in schizophrenic brains; a number of genes that have been linked to schizophrenia code for proteins that influence NMDA function; and there is preliminary evidence that pro-NMDA drugs may be therapeutic in the treatment of schizophrenia. One of the most effective therapeutics for the treatment of substance abuse in schizophrenic people is clozapine, and clozapine may act at the glycine modulatory site to enhance NMDA receptor function. This preliminary line of evidence may link schizophrenia and drug abuse to a common neurochemical base, subnormal NMDA receptor function. People with schizophrenia and drug abusers similarly show deficits in tasks known to be sensitive to ventromedial prefrontal cortical damage, and both groups show decreased activation in the ventral striatum during reward anticipation in functional magnetic resonance imaging studies. These observations implicate common prefrontal cortical-striatal circuits and their modulation by hippocampal projections in schizophrenia and substance abuse. Withdrawal from substance abuse and depression both have been linked to changes in the function of several neurotransmitters including serotonin, dopamine and glutamate. These findings suggest possible common substrates and novel therapeutic approaches. Further studies are needed to fully characterize the neurocircuits and transmitters involved in various psychiatric disorders and their possible common elements in comorbid drug abuse.

Comorbidity implications in brain disease: neuronal substrates of symptom profiles.

The neuronal substrates underlying aspects of comorbidity in brain disease states may be described over psychiatric and neurologic conditions that include affective disorders, cognitive disorders, schizophrenia, obsessive-compulsive disorder, substance abuse disorders as well as the neurodegenerative disorders. Regional and circuitry analyses of biogenic amine systems that are implicated in neural and behavioural pathologies are elucidated using neuroimaging, electrophysiological, neurochemical, neuropharmacological and neurobehavioural methods that present demonstrations of the neuropathological phenomena, such as behavioural sensitisation, cognitive impairments, maladaptive reactions to environmental stress and serious motor deficits. Considerations of neuronal alterations that may or may not be associated with behavioural abnormalities examine differentially the implications of discrete areas within brains that have been assigned functional significance; in the case of the frontal lobes, differential deficits of ventromedial and dorsolateral prefrontal cortex may be associated with different aspects of cognition, affect, remission or response to medication thereby imparting a varying aspect to any investigation of comorbidity.

Genetic variation and shared biological susceptibility underlying comorbidity in neuropsychiatry.

Genetic factors underlying alcoholism, substance abuse, antisocial and violent behaviour, psychosis, schizophrenia and psychopathy are emerging to implicate dopaminergic and cannabinoid, but also monoaminergic and glutamatergic systems through the maze of promoter genes and polymorphisms. Candidate gene association studies suggest the involvement of a range of genes in different disorders of CNS structure and function. Indices of comorbidity both complicate the array of gene-involvement and provide a substrate of hazardous interactivity. The putative role of the serotonin transporter gene in affective-dissociative spectrum disorders presents both plausible genetic variation and complication of comorbidity The position of genetic variation is further complicated through ethnic, contextual and social factors that provide geometric progressions in the comordity already underlying diagnostic obstacles. The concept of shared biological susceptibility to two or more disorder conditions of comorbidity seems a recurring observation, e.g., bipolar disorder with alcoholism or schizophrenia with alcohol/substance abuse or diabetes with schizopsychotic disorder. Several lines of evidence seem to suggest that the factors influencing variation in one set of symptoms and those affecting one or more disorders are observed to a marked extent which ought to facilitate the search for susceptibility genes in comorbid brain disorders. Identification of regional genetic factors is awaited for a more compelling outline that ought eventually to lead to greater efficacy of symptom-disorder arrangements and an augmentation of current pharmacological treatment therapies.