The dopamine D3-preferring D2/D3 dopamine receptor partial agonist, cariprazine, reverses behavioral changes in a rat neurodevelopmental model for schizophrenia

Current antipsychotic medication is largely ineffective against the negative and cognitive symptoms of schizophrenia. One promising therapeutic development is to design new molecules that balance actions on dopamine D2 and D3 receptors to maximise benefits and limit adverse effects. This study used two rodent paradigms to investigate the action of the dopamine D3-preferring D3/D2 receptor partial agonist cariprazine. In adult male rats, cariprazine (0.03-0.3mg/kg i.p.), and the atypical antipsychotic aripiprazole (1-3mg/kg i.p.) caused dose-dependent reversal of a delay-induced impairment in novel object recognition (NOR). Treating neonatal rat pups with phencyclidine (PCP) and subsequent social isolation produced a syndrome of behavioral alterations in adulthood including hyperactivity in a novel arena, deficits in NOR and fear motivated learning and memory, and a reduction and change in pattern of social interaction accompanied by increased ultrasonic vocalisations (USVs). Acute administration of cariprazine (0.1 and 0.3mg/kg) and aripiprazole (3mg/kg) to resultant adult rats reduced neonatal PCP-social isolation induced locomotor hyperactivity and reversed NOR deficits. Cariprazine (0.3mg/kg) caused a limited reversal of the social interaction deficit but neither drug affected the change in USVs or the deficit in fear motivated learning and memory. Results suggest that in the behavioral tests investigated cariprazine is at least as effective as aripiprazole and in some paradigms it showed additional beneficial features further supporting the advantage of combined dopamine D3/D2 receptor targeting. These findings support recent clinical studies demonstrating the efficacy of cariprazine in treatment of negative symptoms and functional impairment in schizophrenia patients

The novel antipsychotic cariprazine stabilizes gamma oscillations in rat hippocampal slices

Background and purpose: Gamma oscillations are fast rhythmic fluctuations of neuronal network activity ranging from 30 to 90 Hz that establish a precise temporal background for cognitive processes such as perception, sensory processing, learning, and memory. Alterations of gamma oscillations have been observed in schizophrenia and are suggested to play crucial roles in the generation of positive, negative, and cognitive symptoms of the disease. Experimental approach: In this study, we investigated the effects of the novel antipsychotic cariprazine, a D3 -preferring dopamine D3 /D2 receptor partial agonist, on cholinergically induced gamma oscillations in rat hippocampal slices from treatment-naïve and MK-801-treated rats, a model of acute first-episode schizophrenia. Key results: The D3 receptor-preferring agonist pramipexole effectively decreased the power of gamma oscillations, while the D3 receptor antagonist SB-277011 had no effect. In treatment-naïve animals, cariprazine did not modulate strong gamma oscillations but slightly improved the periodicity of non-saturated gamma activity. Cariprazine showed a clear partial agonistic profile at D3 receptors at the network level by potentiating the inhibitory effects when the D3 receptor tone was low and antagonizing the effects when the tone was high. In hippocampal slices of MK-801-treated rats, cariprazine allowed stabilization of the aberrant increase in gamma oscillation power and potentiated resynchronization of the oscillations. Conclusion and implications: Data from this study indicate that cariprazine stabilizes pathological hippocampal gamma oscillations, presumably by its partial agonistic profile. The results demonstrate in vitro gamma oscillations as predictive biomarkers to study the effects of antipsychotics preclinically at the network level

The Rat 5.-HydroxytryptaminelB Receptor Is the Species Homo- logue of the Human 5-HydroxytryptaminelD$ Receptor

SUMMARY The relationship between the serotonin 5-hydroxytryptaminelB (5-HT1B) and 5-HT1D receptors has been the topic of much investigation and speculation since their complementary species distribution was first appreciated. The cloning of genes encoding 5-HT1D receptors has provided tools to investigate this relationship directly. In this study, a rat gene has been cloned that encodes the rat 5-HT1B receptor. Evaluation of the structure of this gene shows that it is a member of the guanine nucleotide- These data indicate that, although the 5-HT1B and 5-HT1D receptors are pharmacologically distinct, they are species variants of the same receptor gene, the 5-HTlD gene

Studies of the effect of parasympathetic denervation on the muscarinic cholinergic receptors of the rat parotid gland

High affinity, specific [3H] quinuclidinyl benzilate, ([3H] QNB) binding sites were identified in the rat salivary gland membranes. The binding process exhibited Kd and Bmax of 0.57 ± 0.16 nM and 52 ± 8.02 fmol/mg protein for the parotid gland respectively and 0.3 ± 0.025 nM and 101 ± 9.11 fmol/mg protein for the submaxillary gland respectively. Parasympathetic denervation (Px) of the rat parotid gland by means of avulsion of the auriculo-temporal nerve was found to be specific to the parotid gland and did not affect the submaxillary gland. (Px) caused a maximum reduction of &sim; 30% in the parotid gland wet weight and a maximum decrease of &sim; 80% in choline acetyl transferase (ChAT) activity, 3-6 weeks following surgery. When expressed as fmol/gland Bmax of [3H] QNB was decreased by a maximum of &sim; 30% . This loss was probably due to the removal of the presynaptic nerve terminals. Muscarinic receptors were further studied using [^3H] N-methylscopolamine ([^3H] NMS) which, due to its hydrophilic nature is a more favourable ligand than [^3H] QNB. [^3H] NMS binding was of high affinity and specificity with a Kd of 0.4 ± 0.05 nM and Bmax of 138 ± 9.56 fmol/mg protein. (Px) caused a decrease of &sim; 40% in the Bmax of [3H] NMS expressed as fmol/gland, 3 weeks following surgery. (Px) also caused an increase in the affinity of carbachol as determined from displacement of [3H] NMS binding. The results suggested that denervation causes an increase in the affinity of M1 receptor subtypes. The physiological responsiveness of the rat parotid gland was measured by monitoring K+ transport, measured by 86Rb efflux. Denervation caused a shift to the left of the 86Rb efflux dose-response curve to carbachol and phenylephrine (3.75 and 3.37 fold respectively). Further (Px) increased the intrinsic activity of the partial agonist pilocarpine and converted it to a full agonist. When surface receptors were by-passed using the Ca+ + ionophore A-23187 to elicit 86Rb efflux, control and denervated parotid gland slices were equally responsive. These findings suggest that the observed supersensitivity of receptors on the rat parotid gland caused by (Px) is not due to an increase in receptor number but may be associated with an increase in the affinity of agonists for the receptor subtype M1. Further the possibility of an altered receptor-signal transduction mechanism between the receptor and phospholipid turnover/Ca+ + mobilization requires to be fully investigated. (D72311/87)</p