Background and purpose: The histamine H3 receptor antagonist radioligand 3H‐A‐349821 was characterized as a radiotracer for assessing in vivo receptor occupancy by H3 receptor antagonists that ...affect behaviour. This model was established as an alternative to ex vivo binding methods, for relating antagonist H3 receptor occupancy to blood levels and efficacy in preclinical models.
Experimental approach: In vivo cerebral cortical H3 receptor occupancy by 3H‐A‐349821 was determined in rats from differences in 3H‐A‐349821 levels in the isolated cortex and cerebellum, a brain region with low levels of H3 receptors. Comparisons were made to relate antagonist H3 receptor occupancy to blood levels and efficacy in a preclinical model of cognition, the five‐trial inhibitory avoidance response in rat pups.
Key results: In adult rats, 3H‐A‐349821, 1.5 µg·kg−1, penetrated into the brain and cleared more rapidly from cerebellum than cortex; optimally, 3H‐A‐349821 levels were twofold higher in the latter. With increasing 3H‐A‐349821 doses, cortical H3 receptor occupancy was saturable with a binding capacity consistent with in vitro binding in cortex membranes. In studies using tracer 3H‐A‐349821 doses, ABT‐239 and other H3 receptor antagonists inhibited H3 receptor occupancy by 3H‐A‐349821 in a dose‐dependent manner. Blood levels of the antagonists corresponding to H3 receptor occupancy were consistent with blood levels associated with efficacy in the five‐trial inhibitory avoidance response.
Conclusions and implications: When employed as an occupancy radiotracer, 3H‐A‐349821 provided valid measurements of in vivo H3 receptor occupancy, which may be helpful in guiding and interpreting clinical studies of H3 receptor antagonists.
ROBINSON, T.E., K.E. BROWMAN, H.S. CROMBAG, A. BADIANI.
Modulation of the induction or expression of pyschostimulant sensitization by the circumstances surrounding drug administration. NEUROSCI ...BIOBEHAV REV
22(2), 347–354, 1998. The conditions necessary to induce psychomotor sensitization and to promote its expression are not well understood. Two examples are reviewed here of how the circumstances surrounding drug administration (“set and setting”) can powerfully modulate the sensitization produced by psychostimulant drugs, such as amphetamine or cocaine. In the first example it is suggested that repeated exposure to psychostimulant drugs may induce “neural sensitization” (i.e., produce relevant adaptations in the nervous system). The circumstances surrounding drug administration may determine, however, whether neural sensitization is expressed in behavior. In the second example it is suggested that the circumstances surrounding drug administration may determine whether sensitization is induced at all, or at least the rate and extent of sensitization produced by a given dose of a drug. It is concluded that psychomotor sensitization is not an inevitable consequence of exposure to psychostimulant drugs, but is the result of interactions amongst the pharmacological actions of drugs and the circumstances surrounding drug administration.
Histamine H3 receptor antagonists/inverse agonists have been proposed as potential therapeutic agents for the treatment of a number of neurological disorders ranging from attention deficit ...hyperactivity disorder and Alzheimer's disease to narcolepsy and schizophrenia. With respect to the latter, schizophrenic patients typically exhibit impaired prepulse inhibition (PPI) of startle, a reflex that can be modeled in many animal species. Certain strains of mice naturally display poor PPI and it was recently suggested that these mice might offer a new way to screen for novel antipsychotic compounds. To examine whether H3 receptor antagonists might enhance PPI in mice with naturally occurring deficits, DBA/2 and C57BL/6 were tested in a startle paradigm with three prepulse intensities: 5, 10 and 15 dB above background. Both thioperamide and ciproxifan enhanced PPI in the DBA/2 strain; thioperamide also showed a trend towards enhancing PPI in C57BL/6. Risperidone, an atypical antipsychotic, enhanced PPI in both the DBA/2 and the C57BL/6 strain. These data confirm previous reports describing a natural deficit in PPI in some mouse strains that is amenable to enhancement with known antipsychotics. Further, these data suggest that H3 receptor antagonists/inverse agonists have anti-psychotic potential for disorders such as schizophrenia.
Despite the well-described attention and short-term memory enhancing effects of H
3 receptor antagonists, and evidence to suggest a close relationship between central histaminergic and cholinergic ...systems, there is a paucity of evidence for a role for H
3 receptor blockade in spatial learning. To address this, we investigated two H
3 receptor antagonists in a visual discrimination water maze in rats, and in a Barnes circular maze in mice. Thioperamide and ciproxifan significantly attenuated a scopolamine-induced deficit in the water maze task, while only ciproxifan showed a modest attenuation in the Barnes maze. Taken together, these data suggest a role for H
3 receptors in spatial learning that appears to be task-dependent.
Background and purpose:
The histamine H
3
receptor antagonist radioligand
3
H‐A‐349821 was characterized as a radiotracer for assessing
in vivo
receptor occupancy by H
3
receptor antagonists that ...affect behaviour. This model was established as an alternative to
ex vivo
binding methods, for relating antagonist H
3
receptor occupancy to blood levels and efficacy in preclinical models.
Experimental approach:
In vivo
cerebral cortical H
3
receptor occupancy by
3
H‐A‐349821 was determined in rats from differences in
3
H‐A‐349821 levels in the isolated cortex and cerebellum, a brain region with low levels of H
3
receptors. Comparisons were made to relate antagonist H
3
receptor occupancy to blood levels and efficacy in a preclinical model of cognition, the five‐trial inhibitory avoidance response in rat pups.
Key results:
In adult rats,
3
H‐A‐349821, 1.5 µg·kg
−1
, penetrated into the brain and cleared more rapidly from cerebellum than cortex; optimally,
3
H‐A‐349821 levels were twofold higher in the latter. With increasing
3
H‐A‐349821 doses, cortical H
3
receptor occupancy was saturable with a binding capacity consistent with
in vitro
binding in cortex membranes. In studies using tracer
3
H‐A‐349821 doses, ABT‐239 and other H
3
receptor antagonists inhibited H
3
receptor occupancy by
3
H‐A‐349821 in a dose‐dependent manner. Blood levels of the antagonists corresponding to H
3
receptor occupancy were consistent with blood levels associated with efficacy in the five‐trial inhibitory avoidance response.
Conclusions and implications:
When employed as an occupancy radiotracer,
3
H‐A‐349821 provided valid measurements of
in vivo
H
3
receptor occupancy, which may be helpful in guiding and interpreting clinical studies of H
3
receptor antagonists.
Histamine H
3 receptor antagonists/inverse agonists have been proposed as potential therapeutic agents for the treatment of a number of neurological disorders ranging from attention deficit ...hyperactivity disorder and Alzheimer’s disease to narcolepsy and schizophrenia. With respect to the latter, schizophrenic patients typically exhibit impaired prepulse inhibition (PPI) of startle, a reflex that can be modeled in many animal species. Certain strains of mice naturally display poor PPI and it was recently suggested that these mice might offer a new way to screen for novel antipsychotic compounds. To examine whether H
3 receptor antagonists might enhance PPI in mice with naturally occurring deficits, DBA/2 and C57BL/6 were tested in a startle paradigm with three prepulse intensities: 5, 10 and 15
dB above background. Both thioperamide and ciproxifan enhanced PPI in the DBA/2 strain; thioperamide also showed a trend towards enhancing PPI in C57BL/6. Risperidone, an atypical antipsychotic, enhanced PPI in both the DBA/2 and the C57BL/6 strain. These data confirm previous reports describing a natural deficit in PPI in some mouse strains that is amenable to enhancement with known antipsychotics. Further, these data suggest that H
3 receptor antagonists/inverse agonists have anti-psychotic potential for disorders such as schizophrenia.
The recent development of a highly selective dopamine D
4 receptor agonist, A-412997 (2-(3′,4′,5′,6′-tetrahydro-2′
H-2,4′ bipyridinyl-1′-yl)-
N-
m-tolyl-acetamide), has provided a pharmacological ...tool with which to conduct systematic investigations into the putative role for dopamine D
4 receptors in the central nervous system. These present studies evaluated the potential cognitive enhancing properties of A-412997 in rat models of ADHD (5-trial repeated acquisition inhibitory avoidance in Spontaneous Hypertensive Rat pups) and short-term memory (Social Recognition), in comparison with the less selective dopamine D
4 receptor agonists PD168077 and CP226269. A-412997 showed significant dose-dependent efficacy in both models. PD168077 repeatedly improved acquisition in the 5-trial inhibitory avoidance model but failed to reach significance at any dose tested, although significantly improved social recognition was observed (albeit less potent than A-412997). CP226269 showed a significant enhancement in the 5-trial inhibitory avoidance model. These results support a role for the dopamine D
4 receptor subtype in cognition.
The acute psychomotor response (rotational behavior in rats with a unilateral 6-OHDA lesion), and the development of sensitization, were studied in rats that received seven consecutive daily ...injections of amphetamine (Experiment 1) or cocaine (Experiment 2) either at home or in a ‘novel’ test environment. The home (HOME) and novel (NOVEL) cages were physically identical, but one group lived and was tested in these cages, whereas the rats in the other group were transported from the stainless steel hanging cages where they lived, to these NOVEL test cages, for each test session. In Expt. 1, the acute psychomotor response to 3.0 mg/kg of amphetamine i.p. and the development of sensitization (increase in the rotational response between the first and the seventh test session) were greater in the NOVEL than in the HOME environment. In Expt. 2, there were no significant group differences in the acute response to 20 mg/kg of cocaine i.p., but the animals tested in the NOVEL environment showed greater sensitization than animals tested in the HOME environment. In addition, the animals pretreated with cocaine in the NOVEL environment, but not those pretreated with cocaine in the HOME environment, showed conditioned rotational behavior in response to an injection of saline. These data indicate that: (i) sensitization to the psychomotor activating effects of both amphetamine and cocaine is enhanced in a NOVEL environment; (ii) this phenomenon appears to be independent of the effects of the NOVEL environment on the acute response to these drugs; (iii) a robust conditioned psychomotor response to contextual cues develops only when cocaine treatments are given in the NOVEL test environment.
In previous studies the repeated administration of 0.5 to 1.0 mg/kg of amphetamine i.v. failed to induce psychomotor sensitization if the drug was administered to animals living in the test ...environment (at home). The same doses did induce sensitization if animals were transported to the test environment for each drug treatment. The purpose of the present experiment was to determine the extent to which this effect of environment is dose dependent. Rats either lived in test cages or were transported from the animal colony to test cages where they received an i.v. infusion of one of five doses of amphetamine (0.125, 0.5, 1.0, 4.0 or 8.0 mg/kg) or saline each day for 5 consecutive days. Rotational behavior was used as an index of psychomotor activation. After a 6-day drug-free period all animals were challenged with 0.5 mg/kg of amphetamine to determine the pretreatment dose necessary to induce sensitization. The effect of the drug-treatment environment was to shift the dose-effect curve for the induction of sensitization, such that significantly lower doses were necessary to induce sensitization when amphetamine was given in a novel environment. With high doses, however, sensitization occurred regardless of environmental condition. It is concluded that the circumstances surrounding drug administration can powerfully modulate the ability of psychostimulants to induce sensitization, but this effect is dose dependent.
The acute psychomotor response and development of sensitization to amphetamine is attenuated if i.p. injections are given in the cage where a rat lives relative to when injections are given in a ...novel but physically identical test environment. Furthermore, when the environmental cues predicting i.p. injections are completely eliminated by using remotely activated i.v. injections in the home cage, 1.0 mg/kg amphetamine produces a very small acute response and no sensitization. The same treatments do produce sensitization if i.v. injections are signaled by placement of the rat in a novel test cage. The present experiment was designed to determine if there is a similar effect of environmental condition on the response to i.v. cocaine, and to what extent the effect may be dose-dependent. This was accomplished by comparing the psychomotor activating effects (rotational behavior) of repeated i.v. administrations of one of eight doses of cocaine (0.0, 0.3, 0.6, 1.2, 2.4, 3.6, 4.8, or 7.2 mg/kg) given in the home cage, with infusions of the same doses given in a novel test cage. There was no effect of environment on the acute psychomotor response to cocaine. There was, however, a significant effect of environment on the induction of sensitization. A higher dose of cocaine was required to induce sensitization when i.v. administrations were given in the home cage than when they were given in a physically identical but novel test environment. At high doses, however, cocaine induced sensitization regardless of environmental condition. The results suggest that the effect of this environmental manipulation is to shift the dose-effect curve for the induction of sensitization, and support the notion that the ability of psychostimulant drugs to induce sensitization can be modulated by the circumstances surrounding drug administration.
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