Guanfacine produces differential effects in frontal cortex compared with striatum: assessed by phMRI BOLD contrast.

RATIONALE: Guanfacine (an alpha-(2A) adrenoreceptor agonist) is a drug of benefit in the treatment of attention deficit hyperactivity disorder (ADHD) (Taylor FB, Russo J, J Clin Psychopharmacol 21:223-228, 2001). Assessment of this drug using neuroimaging will provide information about the brain regions involved in its effects. OBJECTIVES: The pharmacological magnetic resonance imaging blood oxygenation level dependent (BOLD) response was determined in rat brain regions following administration of guanfacine. METHODS: Male rats were individually placed into a 2.35 T Bruker magnet for 60 min to achieve basal recording of changes in signal intensity. Either saline (n = 9) or guanfacine (0.3 mg/kg, i.p.; n = 9) was then administered and recording was continued for a further 90 min. Data were analysed for BOLD effects using statistical parametric maps. Respiration rate, blood pressure and blood gases were monitored and remained constant throughout scanning. RESULTS: The main changes observed were negative BOLD effects in the caudate putamen and nucleus accumbens with positive BOLD effects in frontal association, prelimbic and motor cortex areas. CONCLUSIONS: These data suggest that guanfacine can decrease neuronal activity in the caudate while increasing frontal cortex activity. This ability to change neuronal activity in specific areas of rat brain that are known to be impaired in ADHD (Solanto MV, Behav Brain Res 130:65-71, 2002) may contribute to guanfacine's beneficial effects.

Effect of Thunbergia laurifolia, a Thai natural product used to treat drug addiction, on cerebral activity detected by functional magnetic resonance imaging in the rat.

RATIONALE: Thunbergia laurifolia Linn. (TL) is an herbal medicine used to treat alcohol and drug addiction in Thai traditional medicine. A previous study demonstrated that an extract of TL increases rat striatal dopamine release in vitro. OBJECTIVES: This study determined whether a methanol extract of TL altered rat brain region activity using in vivo functional nuclear magnetic resonance imaging (fMRI) in a manner consistent with the observed effects in vitro on dopamine release. METHODS: fMRI was performed on a 2.35-T Bruker MR system. MR images were acquired from rat brain using the rapid acquisition relaxation enhanced sequence (field of view 50 mm). The imaging parameters used for the anatomical scan yielded an in-plane spatial resolution of 0.2x0.2 mm. Consecutive single-slice functional imaging over the rat brain investigated the changes in signal intensity in various parts of the brains induced by TL (200 mg/kg, i.p.) or vehicle administration. RESULTS: These demonstrate that TL increased signal intensity in various brain areas such as nucleus accumbens, globus pallidus, amygdala, frontal cortex, caudate putamen and hippocampus. These are similar to those reported previously to show effects after either cocaine or amphetamine administration. Physiological variables were not affected by the injection of TL (200 mg/kg, i.p.), but there was a small decrease in arterial blood pressure. CONCLUSIONS: The results indicate that TL increases significant neuronal activity in specific brain regions responsible for reward and locomotor behaviour (fixed-effect analysis); however, there is no significant difference between TL and vehicle-treated groups with random-effect analysis (population statistic). The active compound(s) in TL responsible for the pharmacological effects of TL remain to be identified.

Behavioural and pharmacological magnetic resonance imaging assessment of the effects of methylphenidate in a potential new rat model of attention deficit hyperactivity disorder.

RATIONALE: The psychomotor stimulant methylphenidate is used in the treatment of attention deficit hyperactivity disorder (ADHD). Whereas the mechanism is not fully understood it is suggested to involve restoration of impaired dopamine function found in ADHD. OBJECTIVES: The aim of this study was to determine the effects of methylphenidate on brain region activation in vivo using pharmacological magnetic resonance imaging (phMRI) in a potential rat model of ADHD. METHODS: Rats were treated bi-daily [from postnatal day (PND) 24] for 4 days with the dopamine re-uptake inhibitor GBR 12909 (30 mg/kg i.p) or vehicle (control). On PND 57 rats were administered methylphenidate (4 mg/kg i.p) and locomotor activity measured. In a separate group of animals, blood oxygen level dependent (BOLD) response was measured using phMRI to determine changes in brain region activation produced by methylphenidate (4 mg/kg i.p.) in GBR 12909-pretreated or control rats. RESULTS: Methylphenidate produced a greater locomotor-stimulant response in controls compared with GBR 12909 rats. Pretreatment with GBR 12909 reduced the BOLD response produced by methylphenidate compared with that in control animals. The main effects of methylphenidate on the BOLD response were seen in the caudate, frontal cortex, hippocampus and hypothalamus. CONCLUSIONS: Short-term treatment with GBR 12909 in young rats causes long-term changes in dopaminergic systems, altering the methylphenidate-induced behavioural response and brain region activation compared with that in vehicle-pretreated rats. The results further support the view that altered dopaminergic function may be an important factor in ADHD and the value of animal models with this functional neurochemical deficit.

The application of functional magnetic resonance imaging to neuropharmacology.

The technique of functional magnetic resonance imaging (fMRI) has the capacity to acquire data with spatial and temporal resolution that far exceeds other currently available methods of non-invasive investigation of brain function. This coupled with its ability for serial studies makes it an attractive prospect for investigating the effects of pharmacological agents in the brain. Recent advances in fMRI have been made in the areas of reward and dependence, brain trauma and injury, psychotropic drugs and pain using small animals. Although the use of fMRI in pharmacological studies is becoming popular, there are various associated complications, such as the possible interference of drugs with the mechanisms that give rise to the pharmacological fMRI signal, and local or global cardiovascular changes that might produce functional responses unrelated to neural activity. Consideration of these concerns, coupled with careful attention to experimental detail and verification procedures, promises to make pharmacological fMRI use a valuable tool for understanding the actions of drugs in the brain.