Receptor Binding In Brain Regions Research Articles

Low serotonin1B receptor binding potential in the anterior cingulate cortex in drug-free patients with recurrent major depressive disorder

The pathophysiology of major depressive disorder (MDD) is not fully understood and the diagnosis is largely based on history and clinical examination. So far, several lines of preclinical data and a single imaging study implicate a role for the serotonin1B (5-HT1B) receptor subtype. We sought to study 5-HT1B receptor binding in brain regions of reported relevance in patients with MDD. Subjects were examined at the Karolinska Institutet PET centre using positron emission tomography (PET) and the 5-HT1B receptor selective radioligand [11C]AZ10419369. Ten drug-free patients with recurrent MDD and ten control subjects matched for age and sex were examined. The main outcome measure was [11C]AZ10419369 binding in brain regions of reported relevance in the pathophysiology of MDD. The [11C]AZ10419369 binding potential was significantly lower in the MDD group compared with the healthy control group in the anterior cingulate cortex (20% between-group difference), the subgenual prefrontal cortex (17% between-group difference), and in the hippocampus (32% between-group difference). The low anterior cingulate [11C]AZ10419369 binding potential in patients with recurrent MDD positions 5-HT1B receptor binding in this region as a putative biomarker for MDD and corroborate a role of the anterior cingulate cortex and associated areas in the pathophysiology of recurrent MDD.

An anxiety-like phenotype in mice selectively bred for aggression

Using selective bi-directional breeding procedures, two different lines of mice were developed. The NC900 line is highly reactive and attacks their social partners without provocation, whereas aggression in NC100 animals is uncommon in social environments. The enhanced reactivity of NC900 mice suggests that emotionality may have been selected with aggression. As certain forms of anxiety promote exaggerated defensive responses, we tested NC900 mice for the presence of an anxiety-like phenotype. In the open field, light–dark exploration, and zero maze tests, NC900 mice displayed anxiety-like responses. These animals were less responsive to the anxiolytic actions of diazepam in the zero maze than NC100 animals; diazepam also reduced the reactivity and attack behaviors of NC900 mice. The NC900 mice had reduced diazepam-sensitive GABA A receptor binding in brain regions associated with aggression and anxiety. Importantly, there was a selective reduction in levels of the GABA A receptor α 2 subunit protein in NC900 frontal cortex and amygdala; no changes in α 1 or γ 2 subunit proteins were observed. These findings suggest that reductions in the α 2 subunit protein in selected brain regions may underlie the anxiety and aggressive phenotype of NC900 mice. Since anxiety and aggression are comorbid in certain psychiatric conditions, such as borderline personality and posttraumatic stress disorder, investigations with NC900 mice may provide new insights into basic mechanisms that underlie these and related psychiatric conditions.

Frontolimbic Serotonin 2A Receptor Binding in Healthy Subjects Is Associated with Personality Risk Factors for Affective Disorder

Serotonergic dysfunction has been associated with affective disorders. High trait neuroticism, as measured on personality inventories, is a risk factor for major depression. In this study we investigated whether neuroticism is associated with serotonin 2A receptor binding in brain regions of relevance for affective disorders. Eighty-three healthy volunteers completed the standardized personality questionnaire NEO-PI-R (Revised NEO Personality Inventory) and underwent [(18)F]altanserin positron emission tomography imaging for assessment of serotonin 2A receptor binding. The correlation between the neuroticism score and frontolimbic serotonin 2A receptor binding was evaluated by multiple linear regression analysis with adjustment for age and gender. Neuroticism correlated positively with frontolimbic serotonin 2A receptor binding [r(79) = .24, p = .028]. Post hoc analysis of the contributions from the six constituent traits of neuroticism showed that the correlation was primarily driven by two of them: vulnerability and anxiety. Indeed, vulnerability, defined as a person's difficulties in coping with stress, displayed the strongest positive correlation, which remained significant after correction for multiple comparisons (r = .35, p = .009). In healthy subjects the personality dimension neuroticism and particularly its constituent trait, vulnerability, are positively associated with frontolimbic serotonin 2A binding. Our findings point to a neurobiological link between personality risk factors for affective disorder and the serotonergic transmitter system and identify the serotonin 2A receptor as a biomarker for vulnerability to affective disorder.

Maternal Separation Leads to Persistent Reductions in Pain Sensitivity in Female Rats

We determined responses to noxious thermal stimuli, before and after morphine, and mu-opioid receptor binding in brain regions involved in nociception in maternally separated (MS), neonatally handled (H) and nonhandled (NH) female rats. Long-Evans dams were randomly assigned to either 180-minute (MS) or 15-minute (H) minute daily separations from their litters or left undisturbed (NH). At 120 days of age, paw lick latency (50 degrees C hot plate) was determined in offspring during diestrous. Rats were then given 1, 2, 5, or 10 mg/kg morphine and paw lick latency was measured. Rats were killed during diestrous and mu-opioid receptor binding was determined in discrete brain regions, using [(3)H]DAMGO autoradiography. MS rats had significantly longer (P < .05) paw lick latencies compared with H rats. The percent maximal possible effect of morphine was significantly (P < .05) lower in MS compared with H rats for the 5 mg/kg dose. Mu-Opioid receptor binding capacity was significantly greater (P < .05) in MS rats compared with H rats in the medial preoptic nucleus. In conclusion, MS and H treatments led to antipodal differences in pain sensitivity in female rats and differential mu-opioid receptor binding in the medial preoptic nucleus. This article describes the persistent impact of early life adversity on pain sensitivity and the analgesic potency of morphine. Clinically, early life history may play an important role in pain symptoms and responses to opioid analgesics.

Adolescent nicotine administration alters serotonin receptors and cell signaling mediated through adenylyl cyclase

Nicotine is a neuroteratogen that targets synaptic function during critical developmental stages and recent studies indicate that CNS vulnerability extends into adolescence, the age at which smoking typically commences. We administered nicotine to adolescent rats via continuous minipump infusions from PN30 to PN47.5, using 6 mg/kg/day, a dose rate that replicates the plasma nicotine levels found in smokers, and examined 5HT receptors and related cell signaling during nicotine administration (PN45) and in the post-treatment period (PN50, 60, 75). Adolescent nicotine decreased 5HT 2 receptor binding in brain regions containing 5HT projections (hippocampus and cerebral cortex), with selectivity for females in the cerebral cortex; regions containing 5HT cell bodies showed either an increase (midbrain in males) or no change (brainstem). In contrast, there were no significant changes in 5HT 1A receptors; however, the ability of the receptors to signal through adenylyl cyclase (AC) showed a switch from stimulatory to inhibitory effects in females during the post-treatment period. There were also transient alterations in AC responses to β-adrenergic receptor stimulation, as well as pronounced induction of the AC response to the non-receptor-mediated stimulant, forskolin. Our results indicate that adolescent nicotine exposure alters the concentrations and functions of postsynaptic 5HT receptors in a manner commensurate with impaired 5HT synaptic function. The direction of change, emergence of defects after the cessation of nicotine administration, and sex-preference for effects in females, all support a relationship of impaired 5HT function to the higher incidence of depression seen in adolescent smokers.

Maternal exposure to Δ 9-tetrahydrocannabinol facilitates morphine self-administration behavior and changes regional binding to central μ opioid receptors in adult offspring female rats

Opiates and cannabinoids are among the most widely consumed habit-forming drugs in humans. Several studies have demonstrated the existence of interactions between both kind of drugs in a variety of effects and experimental models. The present study has been focused to determine whether perinatal Δ 9-tetrahydrocannabinol (Δ 9-THC) exposure affects the susceptibility to reinforcing effects of morphine in adulthood and whether these potential changes were accompanied by variations in μ opioid receptor binding in brain regions related to drug reinforcement. Adult female rats born from mothers that were daily treated with Δ 9-THC during gestation and lactation periods, exhibited a statistically significant increase in the rate of acquisition of intravenous morphine self-administration behavior when compared with females born from vehicle-exposed mothers, an effect that did not exist in Δ 9-THC-exposed male offspring. This increase was significantly greater on the last day of acquisition period. There were not significant differences when the subjects were lever pressing for food. In parallel, we have also examined the density of μ opioid receptors in the brain of adult male and female offspring that were exposed to Δ 9-THC during the perinatal period. Collectively, perinatal exposure to Δ 9-THC produced changes in μ opioid receptor binding that differed regionally and that were mostly different as a function of sex. Thus, Δ 9-THC-exposed males exhibited a lower density for these receptors than their respective oil-exposed controls in the caudate-putamen area as well as in the amygdala (posteromedial cortical nucleus). On the contrary, Δ 9-THC-exposed females exhibited higher density of these receptors than their respective oil-exposed controls in the prefrontal cortex, the hippocampus (CA3 area), the amygdala (posteromedial cortical nucleus), the ventral tegmental area and the periaqueductal grey matter, whereas the binding was lower than control females only in the lateral amygdala. These results support the notion that perinatal Δ 9-THC exposure alters the susceptibility to morphine reinforcing effects in adult female offspring, in parallel with changes in μ opioid receptor binding in several brain regions.

Age-differences in choline acetyltransferase activities and muscarinic receptor binding in brain regions of C57BL/6J mice

Muscarinic receptor binding and choline acetyltransferase (ChAT, EC.2.3.1.6.) activity were assayed in four brain regions of C57BL/6J mice of four ages (4, 12, 18, and 24 months). In the cerebellum, there were no age differences in either of the cholinergic markers. However, significant age differences were noted in the V max for ChAT and in the B max for [ 3H]quinuclidinyl benzilate ([ 3H]QNB) in the cortex, striatum and hippocampus. Increases were noted in V max of the synthetic enzyme in all three regions and for B max in the hippocampus. B max for [ 3H]QNB decreased in the cortex and striatum. The high- and lower-affinity muscarinic binding constants, the percentage of muscarinic binding to high affinity sites determined by carbamylcholine displacement of [ 3H]QNB, as well as the affinities of ChAT for acetyl coenzyme A and choline chloride showed no age differences in any brain region.

Selective changes of receptor binding in brain regions of aged rats

Binding to several receptors was compared in brain regions of 3 and. 21–23 month-old rats. In crude membrane preparations of aged rats the number of dopamine antagonist receptors in striatum was much reduced (−53%). β-Noradrenergic receptors (cortex) and benzodiazepine receptors (hippocampus and cerebellum) were less but significantly reduced and serotonergic receptors, α 1 noradrenergic receptors (both in cortex) and dopamine agonist receptors (striatum) were unchanged. For each receptor binding the K D values were the same in young and old animals. GABA receptor binding (hippocampus and cerebellum) evaluated at only one 3H-GABA concentration (8 nM) was similar in both groups when expressed per protein content but significantly reduced in aged rats when expressed per tissue wet weight because of the partial purification of the synaptic membranes used for 3H-GABA binding. In our experimental conditions age-related changes of specific binding sites in the central nervous system were selective for some receptors studied and did not seem to be due to general non-specific modification of brain tissue composition.