2008-03-31 notes on increasing repetitive behaviors

Increased repetitive behaviours and prolactin responsivity to oral m-chlorophenylpiperazine in adults with autism spectrum disorders.

Autism is a neurodevelopmental disorder characterized by dysfunction in three primary behavioural domains: repetitive behaviours, social deficits, and language abnormalities. There is evidence that abnormalities exist in the serotonin (5-HT) system in autism spectrum patients. Furthermore, 5-HT is known to play a role in repetitive and social behaviours. This study examined the effect of m-chlorophenylpiperazine (m-CPP) on repetitive behaviours and prolactin response in 11 adults with autism or Aspergers disorder and 8 age- and gender-matched healthy controls via randomized double-blind, m-CPP and placebo challenges. The primary outcome measure was an instrument rating six repetitive behaviours: need to know, repeating, ordering, need to tell/ask, self-injury, and touching. Patients with autism spectrum disorders showed a significant increase in repetitive behaviours at end-point following oral m-CPP in comparison to placebo. Additionally subjects with autism spectrum disorders showed a significantly increased prolactin response to m-CPP compared to normal controls, with neither group responding to placebo. This study provides further evidence for altered 5-HT sensitivity in individuals with autism spectrum disorders, as well as a possible relationship between repetitive behaviours in autism spectrum disorders and abnormalities in the 5-HT system.

In a double-blind study versus placebo, the serotonergic agent m-chlorophenylpiperazine (mCPP) was administered to 20 healthy control subjects and 19 migraineurs to investigate the ability of mCPP (0.5 mg/kg) to induce typical migraine attacks. In the following 24 hours there were more migraines after mCPP than after placebo in both groups. These findings are consistent with involvement of 5HT2B,2C,1A receptor subtypes in the pathophysiology of migraine.

1. Serotonin mediates a slow excitatory potential in mammalian celiac ganglia.
2. Serotonin attenuates a slow inhibitory postsynaptic potential in rat hippocampal neurons.

m-Chlorophenylpiperazine (MCPP) has become an important neuroendocrine and behavioral probe for scrotonin function. MCPP has prominent serotonergic properties, the most important of which behaviorally appears to be activation of the 5-HT:c receptor (Curzon and Kennett 1990; Kennett et al 1989). Anxiogenic effects of MCPP on social interaction in the rat are blocked by antagonists with high affinity for 5-HT:c and 5HT2 recep- tors, but not by selective antagonists of the 5-ITT2 receptor (Kennett et al 1989). In human healthy objects, the anxiogenic action of MCPP is partially blocked by ritanserin, a selective 5-HT2 and 5-HT:c antagonist (Seibyl et al 1991).

ing serotonergic agents in humans, although an increase in hostility has been noted in studies using MCPP in PD patients (Kahn et al 1988) and in patients with antisocial personality in the setting of substance abuse (Moss et al 1990).

5-HT_2C receptor activation by m-chlorophenylpiperazine detected in humans with fMRI

In a subsequent Go/NoGo task, mCPP enhanced activation in right lateral orbitofrontal cortex (p < 0.05 small volume corrected).

Theory is constrained by the quality and versatility of measurement tools. As such, the development of techniques for measurement is critical to the successful development of theory. This paper presents a technique – the Go/No-go Association Task (GNAT) – that joins a family of existing techniques for measuring implicit social cognition generally, with a focus on attitude (evaluation). To expand the measurement potential supplied by its closest cousin, the Implicit Association Test (IAT), the GNAT can be used to examine automatic social cognition toward a single target category. That is, the GNAT obtains a measure of implicit social cognition without requiring the direct involvement of complementary or contrasting objects. Also, by implementing a response deadline in the procedure, the GNAT trades off response latency for sensitivity as the dependent variable measure. This paper provides a description of the technique through a series of experiments (1-5) that reveal its primary features using simple attitude objects. In Experiment 6, the GNAT is used to investigate attitudes toward race (Black and White) and gender (Male and Female). To explore the theoretical leverage offered by this tool, Experiment 6 puts to test a recurring question concerning automatic in-group favoritism versus out-group derogation. Results demonstrate the dual presence of both out-group derogation (e.g., negativity toward Black Americans) and in-group favoritism (positivity toward White Americans), a finding that emerges because the GNAT offers the potential for independent measures of attitude toward the two groups. Through these experiments, the GNAT is shown to be an effective tool for assessing automatic preferences as well as resolving persistent questions that require independent measures of individual attitude objects while maintaining the advantages of response competition tasks.

Association of a glutamate (NMDA) subunit receptor gene (GRIN2B) with obsessive-compulsive disorder --- Recent investigation suggests that a reversible glutamatergically mediated thalamocortical striatal dysfunction may serve as a reliable pathophysiological and treatment response marker for obsessive compulsive disorder (OCD). We postulated that N-methyl-D-aspartate (NMDA) receptors were involved in OCD, and specifically that polymorphisms in the 3' untranslated region of GRIN2B (glutamate receptor, ionotropic, Nmethyl-D-aspartate 2B) were associated with OCD in affected families.

It has been postulated that disturbances in glutamatergic transmission may contribute to the pathophysiology of schizophrenia. This view is based on several findings: (1) the noncompetitive NMDA receptor antagonists, phencyclidine and ketamine, induce both positive and negative psychotic symptoms in humans, which closely resemble those observed in schizophrenia; (2) a number of animal studies have shown that neuroleptics that ameliorate symptoms of schizophrenia (e.g. clozapine) also inhibit the effects of NMDA antagonists; (3) postmortem and in vivo studies have revealed alterations in ionotropic glutamate receptors (NMDA, AMPA, KA) and their modulatory sites in schizophrenia; (4) compounds enhancing the function of NMDA receptors potentiate the antipsychotic effects of neuroleptics in schizophrenic patients.

Furthermore, paradoxical alleviation of negative symptoms was reported after dopamine receptor agonists [209]. To explain these discrepancies, it was recently suggested that psychotic symptoms could result from the unsettled balance between cortical and subcortical dopaminergic systems. Hypofunction of cortical dopaminergic system (prefrontal cortex) may be responsible for the development of negative symptoms, while positive symptoms could be attributed to its enhanced activity in the limbic system [87, 95, 209]. Cortical and subcortical dopaminergic systems are functionally linked via the glutamatergic system, and it was recently suggested that its dysfunction could also precipitate psychotic symptoms.

Psychotic symptoms in humans can be elicited also by compounds binding to other sites at the NMDA receptor complex and blocking its function (e.g. CPP, CPPene, CGS 19755) [cf. 140].

The prefrontal cortex of the primate frontal lobes provides the capacity for judgment which can constantly adapt behavior in order to optimize its outcome. Adjudicating between long-term memory programs and prepotent responses, this capacity reviews all incoming information and provides an interpretation dependent on the events that have just occurred, the events that are predicted to happen, and the alternative response strategies that are available in the given situation. It has been theorized that this function requires two essential integrated components, a central executive which guides selective attention based on mechanisms of associative memory, as well as the second component, working memory buffers, in which information is held online, abstracted, and translated on a mental sketchpad of work in progress. In this review, we critically outline the evidence that the integration of these processes and, in particular, the induction and maintenance of persistent activity in prefrontal cortex and related networks, is dependent upon the interaction of dopamine D1 and glutamate NMDA receptor signaling at critical nodes within local circuits and distributed networks. We argue that this interaction is not only essential for representational memory, but also core to mechanisms of neuroadaptation and learning. Understanding its functional significance promises to reveal major new insights into prefrontal dysfunction in schizophrenia and, hence, to target a new generation of drugs designed to ameliorate the debilitating working memory deficits in this disorder.

A hyperdopaminergic state in humans has been hypothesized to contribute to the pathology of a number of psychiatric illnesses, including schizophrenia, bipolar disorder, and attention deficit hyperactivity disorder. Mice that display elevated synaptic levels of dopamine due to a genetically engineered deletion of the dopamine transporter (DAT) model behavioral deficits that simulate the above conditions. As novel treatment strategies for these disorders have focused on the serotonin (5-HT) 2A receptor, we determined the capacity of the highly selective 5-HT2A receptor antagonist M100907 to reverse behavioral deficits in DAT knockout (KO) mice. Prior to drug treatment, DAT KO mice exhibited increased levels of locomotor activity and highly linearized movement in a novel environment, as well as reduced prepulse inhibition (PPI) of acoustic startle, compared to wild-type littermates. Treatment with M100907 (0.31.0 mg/ kg, but not 0.1 mg/kg) reversed locomotor deficits in DAT KO mice. Similarly, treatment with 1.0 mg/kg M100907 reversed the PPI deficits in DAT KO mice. These data indicate that selective 5-HT2A receptor antagonists, such as M100907, may represent a class of drugs that can be used to treat conditions in which a chronic, elevated dopaminergic tone is present and contributes to abnormal behavior and sensorimotor gating deficits.

The behavioural effects of m-chlorophenylpiperazine (mCPP) in rats and its clinical effects in man are thought to be related to its action at 5-HT2B/2C receptors. However, although mCPP is a partial agonist at these subtypes in rat, its efficacy at human 5-HT2B/2C receptors is unknown. We therefore investigated the activity of mCPP at cloned human 5-HT2B and 5-HT2C receptors. mCPP was a partial agonist at the human 5-HT2C receptor but antagonized the human 5-HT2B receptor. Therefore, while supporting the proposal that at least some of the clinical effects of mCPP are likely to be mediated via stimulation of the 5-HT2C receptor, this study also suggests that any 5-HT2B receptor-mediated effects are more likely to result from receptor blockade than from receptor activation.

[41,42]. The 5-HT2C/2B receptor agonist m-CPP is also known to produce dose-dependent self- grooming [4]. m-CPP-induced self-grooming can be attenuated by mianserin, LY-53857 and metergoline which are antagonists with high affinity for the 5-HT2C and the 5-HT2B receptor site [4].

1. Notes on biomedical psychotherapies (taken today)

D2-agonist quinpirole induces perseveration of routes and hyperactivity but no perseveration of movements.

The behavior in an open field of rats injected with the D2-agonist quinpirole (2 mg/kg; n = 10) and saline (n = 10) was analyzed in terms of routes and movements. Quinpirole induces perseveration of routes without inducing perseveration of movements. Perseveration of routes consists of repeated travel along a few paths in a limited portion of the environment. Lack of perseveration of movements was evidenced by the same distribution of lateral, vertical, and forward movements as in saline-treated animals. Quinpirole also increased the total amount of progression and the total number of movements performed by the rat's body parts along all dimensions of movements. Thus, under quinpirole, animals were hyperactive, stereotyped in route, but free in movement. This profile resembles behavior under low doses of amphetamine but not the behavior under either apomorphine or high doses of amphetamine. Thus, contrary to the current view, administration of a D2-receptor agonist is sufficient to produce a major component of dopamine-induced stereotyped behavior. It is suggested that quinpirole induces perseveration of route by affecting presynaptic release of dopamine, and that the organization of route is independent of the organization of movement.

2008-04-15

intense world syndrome