Oxytocin attenuates phencyclidine hyperactivity and increases social interaction and nucleus accumben dopamine release in rats.

The pituitary neuropeptide oxytocin promotes social behavior, and is a potential adjunct therapy for social deficits in schizophrenia and autism. Oxytocin may mediate pro-social effects by modulating monoamine release in limbic and cortical areas, which was investigated herein using in vivo microdialysis, after establishing a dose that did not produce accompanying sedative or thermoregulatory effects that could concomitantly influence behavior. The effects of oxytocin (0.03-0.3 mg/kg subcutaneous) on locomotor activity, core body temperature, and social behavior (social interaction and ultrasonic vocalizations) were examined in adult male Lister-hooded rats, using selective antagonists to determine the role of oxytocin and vasopressin V1a receptors. Dopamine and serotonin efflux in the prefrontal cortex and nucleus accumbens of conscious rats were assessed using microdialysis. 0.3 mg/kg oxytocin modestly reduced activity and caused hypothermia but only the latter was attenuated by the V1a receptor antagonist, SR49059 (1 mg/kg intraperitoneal). Oxytocin at 0.1 mg/kg, which did not alter activity and had little effect on temperature, significantly attenuated phencyclidine-induced hyperactivity and increased social interaction between unfamiliar rats without altering the number or pattern of ultrasonic vocalizations. In the same rats, oxytocin (0.1 mg/kg) selectively elevated dopamine overflow in the nucleus accumbens, but not prefrontal cortex, without influencing serotonin efflux. Systemic oxytocin administration attenuated phencyclidine-induced hyperactivity and increased pro-social behavior without decreasing core body temperature and selectively enhanced nucleus accumbens dopamine release, consistent with activation of mesocorticolimbic circuits regulating associative/reward behavior being involved. This highlights the therapeutic potential of oxytocin to treat social behavioral deficits seen in psychiatric disorders such as schizophrenia.

The atypical antipsychotic risperidone reverses the recognition memory deficits induced by post-weaning social isolation in rats.

RATIONALE: Rearing rats in isolation from weaning is an established preclinical neurodevelopmental model which induces behavioural deficits with apparent translational relevance to some core symptoms of schizophrenia. OBJECTIVE: This study evaluated the ability of the atypical antipsychotic risperidone to reverse behavioural deficits induced by post-weaning social isolation of rat pups and to further characterise the predictive validity of this model. METHOD: Forty-five male Lister hooded rats were housed in groups of 3-4 (n = 16) or singly (n = 29) for 4 weeks immediately after weaning on postnatal day (PND) 22-24. On PND 51, novel cage-induced locomotor activity (LMA) was assessed to subdivide rats into groups balanced for behavioural response. On PNDs 58, 59, 65 and 72, rats received either vehicle (1 ml/kg; i.p.) or risperidone (0.2 or 0.5 mg/kg; i.p.) 30 min prior to testing in LMA, novel object discrimination (NOD), prepulse inhibition (PPI) of acoustic startle and conditioned emotional response (CER) learning paradigms, respectively. RESULTS: Isolation rearing had no effect on PPI, but produced LMA hyperactivity and impaired NOD and CER compared to group-housed controls. Risperidone caused a dose-dependent reduction in LMA, irrespective of rearing condition, but selectively reversed the NOD deficit in isolation-reared rats. Risperidone did not reverse the isolation rearing-induced CER deficit. CONCLUSIONS: Similar to its clinical profile, risperidone only partially reverses the schizophrenic symptomology; since it reversed some, but not all, of the learning and memory deficits induced by post-weaning isolation, the isolation rearing model may be useful to predict antipsychotic activity of novel therapeutic agents.

Chronic phencyclidine (PCP)-induced modulation of muscarinic receptor mRNAs in rat brain: impact of antipsychotic drug treatment.

Many antipsychotics (APDs) have a high affinity for muscarinic receptors, which is thought to contribute to their therapeutic efficacy, or side effect profile. In order to define how muscarinic receptor gene expression is affected by atypical or typical APDs, rats were treated with chronic (2.58 mg/kg) PCP (a psychotomimetic) or vehicle, plus clozapine (20 mg/kg/day) or haloperidol (1 mg/kg/day), and M1, M2 and M3 receptor mRNA levels were determined in brain sections. Negligible changes in M2 or M3 muscarinic mRNA were detected in any region after clozapine or haloperidol. Chronic PCP administration increased M1 mRNA expression in the prefrontal cortex, which was not reversed by either chronic clozapine or haloperidol treatment. Chronic clozapine treatment in combination with PCP treatment decreased M1 receptor mRNA levels in the nucleus accumbens core, whereas chronic haloperidol in combination with PCP treatment increased M1 receptor mRNA levels in the ventromedial hypothalamus and medial amygdala. Thus M1 receptor gene expression is targeted by APDs, although the regions affected differ according to the APD treatment and whether PCP has been administered. The different brain circuitry modulated, may reflect the differing modes of action of typical and atypical APDs. These data provide support for the dysregulation of M1 receptors in schizophrenia, and furthermore, modulation by antipsychotic agents in the treatment of schizophrenia.

The atypical antipsychotic drug clozapine enhances chronic PCP-induced regulation of prefrontal cortex 5-HT2A receptors.

The ability of antipsychotic drugs to affect 5-HT(2A) receptor function has been widely suggested to contribute to their therapeutic properties. We have compared the ability of the antipsychotic drugs clozapine and haloperidol, alone and in combination with chronic phencyclidine (PCP), to modulate 5-HT(2A) receptor binding and mRNA. Acute (i.p. 45 min) and chronic (21-day) clozapine (osmotic minipump (OMP); 20 mg/kg/day) produced widespread decreases in 5-HT(2A) receptor binding (-60%-80%), measured using [(3)H]ketanserin autoradiography. Conversely, 5-HT(2A) mRNA levels, determined using in-situ hybridisation, were modestly increased by chronic clozapine treatment (+10%-30%). Chronic PCP treatment, at a dose (2.58 mg/kg i.p. intermittently for 28 days) that reproduces many of the neurochemical deficits of schizophrenia, decreased 5-HT(2A) receptor binding in the prefrontal cortex (PFC; -16%), consistent with the changes in post-mortem brain tissue from schizophrenic patients. Combined chronic PCP (i.p.) and clozapine (OMP) treatment down-regulated 5-HT(2A) receptor binding in many areas, similar to the effects of clozapine treatment alone and clozapine further enhanced the effects of PCP in the prefrontal cortex. In contrast 5-HT(2A) mRNA was not altered. Haloperidol treatment alone (1 mg/kg/day; OMP) and in combination with PCP (i.p.), generally produced no changes in 5-HT(2A) receptor protein or mRNA. Hence chronic PCP treatment, as employed here, mimics the decreased 5-HT(2A) receptor binding observed in the PFC of schizophrenic patients. Clozapine's enhancement of the natural response of PCP to down-regulate PFC 5-HT(2A) receptors may contribute to it's improved therapeutic profile against negative symptoms and cognitive deficits.

Induction of metabolic hypofunction and neurochemical deficits after chronic intermittent exposure to phencyclidine: differential modulation by antipsychotic drugs.

Numerous human imaging studies have revealed an absolute or relative metabolic hypofunction within the prefrontal cortex, thalamus and temporal lobes of schizophrenic patients. The former deficit correlates with cognitive deficits and negative symptoms, whereas the latter correlates with positive symptomologies. There is also general consensus that schizophrenia is associated with decreased parvalbumin expression in the prefrontal cortex. Since the drug phencyclidine can induce a psychosis resembling schizophrenia in humans, we have examined whether repeated phencyclidine (PCP) treatment to rats could produce similar metabolic and neurochemical deficits to those occurring in schizophrenia and whether these deficits could be modulated by antipsychotic drugs. We demonstrate here that chronic intermittent exposure to PCP (2.58 mg kg(-1) i.p.) elicits a metabolic hypofunction, as demonstrated by reductions in the rates of glucose utilization, within the prefrontal cortex, reticular nucleus of thalamus and auditory system, key structures displaying similar changes in schizophrenia. Moreover, chronic PCP treatment according to this regime also decreases parvalbumin mRNA expression in the rat prefrontal cortex and reticular nucleus of the thalamus. Chronic coadministration of haloperidol (1 mg kg(-1) day(-1)) or clozapine (20 mg kg(-1) day(-1)) with PCP did not modulate PCP-induced reductions in metabolic activity in the rat prefrontal cortex, but reversed deficits in the structures of the auditory system. Clozapine, but not haloperidol, reversed PCP-induced decreases in parvalbumin expression in prefrontal cortex GABAergic interneurons, whereas both drugs reversed the deficits in the reticular nucleus of the thalamus. These data provide important new information, which strengthen the validity of chronic PCP as a useful animal model of schizophrenia, when administered according to this protocol. Furthermore, we propose that reversal of PCP-induced reductions in parvalbumin expression in the prefrontal cortex may be a potential marker of atypical antipsychotic activity in relation to amelioration of cognitive deficits and negative symptoms of schizophrenia.