Mustansir Diwan

Antidepressant-like effects of medial prefrontal cortex deep brain stimulation in rats.

BACKGROUND Subcallosal cingulate gyrus (SCG) deep brain stimulation (DBS) is being investigated as a treatment for major depression. We report on the effects of ventromedial prefrontal cortex (vmPFC) DBS in rats, focusing on possible mechanisms involved in an antidepressant-like response in the forced swim test (FST). METHODS The outcome of vmPFC stimulation alone or combined with different types of lesions, including serotonin (5-HT) or norepineprhine (NE) depletion, was characterized in the FST. We also explored the effects of DBS on novelty-suppressed feeding, learned helplessness, and sucrose consumption in animals predisposed to helplessness. RESULTS Stimulation at parameters approximating those used in clinical practice induced a significant antidepressant-like response in the FST. Ventromedial PFC lesions or local muscimol injections did not lead to a similar outcome. However, animals treated with vmPFC ibotenic acid lesions still responded to DBS, suggesting that the modulation of fiber near the electrodes could play a role in the antidepressant-like effects of stimulation. Also important was the integrity of the serotonergic system, as the effects of DBS in the FST were completely abolished in animals bearing 5-HT, but not NE, depleting lesions. In addition, vmPFC stimulation induced a sustained increase in hippocampal 5-HT levels. Preliminary work with other models showed that DBS was also able to influence specific aspects of depressive-like states in rodents, including anxiety and anhedonia, but not helplessness. CONCLUSIONS Our study suggests that vmPFC DBS in rats may be useful to investigate mechanisms involved in the antidepressant effects of SCG DBS.

In vivo quantification of regional dopamine-D3 receptor binding potential of (+)-PHNO: Studies in non-human primates and transgenic mice.

Examination of dopamine‐D3 (D3) receptors with positron emission tomography (PET) have been hampered in the past by the lack of a PET ligand with sufficient selectivity for D3 over dopamine‐D2 (D2) receptors. The two types co‐localize in the brain, with D2 density significantly higher than D3, hence nonselective PET ligands inform on D2, rather than D3 status. [11C]‐(+)‐PHNO is a novel PET ligand with a preferential affinity for D3 over D2. We used the selective D3 antagonist, SB‐277011 to dissect regional fractions of the [11C]‐(+)‐PHNO signal attributable to D3 and D2 in primate brain. The results were compared with quantitative autoradiography with 3H‐(+)‐PHNO in wild‐type, D2‐knock‐out, and D3‐knock‐out mice examined at baseline and following administration of SB‐277011. Both sets of results converged to indicate a predominant D3‐related component to (+)‐PHNO binding in extra‐striatal regions, with binding in the midbrain being entirely attributable to D3. The midbrain is thus an excellent target region to examine D3 receptor occupancy with [11C]‐(+)‐PHNO PET in vivo. Synapse 63:782–793, 2009.

Uncoupling the dopamine D1-D2 receptor complex exerts antidepressant-like effects

We report that coupling between dopamine D1 and D2 receptors was markedly increased in postmortem brain of subjects suffering from major depression. Biochemical analyses revealed that D1 and D2 receptors form heterodimers via a direct protein-protein interaction. Administration of an interfering peptide that disrupts the D1-D2 receptor complex substantially reduced immobility in the forced swim test (FST) without affecting locomotor activity, and decreased escape failures in learned helplessness tests in rats.

Effects of different stimulation parameters on the antidepressant-like response of medial prefrontal cortex deep brain stimulation in rats

Subcallosal cingulate gyrus (SCG) deep brain stimulation (DBS) is currently being investigated as a treatment for major depression. Despite the encouraging findings of the initial clinical series, several questions remain unanswered, including the most effective stimulation parameters (i.e., current intensity and frequency) and whether unilateral stimulation is also beneficial. We have recently found that some of the effects of SCG DBS could be modeled by stimulating the ventromedial prefrontal cortex (vmPFC) of rats undergoing the forced swim test (FST). Here we investigate whether changes in a number of DBS parameters, including electrode placement, influence outcome in this paradigm. Overall, we found that the antidepressant-like effects of DBS varied as a function of stimulation settings and target. The strongest response was observed with a current intensity of 200 microA, followed by 100 microA, and 300 microA. In contrast, 400 microA produced no effect. Using 200 microA, a frequency of 130 Hz was more effective than 20 Hz. An intriguing finding was that left unilateral stimulation was as effective as bilateral DBS. When different targets within the vmPFC were considered, a significant antidepressant-like response was observed after PL DBS, whereas IL stimulation was associated with a non-significant reduction in immobility scores. In summary, vmPFC DBS at high frequency and moderate intensity led to a maximal response in the FST.

Less is more: antipsychotic drug effects are greater with transient rather than continuous delivery.

BACKGROUND Most studies on the effects of antipsychotics focus on achieving threshold levels of the drug. The speed and frequency with which drug concentrations reach threshold levels and rise and fall within the day are generally ignored. Based on prior data, we predicted that variations in the within-day kinetics of antipsychotic drug delivery would produce different outcomes, even if we held achieved dose, route, and total duration of treatment constant. METHODS We compared the effects of within-day continuous (via minipump) versus transient (via subcutaneous injection) haloperidol treatment (n = 4-9/condition/experiment) at doses that yield equivalent peak levels of striatal D2 receptor occupancy (approximately 74%). RESULTS Over time, transient haloperidol gained efficacy, while continuous haloperidol lost efficacy in two animal models of antipsychotic-like effects (the suppression of amphetamine-induced locomotion and conditioned avoidance responding). This was related to the fact that continuous treatment led to a greater increase in striatal D2 receptor numbers--particularly D2 receptors in a high-affinity state for dopamine--relative to transient treatment and produced behavioral dopamine supersensitivity (as indicated by an enhanced locomotor response to amphetamine following antipsychotic treatment cessation). Treatment kinetics also influenced the postsynaptic response to haloperidol. Transient treatment increased striatal c-fos messenger RNA (mRNA) expression, while continuous treatment did not. CONCLUSIONS Relative to continuous antipsychotic exposure, within-day transient exposure is more efficacious behaviorally and is associated with a distinct molecular and gene expression profile. Thus, differences in the within-day kinetics of antipsychotic treatment can have different efficacy, and the potential clinical implications of this should be explored further.

Deep brain stimulation in rats: different targets induce similar antidepressant-like effects but influence different circuits.

Recent studies in patients with treatment-resistant depression have shown similar results with the use of deep brain stimulation (DBS) in the subcallosal cingulate gyrus (SCG), ventral capsule/ventral striatum (VC/VS) and nucleus accumbens (Acb). As these brain regions are interconnected, one hypothesis is that by stimulating these targets one would just be influencing different relays in the same circuitry. We investigate behavioral, immediate early gene expression, and functional connectivity changes in rats given DBS in homologous regions, namely the ventromedial prefrontal cortex (vmPFC), white matter fibers of the frontal region (WMF) and nucleus accumbens. We found that DBS delivered to the vmPFC, Acb but not WMF induced significant antidepressant-like effects in the FST (31%, 44%, and 17% reduction in immobility compared to controls). Despite these findings, stimulation applied to these three targets induced distinct patterns of regional activity and functional connectivity. While animals given vmPFC DBS had increased cortical zif268 expression, changes after Acb stimulation were primarily observed in subcortical structures. In animals receiving WMF DBS, both cortical and subcortical structures at a distance from the target were influenced by stimulation. In regard to functional connectivity, DBS in all targets decreased intercorrelations among cortical areas. This is in contrast to the clear differences observed in subcortical connectivity, which was reduced after vmPFC DBS but increased in rats receiving Acb or WMF stimulation. In conclusion, results from our study suggest that, despite similar antidepressant-like effects, stimulation of the vmPFC, WMF and Acb induces distinct changes in regional brain activity and functional connectivity.

Towards a better preclinical model of PTSD: characterizing animals with weak extinction, maladaptive stress responses and low plasma corticosterone.

Most of the available preclinical models of PTSD have focused on isolated behavioural aspects and have not considered individual variations in response to stress. We employed behavioural criteria to identify and characterize a subpopulation of rats that present several features analogous to PTSD-like states after exposure to classical fear conditioning. Outbred Sprague-Dawley rats were segregated into weak- and strong-extinction groups on the basis of behavioural scores during extinction of conditioned fear responses. Animals were subsequently tested for anxiety-like behaviour in the open-field test (OFT), novelty suppressed feeding (NSF) and elevated plus maze (EPM). Baseline plasma corticosterone was measured prior to any behavioural manipulation. In a second experiment, rats underwent OFT, NSF and EPM prior to being subjected to fear conditioning to ascertain whether or not pre-stress levels of anxiety-like behaviours could predict extinction scores. We found that 25% of rats exhibit low extinction rates of conditioned fear, a feature that was associated with increased anxiety-like behaviour across multiple tests in comparison to rats showing strong extinction. In addition, weak-extinction animals showed low levels of corticosterone prior to fear conditioning, a variable that seemed to predict extinction recall scores. In a separate experiment, anxiety measures taken prior to fear conditioning were not predictive of a weak-extinction phenotype, suggesting that weak-extinction animals do not show detectable traits of anxiety in the absence of a stressful experience. These findings suggest that extinction impairment may be used to identify stress-vulnerable rats, thus providing a useful model for elucidating mechanisms and investigating potential treatments for PTSD.

Antagonizing 5-HT2A receptors with M100907 and stimulating 5-HT2C receptors with Ro60-0175 blocks cocaine-induced locomotion and zif268 mRNA expression in Sprague-Dawley rats

Serotonin (5-HT) plays a role in several psychiatric disorders including drug addiction. The 5-HT system modulates the activity of midbrain dopamine (DA) systems, and the behavioural effects of psychostimulants mediated by these systems. The direction of this modulation depends upon the 5-HT receptor subtypes involved, with 5-HT(2A) and 5-HT(2C) receptors having opposing effects. For example the 5-HT(2A) receptor antagonist M100907 and the 5-HT(2C) receptor agonist Ro60-0175 both attenuate several cocaine-induced behavioural and neurochemical effects. To investigate the possible brain regions involved in the interactions between 5-HT(2A) or 5-HT(2C) receptor ligands and cocaine-induced behaviour, we examined the effects of M100907 or Ro60-0175 on cocaine-induced locomotion and mRNA expression of the immediate early gene zif268. Sprague-Dawley rats were pre-treated with M100907 (0.5mg/kg), Ro60-0175 (1.0mg/kg) or vehicle, and then injected with cocaine (15mg/kg) or vehicle. Locomotor activity was monitored for 60 min before rats were sacrificed for zif268 mRNA in situ hybridization mapping. Cocaine increased locomotor activity and zif268 mRNA expression consistently in the nucleus accumbens core, the orbitofrontal cortex and the caudate. M100907 attenuated cocaine-induced locomotion and zif268 mRNA expression in these brain regions in a defined subset of rats but failed to alter any effects of cocaine in another defined subset of rats. Ro60-0175 blocked cocaine-induced locomotion and zif268 mRNA expression in similar brain regions. Our results suggest that despite the opposing actions of 5-HT at 5-HT(2A) and 5-HT(2C) receptors, ligands acting on these receptors likely modulate cocaine-induced locomotion via a common mechanism to influence DA-dependent circuitry.

Prefrontal Cortex Deep Brain Stimulation Improves Fear and Anxiety-Like Behavior and Reduces Basolateral Amygdala Activity in a Preclinical Model of Posttraumatic Stress Disorder

Deep brain stimulation (DBS) is being investigated for a number of psychiatric indications, including posttraumatic stress disorder (PTSD). Preclinical studies continue to be a cornerstone for the development of new DBS applications. We investigate whether DBS delivered to the infralimbic cortex (IL), a region involved in mechanisms of stress resiliency, may counter behavioral abnormalities in rats that present persistent extinction deficits and long-term anxiety after exposure to fear conditioning. Rats undergoing fear conditioning/extinction were segregated into weak and strong extinction groups (WE >70% or SE <30% of freezing during extinction). Following 2 weeks of DBS, animals were exposed to novel recall sessions and tested in the open field, novelty-suppressed feeding, and elevated plus maze. zif268 expression was measured in structures involved in mechanisms of fear and stress. In vivo electrophysiology was used to record activity from the basolateral amygdala (BLA). We found that DBS improved extinction deficits and anxiety-like behavior in WE animals, having no significant effects in SE rats. No major differences in absolute zif268 levels were recorded across groups. However, correlation between zif268 expression in the IL and BLA was disrupted in WE animals, a deficit that was countered by DBS treatment. Electrophysiology experiments have shown that DBS reduced BLA firing of both putative principal cells and interneurons in WE rats, with no significant differences being detected between SE and SE DBS animals. In summary, IL DBS mitigated fear, partially improved anxiety-like behavior, reversed neurocircuitry abnormalities, and reduced BLA cell firing in a preclinical model of PTSD.

Pharmacological and autoradiographic studies on the pathophysiological role of GABAB receptors in the dystonic hamster: pronounced antidystonic effects of baclofen after striatal injections

The GABA(B) receptor (GABA(B)R) agonist baclofen is known to have a beneficial potency in patients who suffer from dystonia, a neurological syndrome characterized by involuntary co-contractions of opposing muscles. The underlying mechanisms of this movement disorder are still unclear. Previous studies in the dt(sz) hamster, an animal model of primary paroxysmal dystonia, revealed alterations of the GABAergic system, including a reduction of striatal GABAergic interneurons and an altered GABA(A) receptor (GABA(A)R) binding in several brain regions. In order to clarify the pathophysiological role of central GABA(B)Rs in the hamster mutant, we performed pharmacological and receptor autoradiographic studies. Systemic administration of the GABA(B)R agonist (R)-baclofen (1.5, 2.5 and 3.5 mg/kg i.p.) produced pronounced antidystonic effects in the dt(sz) hamster. Striatal microinjections of baclofen (0.125, 0.25 and 0.5 microg/0.5 microl) also strongly reduced the severity of dystonia. Single striatal administration of the selective GABA(B)R antagonist CGP 35348 [(3-Aminopropyl)(diethoxymethyl)phosphinic acid, 5 and 10 microg/0.5 microl] did not influence the severity of dystonia, but antagonized the antidystonic effect of baclofen. For receptor autoradiographic studies, [H3]-CGP 54626 ([S-(R*,R*)]-[3-[[1-(3,4-Dichlorophenyl)ethyl]amino]-2-hydroxypropyl](cyclohexylmethyl)phosphinic acid) binding was determined in dt(sz) hamsters in comparison to non-dystonic control hamsters. [H3]-CGP 54626 binding was not altered in motor areas but in some limbic structures of dt(sz) hamsters. In view of the absence of striatal changes in GABA(B) binding, the strong antidystonic effect of baclofen after its striatal microinjection is probably related to a suppression of a pathophysiologically increased synaptic activity.