Darragh P. Devine

Habit-forming actions of nomifensine in nucleus accumbens

Rats learned to lever-press when reinforced with response-contingent microinfusions of the dopamine uptake inhibitor nomifensine (1.7 nmol per injection) into the ventro-medial (shell) region of nucleus accumbens septi (NAS). The drug was not effective when similar injections were given either in random relation to lever-pressing, into the more dorso-lateral (core) region of NAS, or into the frontal cortex. Cocaine was also effective in NAS, but considerably less so. These data suggest that response-contingent dopamine uptake blockade within the NAS is sufficient to establish and maintain instrumental response habits.

The novel neuropeptide orphanin FQ fails to produce conditioned place preference or aversion

An unbiased conditioned place preference procedure was used to determine whether the newly-identified neuropeptide orphanin FQ produced motivational effects after intracerebroventricular microinjections. Microinjections of orphanin FQ (0.1-100 nmol) failed to produce conditioned place preference or aversion, but a pronounced motor impairment was observed during conditioning sessions with the two highest doses. Thus, it appears that orphanin FQ lacks motivational effects when administered at behaviourally active doses.

Rats rapidly develop tolerance to the locomotor-inhibiting effects of the novel neuropeptide orphanin FQ.

We examined the effects of intracerebroventricular (i.c.v.) administration of orphanin FQ (OFQ) on locomotor activity in rats. The rats were habituated to locomotor-testing boxes and then injected i.c.v. with OFQ (0–10 nmoles). Acute injections of OFQ produced dose-orderly reductions in horizontal locomotion and rearing activity. This suppression of motor activity was characterized by a disruption of balance and muscle control. Within minutes of i.c.v. injection of the higher doses of OFQ, the rats exhibited flaccid muscle tone. They each lay in an atypical posture, pressing the abdomen against the floor, and splaying the hindlimbs. When these rats locomoted, their gate was unsteady. They wobbled from side to side, and frequently fell over. Repeated daily injections of OFQ resulted in a rapid development of tolerance to the OFQ-induced suppression of locomotion and rearing activity. Tolerance to the observed impairments of motor control were also apparent. In the rats that were repeatedly treated with the highest dose (10 nmol) of OFQ, tolerance to the motoric effects was still apparent after 7 days without OFQ treatment.

Nociceptin/orphanin FQ regulates neuroendocrine function of the limbic-hypothalamic-pituitary-adrenal axis

We examined the effects of the neuropeptide nociceptin/orphanin FQ on activity of the limbic-hypothalamic-pituitary-adrenal axis (also known as the stress axis) in rats. This axis regulates important metabolic functions, and initiates critical neuroendocrine responses that cope with environmental threats and challenges to homeostatic functioning. Disregulation of the limbic-hypothalamic-pituitary-adrenal axis is associated with impaired physical and psychological health. In the present experiments, rats were treated with intracerebroventricular injections of nociceptin/orphanin FQ in the presence or absence of acute stressors. Plasma adrenocorticotrophic hormone and corticosterone concentrations were assayed 15 or 30min after injections. In the rats that were not exposed to stress, nociceptin/orphanin FQ produced dose-orderly elevations of circulating adrenocorticotrophic hormone and corticosterone concentrations. These effects were also found after administration of the nociceptin/orphanin FQ analogues, des-Phe orphanin FQ and [Phe(1)psi(CH(2)-NH)Gly(2)]nociceptin((1-13))NH(2). In rats that were exposed to the mild stress of a novel environment, nociceptin/orphanin FQ administration enhanced the stress-induced elevations of plasma adrenocorticotrophic hormone concentrations and prolonged the stress-induced elevations of plasma corticosterone concentrations. In rats that were exposed to restraint stress, nociceptin/orphanin FQ administration did not augment the stress-induced elevations in plasma hormones, perhaps because of a ceiling effect. We conclude that administration of nociceptin/orphanin FQ activates neuroendocrine activity of the limbic-hypothalamic-pituitary-adrenal axis even in the absence of a stressor, and may delay the shutdown of these physiological responses after exposure to acute mild stress. In light of the known functions of this axis, it appears that nociceptin/orphanin FQ participates in the regulation of important metabolic functions, and may be implicated in physiological responses to stress. This interaction between nociceptin/orphanin FQ and the limbic-hypothalamic-pituitary-adrenal axis implicates nociceptin/orphanin FQ in important aspects of physiological and psychological well-being.

Differential effects of stress on escape and reflex responses to nociceptive thermal stimuli in the rat

Acute stress has been shown to increase latencies of nociceptive reflexes, and this effect is considered evidence for stress-induced analgesia. However, tests for nociception that rely on motivated operant escape assess cerebral processing of pain and could be modulated independent of reflex responses. We therefore compared the effects of an acute stressor (restraint) on escape responses and lick/guard reflexes to stimulation of the paws by a thermally regulated floor. Testing sessions included a pre-test exposure to 36 degrees C, followed by a test trial in which either escape from 44 or 36 degrees C or reflex responses to 44 degrees C were observed. Behavioral responses to stress were assessed during a three day period, with baseline testing on day 1, post-stress or control testing on day 2, and evaluation of long-term stress effects on day 3. On day 2, half the animals received 15 min of restraint stress, followed by 15-min pre-test and test trials. Licking and guarding responses to thermal stimulation during 44 degrees C test trials were significantly reduced by restraint stress, confirming previously reported stress effects on nociceptive reflexes. In contrast, learned escape responses to the same thermal stimulus were significantly enhanced after stress. The increase in operant sensitivity suggests that acute restraint, a form of psychological stress, produces hyperalgesia for a level of thermal stimulation that preferentially activates C nociceptors. These results are discussed in relation to studies involving physical or psychological forms of stress, different nociceptive stimuli, and assessment strategies used to evaluate thermal pain sensitivity.

Mesolimbic dopamine neurotransmission is increased by administration of μ-opioid receptor antagonists

Microdialysis and high pressure liquid chromatography were used to assess the effects of ventral tegmental area microinjections of the mu-opioid receptor antagonists D-Pen-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) and beta-funaltrexamine (beta-FNA) on extracellular ventral striatal dopamine and metabolite concentrations. While CTOP is known to antagonize the increases in extracellular ventral striatal dopamine and dopamine metabolite concentrations induced by ventral tegmental area microinjections of a mu-opioid receptor agonist, it produced dose-orderly increases in ventral striatal dopamine and dopamine metabolite concentrations when administered by itself. beta-FNA also elevated dopamine and metabolite concentrations. These mu-agonist-like effects of the mu-opioid receptor antagonists were unexpected and suggest that a complex local circuitry mediates opioid-dopamine interactions in the ventral tegmental area. Since mu-opioids are known to act on ventral tegmental neurons that contain gamma-aminobutyric acid (GABA), a model of interactions between GABAergic afferents to the ventral tegmental area and ventral tegmental GABAergic interneurons is proposed.

Roles of the bed nucleus of stria terminalis and of the amygdala in N/OFQ-mediated anxiety and HPA axis activation

Nociceptin/orphanin FQ (N/OFQ) is an opioid-related neuropeptide that is widely distributed in limbic regions of the brain. After intracerebroventricular (icv) injections in rodents, N/OFQ produces elevations in hypothalamic-pituitary-adrenal (HPA) axis activity, and has been reported to produce both anxiogenic and anxiolytic actions. We examined the neuroanatomical basis of these effects with injections of N/OFQ (0.01-1.0nmol) into the lateral ventricle, the amygdala, and the bed nucleus of stria terminalis (BNST) in independent groups of well-handled rats under low stress conditions. Anxiety-related behaviors were evaluated in a neophobic test of anxiety. The latency to enter, total time spent in, and number of entries into an unfamiliar open field and its central zone were measured. After the open field testing, plasma samples were obtained for analysis of HPA axis activity. The N/OFQ-treated rats displayed more anxiety-related behaviors than vehicle-treated rats did with all three of the injection types. However, these effects were greater and more consistent after the icv injections (0.01-1.0nmol) than they were after the amygdala (0.10-1.0nmol) or BNST (1.0nmol) injections. The icv and BNST injections also produced elevations in circulating corticosterone, indicating that the HPA axis was activated in these rats. Intra-amygdaloid injections did not affect corticosterone levels during the open field testing. These results indicate that the amygdala and BNST participate in the anxiogenic behavioral effects of N/OFQ. However, since the most potent effects were seen after icv N/OFQ injections, the anxiogenic and HPA axis-activating effects of N/OFQ appear to occur through additive actions in multiple limbic (and perhaps cortical and brainstem) sites.

Sensory and motor characterization in the postnatal valproate rat model of autism.

Although autism is diagnosed according to three core features of social deficits, communication impairments, and repetitive or stereotyped behaviors, other behavioral features such as sensory and motor impairments are present in more than 70% of individuals with autism spectrum disorders (ASD). Exposure of rat pups to the teratogen valproate during sensitive periods of brain development has been shown to elicit behavioral features associated with autism diagnosis and has been proposed as a valid animal model of the disorder. The purpose of this study was to characterize sensory and motor performance in rats postnatally treated with valproate. Thirty-four rat pups were injected with either valproate (150 mg/kg) or saline on postnatal days 6–12. Auditory and tactile startle as well as auditory sensory gating was assessed during both the juvenile and adolescent stages of development; motor testing was conducted during late adolescence and included a sunflower seed eating task and a vermicelli handling task. Valproate-treated rats were underresponsive to auditory stimuli, showed deficits in auditory sensory gating, and demonstrated impairments in motor speed and performance. These findings suggest that postnatal valproate treatment elicits sensory and motor features often seen in individuals with ASD. Further, the hyposensitivity seen in postnatally valproate-treated rats contrasted with hypersensitivity previously reported in prenatally valproate-exposed rats. This suggests that timing of teratogenic exposure during early brain development may be important to consider when investigating the neurobiological basis of sensorimotor impairments in ASD.

Effects of Environmental Enrichment on Repetitive Behaviors in the BTBR T+tf/J Mouse Model of Autism

Lower order and higher order repetitive behaviors have been documented in the BTBR T+tf/J (BTBR) mouse strain, a mouse model that exhibits all three core behavioral domains that define autism. The purpose of this study was to evaluate the effectiveness of environmental enrichment for reducing repetitive behaviors in BTBR mice. Lower order behaviors were captured by assaying the time and sequence of grooming, while higher order behaviors were measured using pattern analysis of an object exploration task from digital recordings. Baseline scores were established at 7 weeks of age, followed by 30 days of housing in either a standard or enriched cage. As expected, BTBR mice spent significantly more time grooming and had a more rigid grooming sequence than control C57BL/6J mice did at baseline. After 30 days of enrichment housing, BTBR mice demonstrated a significant reduction in time spent grooming, resulting in levels that were lower than those exhibited by BTBR mice in standard housing. However, no changes were noted in the rigidity of their grooming sequence. In contrast to previous findings, there was no difference in repetitive patterns of exploration at baseline between BTBR and C57BL/6J mice in the object exploration test. Subsequently, enrichment did not significantly alter the number of repetitive patterns at posttest. Overall, the results suggest that environmental enrichment may be beneficial for reducing the time spent engaging in lower order repetitive behaviors, but may not change the overall quality of the behaviors when they do manifest. Autism Res 2013, ●●: ●●–●●.

Ventral mesencephalic ∂ opioid receptors are involved in modulation of basal mesolimbic dopamine neurotransmission : an anatomical localization study

Microdialysis was used to examine the anatomical localization of mesencephalic delta opioid receptors that participate in modulation of mesolimbic dopamine (DA) neurotransmission. Independent groups of rats were injected with DPDPE into the ventral tegmental area (VTA) or interpeduncular nucleus (IPN). Extracellular nucleus accumbens DA and DOPAC concentrations were elevated after DPDPE injections into either site, but injections into the VTA were effective at lower doses than were injections into the IPN. Thus, it appears that the DA-modulating actions of DPDPE are mediated in the VTA rather than the IPN.