Multiple lines of evidence indicate that hypocretin/orexin (HCRT) participates in the regulation of arousal and arousal-related process. For example, HCRT axons and receptors are found within a variety of arousal-related systems. Moreover, when administered centrally, HCRT exerts robust wake-promoting actions. Finally, a dysregulation of HCRT neurotransmission is associated with the sleep/arousal disorder, narcolepsy. Combined, these observations suggested that HCRT might be a key transmitter system in the regulation of waking. Nonetheless, subsequent evidence indicates that HCRT may not play a prominent role in the initiation of normal waking. Instead HCRT may participate in a variety of processes such as consolidation of waking and/or coupling metabolic state with behavioral state. Additionally, substantial evidence suggests a potential involvement of HCRT in high-arousal conditions, including stress. Thus, HCRT neurotransmission is closely linked to high-arousal conditions, including stress, and HCRT administrations exerts a variety of stress-like physiological and behavioral effects that are superimposed on HCRT-induced increases in arousal. Combined, this evidence suggests the hypothesis that HCRT may participate in behavioral responding under high-arousal aversive conditions. Importantly, these actions of HCRT may not be limited to stress. Like stress, appetitive conditions are associated with elevated arousal levels and a stress-like activation of various physiological systems. These and other observations suggest that HCRT may, at least in part, exert affectively-neutral actions that are important under high-arousal conditions associated with elevated motivation and/or need for action.

The hypocretin/orexin (HCRT) neuropeptide system modulates behavioral state and state-dependent processes via actions on multiple neuromodulatory transmitter systems. Recent studies indicate that HCRT selectively increases dopamine (DA) neurotransmission within the prefrontal cortex (PFC) and the shell subregion of the nucleus accumbens (NAs), but not the core subregion of the nucleus accumbens (NAc). The circuitry underlying the differential actions of HCRT across distinct DA systems is unclear. The current study examined whether HCRT preferentially activates PFC- and NAs-projecting relative to NAc-projecting DA neurons within the VTA. One week after infusion of the retrograde tracer fluorogold (FG) into the medial PFC, NAc or NAs, animals received a ventricular infusion of HCRT-1. Subsequent analyses conducted across the rostral-caudal extent of the VTA determined the degree to which:(i) Fos-immunoreactivity (ir) was observed within tyrosine hydroxylase (TH)-ir neurons;(ii) TH-ir was observed within FG-ir neurons; and (iii) Fos-ir was observed within FG-ir neurons. HCRT significantly increased Fos-ir in VTA DA (TH-ir) neurons, primarily in a restricted population of small-to-medium-sized DA neurons located within the caudomedial VTA. Furthermore, within this region of the VTA, PFC- and NAs-projecting TH-ir neurons were more likely to contain Fos-ir than were NAc-projecting TH-ir neurons. These results provide novel evidence that HCRT selectively activates PFC- and NAs-projecting DA neurons within the VTA, and suggest a potential role for HCRT in PFC- and NAs-dependent cognitive and/or affective processes. Moreover, these and other observations suggest that the dysregulation of HCRT-DA interactions could contribute to cognitive/affective dysfunction associated with a variety of behavioral disorders.

When faced with an inescapable stressor, animals may engage in 'coping' behaviors, such as chewing inedible objects, that attenuate some physiological responses to the stressor. Previous evidence indicates that dopamine neurotransmission in the right prefrontal cortex is modulated by coping processes. Here we tested whether medial prefrontal cortical (mPFC) neuronal activation, as measured by Fos-immunoreactivity (Fos-ir), was altered in rats chewing inedible objects during exposure to novelty stress. We found that chewing caused an increase in Fos-ir that was selective for the right hemisphere of the mPFC along with a decrease in Fos-ir that was selective for the right central nucleus of the amygdala (CeA), a region that may regulate dopamine neurotransmission in mPFC. These observations suggest that coping during stress engages mPFC and CeA neuronal activity asymmetrically. Synapse 63:82-85, 2009.(c) 2008 Wiley-Liss, Inc.

BACKGROUND: Despite widespread use of low-dose psychostimulants for the treatment of attention-deficit/hyperactivity disorder (ADHD), the neural basis for the therapeutic actions of these drugs are not well understood. We recently demonstrated that low-dose methylphenidate (MPH) increases catecholamine efflux preferentially within the prefrontal cortex (PFC), suggesting that the PFC is a principal site of action in the behavioral-calming and cognition-enhancing effects of low-dose psychostimulants. To understand better the neural mechanisms involved in the behavioral actions of low-dose stimulants, this study examined the effects of low-dose MPH on the discharge properties of individual and ensembles of PFC neurons. METHODS: Extracellular activity of multiple individual PFC neurons was recorded in freely moving rats using multichannel recording techniques. Behavioral studies identified optimal, working memory-enhancing doses of intraperitoneal MPH. The effects of these low-doses of MPH on PFC neuronal discharge properties were compared with 1) the effects of high-dose MPH on PFC neuronal discharge and 2) the effects of low-dose MPH on neuronal discharge within the somatosensory cortex. RESULTS: Only working memory-enhancing doses of MPH increased the responsivity of individual PFC neurons and altered neuronal ensemble responses within the PFC. These effects were not observed outside the PFC (i.e., within somatosensory cortex). In contrast, high-dose MPH profoundly suppressed evoked discharge of PFC neurons. CONCLUSIONS: These observations suggest that preferential enhancement of signal processing within the PFC, including alterations in the discharge properties of individual PFC neurons and PFC neuronal ensembles, underlie the behavioral/cognitive actions of low-dose psychostimulants.

Through a highly divergent efferent projection system, the locus coeruleus-noradrenergic system supplies norepinephrine throughout the central nervous system. State-dependent neuronal discharge activity of locus coeruleus neurons has long-suggested a role of this system in the induction of an alert waking state. More recent work supports this hypothesis, demonstrating robust wake-promoting actions of the locus coeruleus-noradrenergic system. Norepinephrine enhances arousal, in part, via actions of beta- and alpha(1)-receptors located within multiple subcortical structures, including the general regions of the medial septal area and the medial preoptic areas. Recent anatomical studies suggest that arousal-enhancing actions of norepinephrine are not limited to the locus coeruleus system and likely include the A1 and A2 noradrenergic cell groups. Thus, noradrenergic modulation of arousal state involves multiple noradrenergic systems acting within multiple subcortical regions. Pharmacological studies indicate that the combined actions of these systems are necessary for the sustained maintenance of arousal levels associated with spontaneous waking. Enhanced arousal state is a prominent aspect of both stress and psychostimulant drug action and evidence indicates that noradrenergic systems likely play an important role in both stress-related and psychostimulant-induced arousal. These and other observations suggest that the dysregulation of noradrenergic neurotransmission could well contribute to the dysregulation of arousal associated with a variety of behavioral disorders including insomnia and stress-related disorders.

The neuropeptide, corticotropin-releasing factor (CRF) has been shown to disrupt prepulse inhibition of the acoustic startle response in rodents. Prepulse inhibition is deficient in a number of psychiatric disorders. In Experiment 1, we examined whether repeated central infusion of CRF alters the reduction in prepulse inhibition caused by subsequent CRF infusion or apomorphine injection. Repeated intracerebroventricular infusion of CRF (0.3 mug) did not cause tolerance to the effect of CRF on prepulse inhibition. Additionally, repeated CRF did not alter the effect of apomorphine (0.25 mg/kg, i.p.) on prepulse inhibition. In contrast to other reported results, both CRF and apomorphine reduced baseline startle amplitude in the Brown Norway rats, which show low prepulse inhibition. In Experiment 2, we showed that a CRF-induced change in baseline startle amplitude does not contribute to the CRF-induced decrease in percent prepulse inhibition. In Experiment 3, we found that methylphenidate (20.0 mg/kg, i.p.) increased baseline startle amplitude in Brown Norway rats, yet it also decreased percent prepulse inhibition. These results suggest that CRF can be administered repeatedly without diminution of its effects on prepulse inhibition, and that in Brown Norway rats, compounds that either increase or decrease baseline startle amplitude can reduce percent prepulse inhibition independently of the effects on baseline startle.

Methylphenidate (MPH) and other psychostimulants are highly effective in the treatment of attention deficit hyperactivity disorder (ADHD). Available evidence indicates the therapeutic actions of stimulants in ADHD likely involve the locus coeruleus (LC)-norepinephrine (NE) system. LC neurons display different firing modes (tonic and phasic), each associated with distinct behavioral and cognitive processes. To date, the impact of low, clinically-relevant doses of psychostimulants on LC discharge is unknown. The present study examined the effects of low-dose MPH on LC tonic and phasic discharge in the halothane-anesthetized rat. In these studies, MPH produced a dose-dependent suppression of tonic and phasic discharge that was relatively modest at the lower doses. Nonetheless, these lower doses of MPH suppressed the signal-to-noise ratio of excitatory phasic discharge and increased the signal-to-noise ratio of the inhibitory component of the phasic response. Largely comparable effects were observed with oral and intraperitoneal administration of MPH. Combined, these observations indicate relatively modest suppression of LC neuronal discharge activity by low-dose MPH and that evoked-discharge may be more sensitive than tonic activity to the lowest doses of MPH. It is posited that the behavioral-calming and cognition-enhancing effects of low-dose psychostimulants likely involve modest alterations in LC discharge combined with increased catecholamine efflux within select forebrain regions (i.e. the prefrontal cortex).

Extensive research has provided substantial insight into the neurobiological mechanisms underlying the reinforcing, locomotor-activating and stereotypy-inducing actions of psychostimulants. The diverse behavioral effects of these drugs are superimposed on potent arousal-enhancing actions. Psychostimulant-induced arousal is a prominent contributing factor to the widespread use and abuse of these drugs. Moreover, enhanced arousal may be a critical component of the reinforcing and other behavioral actions of these drugs. Although long overlooked, recent work begins to identify the neural mechanisms involved in psychostimulant-induced arousal. For example, microdialysis studies demonstrate a close relationship between amphetamine-induced waking/arousal and amphetamine-induced increases in norepinephrine and dopamine efflux. Additionally, it is now clear that both norepinephrine and dopamine exert robust wake-promoting actions. The wake-promoting effects of norepinephrine involve synergistic actions of alpha(1)- and beta-receptors, whereas dopamine-induced waking involves both D1 and D2 receptors. Finally, additional studies have identified subcortical regions involved in the wake-promoting actions of both norepinephrine and amphetamine. These regions include, but may not be limited to, the medial septal area, the medial preoptic area, and the lateral hypothalamus. Combined, these and other observations indicate a prominent involvement of both norepinephrine and dopamine in stimulant-induced arousal via actions within a network of subcortical regions. Although it is clear that both norepinephrine and dopamine contribute to psychostimulant-induced arousal, the degree to which each transmitter system is necessary for the expression of stimulant-induced arousal remains to be fully elucidated.Neuropsychopharmacology advance online publication, 19 July 2006; doi:10.1038/sj.npp.1301159.

BACKGROUND: Low doses of psychostimulants, such as methylphenidate (MPH), are widely used in the treatment of attention-deficit/hyperactivity disorder (ADHD). Surprisingly little is known about the neural mechanisms that underlie the behavioral/cognitive actions of these drugs. The prefrontal cortex (PFC) is implicated in ADHD. Moreover, dopamine (DA) and norepinephrine (NE) are important modulators of PFC-dependent cognition. To date, the actions of low-dose psychostimulants on PFC DA and NE neurotransmission are unknown. METHODS: In vivo microdialysis was used to compare the effects of low-dose MPH on NE and DA efflux within the PFC and select subcortical fields in male rats. Doses used (oral, 2.0 mg/kg; intraperitoneal,.25-1.0 mg/kg) were first determined to produce clinically relevant plasma concentrations and to facilitate both PFC-dependent attention and working memory. RESULTS: At low doses that improve PFC-dependent cognitive function and that are devoid of locomotor-activating effects, MPH substantially increases NE and DA efflux within the PFC. In contrast, outside the PFC these doses of MPH have minimal impact on NE and DA efflux. CONCLUSIONS: The current observations suggest that the therapeutic actions of low-dose psychostimulants involve the preferential activation of catecholamine neurotransmission within the PFC.

Norepinephrine acts within select basal forebrain regions to modulate behavioral state and/or state-dependent processes, including the general regions encompassing the medial septal area, the medial preoptic area, and the substantia innominata. The present study examined the origin and organization of noradrenergic efferents to these basal forebrain regions by using combined immunohistochemical identification of noradrenergic neurons with retrograde tracing. Results indicate that the locus coeruleus provides the majority of noradrenergic input to these regions. Lesser, although at times substantial, contributions from the A1/C1 and A2/C2 adrenergic cell groups were also observed, particularly in the case of the medial preoptic region. Given the prominent state-modulating actions of the locus coeruleus, additional studies examined: 1) lateralization of locus coeruleus efferents to these regions; 2) the topographical organization of basal forebrain-projecting locus coeruleus neurons; and 3) the degree of collateralization of individual locus coeruleus neurons across these regions. Approximately 80-85% of locus coeruleus efferents to these regions project ipsilaterally. In general, basal forebrain-projecting neurons were distributed throughout the entire dorsoventral and rostrocaudal extent of the locus coeruleus. Additionally, a large proportion of locus coeruleus neurons project simultaneously to these basal forebrain terminal fields. Combined, these observations indicate coordinated actions of locus coeruleus neurons across these basal forebrain regions implicated in the regulation of behavioral state and/or state-dependent processes. J. Comp. Neurol. 496:668-683, 2006.(c) 2006 Wiley-Liss, Inc.