Antidepressants and Ketamine Induce Resilience in Animals Susceptible to Depression-Like Behavior

October 14, 2014 · Posted in Neurobiology · Comment 

ratTo study depression in humans, researchers look to rodents to learn more about behavior. Rodents who are repeatedly defeated by more aggressive animals often begin to exhibit behavior that resembles depression. At the 2014 meeting of the International College of Neuropsychopharmacology (CINP), researcher Andre Der-Avakian reported that in a recent study, repeated experiences of social defeat led to depressive behavior in a subgroup of animals (which he calls susceptible), but not in others (which he calls resilient). Among many biological differences, the resilient animals showed increases in neurogenesis in the dentate gyrus of the hippocampus.

Chronic treatment of the susceptible animals with the selective serotonin reuptake inhibitor (SSRI) antidepressant fluoxetine or the tricyclic antidepressant desipramine, which both increase neurogenesis, also reversed the depressive behavior in about half of the animals. A single injection of the anesthetic ketamine (which has rapid-acting antidepressant effects in humans) reversed social avoidance behavior in about 25% of the animals. One depression-like symptom was anhedonia (loss of pleasure from previously enjoyed activities), which researchers measured by observing to what extent the animals engaged in intracranial self-stimulation, pressing a bar to stimulate the brain pleasurably. The effectiveness of the drugs in inducing resilient behavior was related to the degree of anhedonia seen in the animals. The drugs worked less well in the more anhedonic animals (those who gave up the intracranial stimulation more easily, indicating that they experienced less reward from it.)

How the Chemicals in Marijuana Work in the Brain

October 9, 2014 · Posted in Neurochemistry · Comment 

marijuana

Raphael Mechoulam, who first synthesized THC, the main ingredient in marijuana, gave the history of marijuana and its receptors in the central nervous system in a plenary talk at the 2014 meeting of the International College of Neuropsychopharmacology. In Syria hundreds of years ago the drug was named ganzigunnu, meaning “the drug that takes away the mind.” It has also been called azalla, meaning “hand of the ghost.” Among the 100 compounds in marijuana, the best-known ingredient is delta-9-tetrahydrocannabinol (delta-9 THC), which produces most of the actions of the drug. There is another active ingredient, cannabidiol (CBD), which has calming and anti-anxiety effects, but is present in very low levels.

The brain has cannabinoid receptors that respond to ingredients in marijuana in addition to other chemicals produced in the brain. They modulate calcium ions and decrease the release of many neurotransmitters.

THC acts at CB-1 receptors, producing the high. The CB-1 receptor is synthesized on demand, post-synaptically, and is transferred to the pre-synaptic terminal where it decreases calcium and transmitter release. Consistent with marijuana’s appetite-stimulating properties (“the munchies”), if the CB-1 receptor is blocked in animals, they lose their appetite and die of hunger.

There are also low levels of CB-2 receptors in the brain, whose activation does not cause a high, and whose levels may increase dramatically in pathological situations. Activation of the CB-2 receptor is anti-inflammatory and, in the same way that the immune system acts against foreign proteins, CB-2 acts as a protector against non-proteins.

CBD does not bind to any cannabinoid receptors, but its actions are blocked by cannabinoid antagonists.

There are two chemicals in the brain (endogenous ligands) that act at cannabinoid receptors—anandamide and 2-arachidonoylglycerol (2-AG). They are soluble only in lipids (not in water), and have never been given to people. In animals, 2-AG has neuroprotective effects, decreases the size of a stroke by 60%, and increases recovery from stroke.

Marijuana and CBD in particular have also had beneficial effects in people. Marijuana decreases the nausea and vomiting associated with chemotherapy in children, has anti-inflammatory effects in rheumatoid arthritis (decreasing inflammatory marker TNF alpha), and has anti-diabetes and anti-convulsant effects.

In 2012, researcher F. Markus Leweke and colleagues showed that CBD was about as effective as the atypical antipsychotic amisulpiride in alleviating the psychotic symptoms of schizophrenia. CBD’s other effects include reducing anxiety and improving psoriasis by increasing DNA methylation (Pucci et al. 2013).

It seems possible that some of these myriad effects of marijuana and endogenous ligands at CB receptors could be exploited for clinical therapeutics, as Mechoulam endorses, but when and how that will take place remains an unanswered question.

Editor’s Note:  Despite all these potential positives of CBD, it should be noted that its levels are very low in marijuana, and that heavy smoking of marijuana has substantial adverse effects. These include low motivation, a doubling of the risk of psychosis, a hastening of the onset of bipolar disorder and schizophrenia, and cognitive impairment, as well as some changes in brain structure seen via magnetic resonance imaging (MRI). It may be becoming legal in many states, but is a bad idea for those at high risk for mood, anxiety, or bipolar disorders or for schizophrenia.

Agomelatine in an Animal Model of PTSD

October 1, 2014 · Posted in Neurobiology, Potential Treatments · Comment 

rat

At the 2014 meeting of the International College of Neuropsychopharmacology, researcher Joseph Zohar presented a poster on the effects of early post-stressor intervention with the drug agomelatine in animals who showed behavioral and molecular responses to stress that served as a model of post-traumatic stress disorder (PTSD).

Agomelatine is available clinically as an antidepressant in Canada and Europe (but not in the US), and can also reduce anxiety and re-synchronize circadian rhythms. Agomelatine is a melatonin (MT1/MT2) receptor agonist and a serotonin 5HT2C antagonist (increasing dopamine and norepinephrine in the frontal cortex).

Long-term behavioral, molecular and structural effects of the drug were assessed in animals. Adult male Sprague-Dawley rats were exposed to the scent of a predator for 10 minutes, and one hour later they were treated acutely for this stress with agomelatine (50mg/kg i.p.) or placebo.

Agomelatine decreased the prevalence of extreme, PTSD-like behavioral and molecular responses to the stressor, such as freezing in place and increased corticosterone. Agomelatine also normalized decreases in brain-derived neurotrophic factor (BDNF) observed in the dentate gyrus of the hippocampus, the cortex (layer III), and the basolateral amygdala. In line with this, agomelatine-treated stressed animals displayed significantly increased number and length of dendrites at glutamate synapses in the hippocampus (including the dentate gyrus and CA1) and reversed the hippocampal neuronal retraction observed in the rats who were given the placebo.

Agomelatine also affected the expression of clock genes in the rats, which regulate biorhythms. These genes lead to the production of the major clock gene proteins Per1 and Per2. Agomelatine normalized Per1 increases in three parts of the brain: the CA3, another glutamate synapse near the dentate gyrus; the suprachiasmatic nucleus over the optic chiasm, important for circadian rhythms; and the basolateral amygdala. Per2, a protein that also drives circadian rhythms, increased in the CA1 synapse of the hippocampus, the suprachiasmatic nucleus and the basolateral amygdala of the stressed rats.

The researchers concluded that the data provide “initial evidence that a single dose of agomelatine administered in the acute aftermath of stress promotes recovery while promoting enhanced neuronal and synaptic plasticity and connectivity in the secondary prevention of PTSD in this model.”

Patients with Schizophrenia Have Short Telomeres, Atypical Antipsychotics Increased Telomere Length in Animals

September 30, 2014 · Posted in Neurobiology · Comment 

telomereTelomeres sit at the end of DNA strands and shorten with each cell replication. A person’s percentage of short telomeres increases with aging. Telomeres also shorten with childhood adversity and as a function of number of depressive episodes.

In a recent study, researcher Kazuya Torimi found that telomeres in white cells were shorter in 42 patients with schizophrenia compared to 56 healthy control participants.

Torimi also treated mice with various antipsychotics for 2-week periods. Treatment with atypical antipsychotics, such as risperidone, olanzapine and aripiprazole, but not typical antipsychotics like haloperidol, elongated telomere length in the hippocampus. This probably occurred through effects on serotonin.

Torimi suggests that atypical antipsychotics improve negative symptoms in part through the modulation of telomere length.

Editor’s Note: Lithium has been found to increase telomere length in patients with bipolar disorder, and appears to do this through a direct effect on telomerase, an enzyme responsible for adding to telomere length. Short telomeres are associated with a large number of medical and psychiatric illnesses.

Clarifying the role of melatonin receptors in sleep

September 24, 2014 · Posted in Neurobiology · Comment 

sleeping mouse

The antidepressant agomelatine (which is available in many countries, but not the US) and the anti-insomnia drug ramelteon (Rozerem) both act as agonists at melatonin M1 and M2 receptors. New research is clarifying the role of these receptors in sleep.

In new research from Stefano Comai et al., mice who were genetically altered to have no M1 receptor (MT1KO knockout mice) showed a decrease in rapid eye movement (REM) sleep, which is linked to dreaming, and an increase in slow wave sleep. Mice who were missing the M2 receptor (MT2KO knockout mice) showed a decrease in slow wave sleep. The effects of knocking out a particular gene like M1 or M2 end up being opposite to the effect of stimulating the corresponding receptor.

The researchers concluded that MT1 receptors are responsible for REM sleep (increasing it while decreasing slow wave sleep), and MT2 receptors are responsible for slow wave non-REM sleep.

The new information about these melatonin receptors may explain why oral melatonin supplements can make a patient fall asleep faster, but do not affect the duration of non-REM sleep. The authors suggest that targeting MT2 receptors could lead to longer sleep by increasing slow wave sleep, potentially helping patients with insomnia.

In Mice, Autism-Like Behavior Connected to Problems Pruning Dendritic Spines

September 11, 2014 · Posted in Neurobiology · Comment 
spines on a dendrite

Spines on a dendrite

Autism spectrum disorders are associated with developmental abnormalities at excitatory synapses. Dendrites, the branched projections of neurons where electrical signals are passed from one cell to the next, are covered in hundreds to thousands of spines that facilitate the synaptic connections with other neurons. These spines are created and also pruned as part of normal learning and development.

Post-mortem examination of the brains of patients with autism spectrum disorders shows increased density of dendritic spines and less pruning in certain neurons in the temporal lobe. These examinations also show impaired mTOR autophagy. MTOR is a protein that plays a role in cell growth and survival. Autophagy is the normal process by which some components of cells are broken down.

A 2014 study by Guomei Tang et al. in the journal Neuron showed that mice that are genetically altered to have overactive mTOR also have reduced dendritic spine pruning, blockade of autophagy, and increased autism-like behaviors. An immunosuppressant drug called rapamycin inhibits mTOR, and treating the mice with this drug corrected the problems with spine pruning and the autism-like behaviors. (This was not true for mice who had been altered to have another type of autophagy.) Normal spine formation was not affected by the restored pruning ability.

Tang et al. concluded that mTOR autophagy plays an important role in dendritic spine pruning, and that restoring neuronal autophagy can correct synaptic abnormalities and restore normative social behavior in mice with hyperactive mTOR.

Thalamus Implicated in Depression-Like Behavior and Resilience to It

September 10, 2014 · Posted in Neurobiology · Comment 
thalamus

thalamus

At the 2014 meeting of the International College of Neuropsychopharmacology, researcher Scott Russo described characteristics of rodents who showed depression-like behavior after 10 days of exposure to a larger, more aggressive animal (a phenomenon known as defeat stress). These animals exhibited many behaviors that resembled human depression, including anxiety-like behaviors while navigating a maze; activation of the hypothalamic-pituitary-adrenal axis; circadian rhythm abnormalities; metabolic changes such as glucose intolerance; susceptibility to addiction; anhedonia, a lack of interest in sucrose, sex or intracranial self-stimulation; and profound and permanent social avoidance.

In susceptible animals, Russo found anatomical changes in the GABAergic neurons of the nucleus accumbens (also known as the ventral striatum), including increased numbers of synapses and a greater number of stubby spines on dendrites (the branched projections of neurons where electrical signals are passed from one cell to the next), as well as greater excitability of glutamatergic input, observed as excitatory post-synaptic potentials.

Russo’s attempt to identify these key neurons among the billions of neurons and the 100 to 500 trillion synapses in the brain was like the search for a needle in a haystack, but thinks he found it. The medium spiny neurons of the nucleus accumbens contain GABA and receive synapses from the prefrontal cortex, amygdala, and intralaminar nucleus of the thalamus (ILT), in addition to dopamine inputs from the VTA, and cholinergic, somatostatin, and orexin inputs. Russo found that it was the ILT inputs that conveyed susceptibility to defeat stress, and their presynaptic endings showed increased levels of glutamate transporters (VGLUT-2). Driving the ILT was sufficient to cause the rodents to display the depression-like behaviors, and silencing the ILT during defeat stress prevented the susceptible behaviors (like social avoidance) and promoted resilience.

Methamphetamine Kills Dopamine Neurons in the Midbrain of Mice

July 18, 2014 · Posted in Neurobiology, Risk Factors · Comment 

mice receiving an injection

Epidemiological studies have linked methamphetamine use to risk of Parkinson’s disease, and animal studies of the illicit drug have shown that it harms dopamine neurons. A 2014 study by Sara Ares-Santos et al. in the journal Neuropsychopharmacology compared the effects of repeated low or medium doses to those of a single high dose on mice. Loss of dopaminergic terminals, where dopamine is released, was greatest after three injections of 10mg/kg given at three-hour intervals, followed by three injections of 5 mg/kg at three-hour intervals, and a one-time dose of 30mg/kg. All of the dosages produced similar rates of degeneration of dopamine neurons via necrosis (cell destruction) and apoptosis (cell suicide) in the substantia nigra pars compacta (the part of the brain that degenerates in Parkinson’s disease) and the striata.

Patients with Bipolar Disorder More Creative; Creativity Associated with Worse Functional Connectivity of Brain Regions

May 12, 2014 · Posted in Neurobiology · Comment 

woman paintingWhile bipolar disorder can be a devastating illness, multiple studies indicate it is also associated with high levels of creativity. Researchers T. Su and Y. Kuan compared highly creative and normally creative patients with bipolar disorder to healthy controls with either normal or high creativity in the hopes of clarifying some characteristics of creativity in bipolar disorder. At the 2014 meeting of the International Society for Bipolar Disorders, the researchers reported finding greater creativity in patients with bipolar disorder compared to normal controls, and that high creativity was associated with altered functional connectivity of two regions of the brain: the medial prefrontal cortex and the striatum.

The researchers hope to contribute to treatment solutions that can help patients with bipolar disorder reduce their emotional disturbance without losing their more positive cognitive functions like creativity.

Editor’s Note: Benson et al. found that compared to normal controls, bipolar patients had more positive hyperconnectivity of many brain regions using positron emission tomography (PET) scans with fludeoxyglucose to measure brain activity. Su and Kuan used functional magnetic resonance imaging (fMRI) and found less connectivity of these two regions. How these differences relate to bipolar disorder and its links to creativity remain to be further studied.

Mania-like State Produced in Rats By Kindling the Lateral Hypothalamus

April 25, 2014 · Posted in Neurobiology · Comment 

rats

The lateral hypothalamus is responsible for certain physiological functions (the sleep-wake cycle, appetite, energy expenditure, and sexual functions) that are disrupted during mania. At the 2014 meeting of the International Society for Bipolar Disorders, researcher O. Abulseoud et al. presented evidence that a mania-like state could be produced in rats by “kindling” the lateral hypothalamus with an electrode.

The kindled rats engaged in more motor activity; less rest; more sexual self-stimulation; excessive rearing, feeding, and grooming; and more ethanol consumption. Non-kindled rats (and those kindled in other areas such as the nucleus accumbens shell and the infralimbic cortex) did not engage in this combination of behaviors.

To test the similarity between the mania-like behaviors and human mania, the researchers treated the kindled rats with saline solution, lithium, or valproic acid. Lithium and valproic acid reduced these behaviors significantly compared to the saline solution. These treatments also produced long-term increases in mRNA for certain genes (Per1 and CLOCK) that are dysregulated in people with mania.

This animal model may become useful in future research on manic psychopathology in humans.

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