Gerard J. Marek

Antidepressant effects assessed using behavior maintained under a differential-reinforcement-of-low-rate (DRL) operant schedule

Behavior maintained under a differential-reinforcement-of-low-rate (DRL) 72-s operant schedule, which reinforces responses with interresponse times greater than 72 s, exhibits a rather unique sensitivity to antidepressant drugs. Antidepressants from a number of pharmacological classes, including tricyclic antidepressants, selective serotonin or norepinephrine reuptake inhibitors, monoamine oxidase inhibitors, as well as a number of atypical antidepressants and putative antidepressants, reduce response rate and increase reinforcement rate of rats under this schedule. These effects are observed acutely but persist or are augmented with repeated treatment. By contrast, drugs from a number of other psychotherapeutic classes do not, in general, produce similar effects. This includes anxiolytic, sedative, stimulant, opioid, antihistaminic, and anticholinergic drugs, which can produce false positive results in some preclinical tests for antidepressant efficacy. There are conflicting data regarding the utility of DRL behavior for discriminating the effects of antidepressant and antipsychotic drugs. This results in part from methodological differences among studies, but likely also reflects the overlap between the neuropharmacological and clinical effects of some antipsychotic and antidepressant drugs. DRL behavior also has proven useful for identifying neurochemical and neuroanatomical mediators of antidepressant effects on behavior. Consistent with clinical data, it appears that activation of noradrenergic or serotonergic systems provides for parallel means of producing antidepressant-like effects on DRL behavior. Finally, the results of studies using DRL behavior highlight important roles for central beta-1 adrenergic receptors, as well as 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT2C receptors, in the mediation of antidepressant-like behavioral effects.

Development of the 2nd generation neurokinin-1 receptor antagonist LY686017 for social anxiety disorder.

The neurokinin-1 (NK-1) antagonist LY686017 showed activity in preclinical anxiety models. The clinical development of LY686017 included a PET study and a proof-of-concept in social anxiety disorder (SAD). [(11)C]GR205171 was used healthy volunteers receiving 1-100mg/d LY686017 for 28 days to determine brain receptor occupancy (RO). The mean NK-1 RO increased ranged from 25% with 1mg to 93% with 100mg. Subsequently, a 12-week randomized clinical trial tested LY686017 vs. paroxetine, or placebo in SAD. Pharmacokinetic (PK)/RO modeling based on the PET results predicted that once daily dosing of >30mg LY686017 led to sustained trough RO of over 80%. 189 outpatients(1) suffering from SAD were randomly assigned to 12-weeks treatment with 50mg/d LY686017 (N=77), placebo (N=74), or 20mg/d paroxetine (N=38). There was no significant difference between LY686017 and placebo as measured with the Liebowitz Social Anxiety scale (LSAS). The active comparator paroxetine showed positive trends on primary and secondary measures. The plasma concentrations were above the level expected to produce maximal brain NK-1 RO based on the PK/RO relationship obtained in the human PET investigation. Thus, further evaluation of LY686017 for the treatment of SAD does not seem warranted.

Serotonin and Dopamine Interactions in Rodents and Primates: Implications for Psychosis and Antipsychotic Drug Development

Since the late 1950s, appreciation of dopamine receptor blockade has played a primary role in understanding the mechanism underlying the therapeutic effects of antipsychotic drugs in schizophrenic patients in treating the positive symptoms of schizophrenia (e.g., delusions and hallucinations). Development of the second generation of antipsychotic drugs, otherwise known as atypical antipsychotic drugs, has resulted in treatments with improved subjective tolerability but relatively modest improvements in the negative symptoms of schizophrenia such as avolition, flat affect, and anhedonia. The major current challenge is to develop medications which can further improve negative symptoms treatment and also tackle the intractable clinical problems of cognitive impairment associated with schizophrenia. Further advances along these lines with respect to the dopaminergic and serotonergic neurostransmitter systems will be aided by an appreciation of the interaction between dopamine and serotonin receptor subtypes in a range of key brain structures, such as the prefrontal cortex, thalamus, striatum, amygdala, hippocampus, and the brain stem nuclei, from which the cell bodies of monoaminergic-containing neurons originate. Increasing emphasis on the use of animal models which are homologous to critical aspects of the pathophysiology in the brains of schizophrenic patients will also be required, especially as negative symptoms and cognitive impairment become an important focus for generating novel therapeutics.

Activation of metabotropic glutamate 5 (mGlu5) receptors induces spontaneous excitatory synaptic currents in layer V pyramidal cells of the rat prefrontal cortex

Serotonin and norepinephrine, in addition to direct postsynaptic excitatory effects, also enhances glutamate release onto layer V pyramidal cells of the prefrontal cortex/neocortex via G(q/11)-coupled 5-hydroxytryptamine(2A) (5-HT(2A)) and alpha(1)-adrenergic receptors, respectively. Therefore, the present study was designed to test whether a metabotropic glutamate (mGlu) receptor subtype also coupled to G(q/11)-proteins, the mGlu5 receptor, also induces EPSCs when recording from layer V cortical pyramidal cells of the rat medial prefrontal cortex (mPFC). The mGlu1/5 receptor agonist (S)-3,5-dihydroxyphenylglycine (DHPG) induces EPSCs at a similar frequency as a near-maximally effective 5-HT concentration. The mGlu5 receptor negative allosteric modulator 2-methyl-6-(phenylethynyl)pyridine (MPEP, 300 nM) potently blocked DHPG-induced EPSCs. Previous work has suggested that activation of 5-HT(2A) and OX2 receptors induces glutamate release, while mGlu2, mGlu4, and mGlu8 receptor activation suppress transmitter release from thalamocortical terminals. Taken together with past results, these findings suggest that mGlu2, mGlu4, mGlu5 and mGlu8 may all act to modulate glutamate release from afferents impinging on layer V pyramidal cells of the mPFC. These findings further suggest that monoamines, neuropeptides and glutamate itself all enhance the excitability of prefrontal cortical output cells indirectly via modulation of glutamate release.

Developing Therapeutics for Schizophrenia and Other Psychotic Disorders

SummaryAlthough the second-generation or atypical antipsychotic drugs have been breakthrough medicines for the treatment of schizophrenia and other psychotic conditions, cognitive dysfunction and to some extent negative symptoms of the disease continue to be the main cause of poor vocational status of the patients. Thus, the majority of investigational drug development efforts today target these unmet medical needs. This review postulates that the field of schizophrenia research has advanced sufficiently to develop biochemical hypotheses of the etiopathology of the disease and target the same for revolutionary disease modifying therapy. This postulate is based on recent studies that have begun to provide a testable etiopathology model that integrates interactions between genetic vulnerability factors, neurodevelopmental anomalies, and neurotransmitter systems. This review begins with a brief overview of the nosology and etiopathology of schizophrenia and related psychotic disorders to establish a context for subsequent detailed discussions on drug discovery and development for psychotic disorders. Particular emphasis is placed on recent advances in genetic association studies of schizophrenia and how this can be integrated with evidence supporting neurodevelopmental abnormalities associated with the disease to generate a testable model of the disease etiopathology. An in-depth review of the plethora of new targets and approaches targeting the unmet medical need in the treatment of schizophrenia exemplify the challenges and opportunities in this area. We end the review by offering an approach based on emerging genetic, clinical, and neurobiological studies to discover and validate novel drug targets that could be classified as disease modifying approaches.

Activation of adenosine1 (A1) receptors suppresses head shakes induced by a serotonergic hallucinogen in rats

Modulation of glutamatergic neurotransmission by metabotropic glutamate2/3 (mGlu2/3) receptor agonists effectively treats seemingly diverse neuropsychiatric illness such as generalized anxiety disorder and schizophrenia. Activation of adenosine A(1) heteroceptors, like mGlu2 autoreceptors, decreases glutamate release in the medial prefrontal cortex (mPFC) and other limbic brain regions. Previously, we have reported electrophysiological, neurochemical and behavioral evidence for interactions between the 5-hydroxytryptamine(2A) (5-HT(2A)) and mGlu2/3 receptors in the mPFC. The present studies were designed to investigate the effects in rats of adenosine A(1) receptor activation/blockade on a behavior modulated by 5-HT(2A) receptor activation/blockade in the mPFC: head shakes induced in the rat by phenethylamine hallucinogens. An adenosine A(1) receptor agonist, N(6)-cyclohexyladenosine (CHA) suppressed head shakes induced by activation of 5-HT(2A) receptors with the phenethylamine hallucinogen (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI). An adenosine A1 receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), enhanced DOI-induced head shakes and blocked the suppressant action of an adenosine A(1) receptor agonist on DOI-induced head shakes. Thus, the pattern of activity for an agonist and antagonist at the adenosine A1 receptor with respect to modulating DOI-induced head shakes is similar to the pattern observed with mGlu2/3 receptor agonists and antagonists. These novel observations with an adenosine A(1) receptor agonist suggest that this pharmacological action could contribute to antipsychotic effects in addition to thymoleptic effects.

Regulation of rat cortical 5-hydroxytryptamine2A receptor-mediated electrophysiological responses by repeated daily treatment with electroconvulsive shock or imipramine

Down-regulation of 5-hydroxytryptamine(2A) (5-HT(2A)) receptors has been a consistent effect induced by most antidepressant drugs. In contrast, electroconvulsive shock (ECS) up-regulates the number of 5-HT(2A) receptor binding sites. However, the effects of antidepressants on 5-HT(2A) receptor-mediated responses on identified cells of the cerebral cortex have not been examined. The purpose of the present study was to compare the effects of the tricyclic antidepressant imipramine and ECS on 5-HT(2A) receptor-mediated electrophysiological responses involving glutamatergic and GABAergic neurotransmission in the rat medial prefrontal cortex (mPFC) and piriform cortex, respectively. The electrophysiological effects of activating 5-HT(2A) receptors were consistent with 5-HT(2A) receptor binding regulation for imipramine and ECS except for the mPFC where chronic ECS decreased the potency of 5-HT at a 5-HT(2A) receptor-mediated response. These findings are consistent with the general hypothesis that chronic antidepressant treatments shift the balance of serotonergic neurotransmission towards inhibitory effects in the cortex.

Cortical 5-hydroxytryptamine2A-receptor mediated excitatory synaptic currents in the rat following repeated daily fluoxetine administration.

Down-regulation of 5-hydroxytryptamine(2A) (5-HT(2A)) receptors has been a consistent effect induced by most antidepressant drugs. The evidence for down-regulation of 5-HT(2A) receptor binding following subchronic treatment with fluoxetine and other selective serotonin reuptake inhibitors (SSRIs) is mixed. The question of 5-HT(2A) receptor sensitivity during chronic administration of antidepressants is important since activation of 5-HT(2A) receptors is associated with impulsivity. Continued activation of 5-HT(2A) receptors may functionally oppose activation of other non-5-HT(2A) receptors in the prefrontal cortex associated with the clinical efficacy of SSRI treatment. Therefore, the effects of repeated daily administration of fluoxetine (10 mg/kg, i.p. x 3 weeks) on pharmacologically characterized electrophysiological response mediated by 5-HT(2A) receptor activation, 5-HT-induced excitatory postsynaptic currents (EPSCs), in rat prefrontal cortical slices was examined. The concentration-response curve for 5-HT-induced EPSCs was unchanged following subchronic fluoxetine treatment. This subchronic fluoxetine treatment failed to modify electrophysiological responses to AMPA in layer V pyramidal cells as well. These findings would be consistent with the hypothesis that blockade of 5-HT(2A) receptors may enhance the effects of SSRIs or serotonin/norepinephrine reuptake inhibitors (SNRIs).

Metabotropic Glutamate2 Receptors Play a Key Role in Modulating Head Twitches Induced by a Serotonergic Hallucinogen in Mice

There is substantial evidence that glutamate can modulate the effects of 5-hydroxytryptamine2A (5-HT2A) receptor activation through stimulation of metabotropic glutamate2/3 (mGlu2/3) receptors in the prefrontal cortex. Here we show that constitutive deletion of the mGlu2 gene profoundly attenuates an effect of 5-HT2A receptor activation using the mouse head twitch response (HTR). MGlu2 and mGlu3 receptor knockout (KO) as well as age-matched ICR (CD-1) wild type (WT) mice were administered (±)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and observed for head twitch activity. DOI failed to produce significant head twitches in mGlu2 receptor KO mice at a dose 10-fold higher than the peak effective dose in WT or mGlu3 receptor KO mice. In addition, the mGlu2/3 receptor agonist LY379268, and the mGlu2 receptor positive allosteric modulator (PAM) CBiPES, potently blocked the HTR to DOI in WT and mGlu3 receptor KO mice. Conversely, the mGlu2/3 receptor antagonist LY341495 (10 mg/kg) increased the HTR produced by DOI (3 mg/kg) in mGlu3 receptor KO mice. Finally, the mGlu2 receptor potentiator CBiPES was able to attenuate the increase in the HTR produced by LY341495 in mGlu3 receptor KO mice. Taken together, all of these results are consistent with the hypothesis that that DOI-induced head twitches are modulated by mGlu2 receptor activation. These results also are in keeping with a critical autoreceptor function for mGlu2 receptors in the prefrontal cortex with differential effects of acute vs. chronic perturbation (e.g., constitutive mGlu2 receptor KO mice). The robust attenuation of DOI-induced head twitches in the mGlu2 receptor KO mice appears to reflect the critical role of glutamate in ongoing regulation of 5-HT2A receptors in the prefrontal cortex. Future experiments with inducible knockouts for the mGlu2 receptor and/or selective mGlu3 receptor agonists/PAMs/antagonists could provide an important tools in understanding glutamatergic modulation of prefrontal cortical 5-HT2A receptor function.

Lewis Seiden, Ph.D. (1934–2007)

Lewis S. Seiden, a pioneering psychopharmacologist, dedicated mentor, and inspiring colleague died on July 26, 2007, at the age of 72 years, not far from where he was born on August 1, 1934. Lew grew up in the South Shore neighborhood of Chicago and, with his characteristically infectious smile and twinkling eyes, was quite fond of telling visitors about being a high school dropout...before relating that he entered the University of Chicago at the age of 16 with a full-tuition scholarship. Lew was planning on studying medicine as an undergraduate, but was tragically stricken with dystonia musculorum deformans shortly before his anticipated graduation in 1950. He subsequently resumed studies after a year of convalescence and learning to adapt to substantial impairments in balance, movement, and speech as the result of his illness. He earned first a B.A. in Liberal Arts in 1956 prior to a B.S. in Biology in 1958. Lew remained at the University of Chicago for graduate school where he earned his Ph.D. in Biopsychology in 1962 and married Anne Maxwell Seiden, M.D.; they had three children Alex, Evelyn, and Samuel, and one grandchild, Alex’s son Lewis. Lew spent his entire academic career at the University of Chicago except for two brief but transforming experiences. He spent 2 years bringing behavioral pharmacology to the laboratory of future Nobel laureate Arvid Carlsson in Göteborg, Sweden, from 1962–1963. There, he published several papers on reserpine, L-DOPA, and the conditioned avoidance response. Carlsson later stated, “The remarkable thing about Lew’s stay with us was that he was able to teach us just as much as we could teach him.” Lew was awarded an Honorary Doctorate in medicine by the University of Göteborg in 1999. Lew moved back to the University of Chicago following a second postdoctoral fellowship in Keith Killam’s laboratory at Stanford University from 1964–1965. He moved up the ranks, becoming a full Professor in 1977 in the Pharmacology and the Psychiatry departments. One of the important, and certainly revolutionary, themes of Lew’s work during this time was not only the measurement of drug effects on the brain and behavior but also the compelling observations that the environment and the state of the brain/behavior axis itself can modulate the effects of drugs upon the brain chemistry and behavior. This was a theme of a textbook Lew wrote in 1977 with Linda Dykstra entitled Psychopharmacology: A Biochemical and Behavioral Approach. For anyone interested in understanding how drugs work and how to discover new drugs, these lessons remain fresh today. Psychopharmacology (2008) 195:457–458 DOI 10.1007/s00213-007-0989-3