Drugs of abuse , stress , and addiction

Drugs of abuse , stress , and addiction

Neuroplasticity, the putative mechanism underlying learning and memory, is modified by drugs of abuse, alcohol and may contribute to the development of the eventual addicted state. Innovative treatments directly targeting these drug-induced changes in brain reward components and circuits may be efficacious in reducing drug use and relapse.

Nicotine promotes glutamatergic synaptic plasticity in dopaminergic (DA) neurons in the ventral tegmental area (VTA), which is thought to be an important mechanism underlying nicotine reward. However, it is unclear whether exposure of nicotine alone to VTA slice is sufficient to increase glutamatergic synaptic strength on DA neurons and which nicotinic acetylcholine receptor (nAChR) subtype mediates this effect. Here, we report that the incubation of rat VTA slices with 500 nM nicotine induces glutamatergic synaptic plasticity in DA neurons. We measure the ratio of AMPA and NMDA receptor-mediated currents (AMPA/NMDA) and compare these ratios between nicotine-treated and -untreated slices. Our results demonstrate that the incubation of VTA slices with 500 nM nicotine for 1 h (but not for 10 min) significantly increases the AMPA/NMDA ratio when compared with controls. Preincubation with 10 nM of the α7-nAChR antagonist, methyllycaconitine (MLA) but not 1 μM α4-containing nAChR antagonist, dihydro-β-erythroidine (DHβE) prevents nicotinic effect, suggesting that α7-nAChRs are mainly mediated this nicotinic effect. This finding is further supported by the disappearance of this nicotinic effect in nAChR α7 knockout (KO) mice. Furthermore, nicotine reduced paired-pulse ratio (PPR) of evoked excitatory postsynaptic potential (eEPSP) in the VTA slices prepared from wild-type (WT) mice but not α7 KO mice. Collectively, these findings suggest that exposure of smoking-relevant concentrations of nicotine to VTA slices is sufficient to increase glutamatergic synaptic strength on DA neurons and that α7-nAChRs likely mediate this nicotinic effect through increasing presynaptic release of glutamate. Synapse, 2011. © 2010 Wiley-Liss, Inc.

Alterations in neuronal activity can elicit long-lasting changes in the strength of synaptic transmission at excitatory synapses and, as a consequence, may underlie many forms of experience-dependent plasticity, including learning and memory. The best-characterized forms of such synaptic plasticity are the long-term depression (LTD) and long-term potentiation (LTP) observed at excitatory synapses in the CA1 region of the hippocampus. It is now well accepted that the trafficking of AMPA receptors to and away from the synaptic plasma membrane plays an essential role in both LTP and LTD, respectively.

In an ever-changing environment, animals must learn new behavioral strategies for the successful procurement of food, sex, and other needs. Synaptic plasticity within the mesolimbic system, a key reward circuit, affords an animal the ability to adapt and perform essential goal-directed behaviors. Ironically, drugs of abuse can also induce synaptic changes within the mesolimbic system, and such changes are hypothesized to promote deleterious drug-seeking behaviors in lieu of healthy, adaptive behaviors. In this review, we will discuss drug-induced neuroadaptations in excitatory transmission in the ventral tegmental area and the nucleus accumbens, two critical regions of the mesolimbic system, and the possible role of dopamine receptors in the development of these neuroadaptations. In particular, we will focus our discussion on recent studies showing changes in AMPA receptor function as a common molecular target of addictive drugs, and the possible behavioral consequences of such neuroadaptations.

The main characteristics of cocaine addiction are compulsive drug use despite adverse consequences and high rates of relapse during periods of abstinence. A current popular hypothesis is that compulsive cocaine use and cocaine relapse is due to drug-induced neuroadaptations in reward-related learning and memory processes, which cause hypersensitivity to cocaine-associated cues, impulsive decision making and abnormal habit-like learned behaviours that are insensitive to adverse consequences. Here, we review results from studies on the effect of cocaine exposure on selected signalling cascades, growth factors and physiological processes previously implicated in neuroplasticity underlying normal learning and memory. These include the extracellular signal-regulated kinase (ERK) signalling pathway, brain-derived neurotrophic factor (BDNF), glutamate transmission, and synaptic plasticity (primarily in the form of long-term potentiation and depression, LTP and LTD). We also discuss the degree to which these cocaine-induced neuroplasticity changes in the mesolimbic dopamine system mediate cocaine psychomotor sensitization and cocaine-seeking behaviours, as assessed in animal models of drug addiction. Finally, we speculate on how these factors may interact to initiate and sustain cocaine psychomotor sensitization and cocaine seeking.

Synaptic plasticity in the ventral tegmental area (VTA) is modulated by drugs of abuse and stress and is hypothesized to contribute to specific aspects of addiction.

Both excitatory and inhibitory synapses on dopamine neurons in the VTA are capable of undergoing long-term changes in synaptic strength. While the strengthening or weakening of excitatory synapses in the VTA has been widely examined, the role of inhibitory synaptic plasticity in brain reward circuitry is less established. Here, we investigated the effects of drugs of abuse, as well as acute stress, on long-term potentiation of GABAergic synapses onto VTA dopamine neurons (LTPGABA). Morphine (10 mg/kg i.p.) reduced the ability of inhibitory synapses in midbrain slices to express LTPGABA both at 2 and 24 h after drug exposure but not after 5 days. Cocaine (15 mg/kg i.p.) impaired LTPGABA 24 h after exposure, but not at 2 h. Nicotine (0.5 mg/kg i.p.) impaired LTPGABA 2 h after exposure, but not after 24 h. Furthermore, LTPGABA was completely blocked 24 h following brief exposure to a stressful stimulus, a forced swim task. Our data suggest that drugs of abuse and stress trigger a common modification to inhibitory plasticity, synergizing with their collective effect at excitatory synapses. Together, the net effect of addictive substances or stress is expected to increase excitability of VTA dopamine neurons, potentially contributing to the early stages of addiction.

What to eat to prevent drug and alcohol negative effects? Dietary Amino Acids

Hypothalamic orexin/hypocretin (orx/hcrt) neurons regulate energy balance, wakefulness, and reward; their loss produces narcolepsy and weight gain. Glucose can lower the activity of orx/hcrt cells, but whether other dietary macronutrients have similar effects is unclear. We show that orx/hcrt cells are stimulated by nutritionally relevant mixtures of amino acids (AAs), both in brain slice patch-clamp experiments, and in c-Fos expression assays following central or peripheral administration of AAs to mice in vivo. Physiological mixtures of AAs electrically excited orx/hcrt cells through a dual mechanism involving inhibition of KATP channels and activation of system-A amino acid transporters. Nonessential AAs were more potent in activating orx/hcrt cells than essential AAs. Moreover, the presence of physiological concentrations of AAs suppressed the glucose responses of orx/hcrt cells. These results suggest a new mechanism of hypothalamic integration of macronutrient signals and imply that orx/hcrt cells sense macronutrient balance, rather than net energy value, in extracellular fluid.

Nutritionally Relevant Mixes of Amino Acids Excite orx/hcrt Neurons In Situ

To test whether the activity of orx/hcrt cells is modulated by dietary amino acids (AAs), we first used a mixture of amino acids (“AA mix”; see Table S1 available online) based on microdialysis samples from the rat hypothalamus (Choi et al., 1999). Whole-cell patch-clamp recording showed that orx/hcrt cells depolarized and increased their firing frequency in response to the AA mix (Figure 1A; all statistics are given in the figure legends unless stated otherwise). The latency of response onset was 66 ± 5 s (n = 25). This response was unaffected by blockers of ionotropic glutamate, GABA, and glycine receptors (Figure 1B), or by blockade of spike-dependent synaptic transmission with tetrodotoxin (Figure 1C). We did not observe such AA responses in neighboring lateral hypothalamic GAD65 neurons (Figures 1D and 1F; see Experimental Procedures), or in cortical pyramidal cells (Figures 1E and 1F).

Highlights

► Brain orexin/hypocretin cells are stimulated by dietary amino acids (AAs) ► AA sensing involves K-ATP channels and system-A transporters ► Nonessential AAs stimulate orexin/hypocretin cells more than essential AAs ► AA presence prevents glucose from blocking orexin/hypocretin cells

 Effects of Physiological Amino Acid Mixes on the Membrane Potential of orx/hcrt and Other Central Neurons

(A) Effect of “AA mix” (see Table S1) on orx/hcrt cells (n = 25). Membrane potential during AA application (−39.4 ± 0.8 mV) was higher than preapplication (−51.8 ± 0.6 mV, p < 0.0001) or postapplication (−51.0 ± 1.1 mV, p < 0.0001).

(B) Same with synaptic blockers (see Experimental Procedures, n = 5). Membrane potential during AA application (−40.1 ± 1.1 mV) was depolarized relative to preapplication (−50.4 ± 0.5 mV, p < 0.002) or postapplication (−48.0 ± 1.6 mV, p < 0.02).

(C) Same as A with tetrodotoxin (0.5 μM, n = 5). Membrane potential during AA application (−42.2 ± 1.4 mV) was higher than preapplication (−53.5 ± 0.8 mV, p < 0.002) or postapplication (−51.2 ± 1.0 mV, p < 0.001).

(D) Effect of “AA mix” on non-orx/hcrt lateral hypothalamic neurons expressing GAD65 (n = 7, see Experimental Procedures). Membrane potential during AA application (−46.6 ± 1.2 mV) was not different from preapplication (−48.8 ± 1.0 mV, p > 0.15) or postapplication (−47.5 ± 1.7 mV, p > 0.6).

(E) Effect of “AA mix” on neurons from secondary somatosensory cortex layer 2-4 (n = 7). Membrane potential during AA application (−49.1 ± 0.8 mV) was not different from preapplication (−49.6 ± 0.6 mV, p > 0.3) or postapplication (−48.8 ± 1.1 mV, p > 0.8).

(F) Depolarization (means ± SEM) caused by the AA mix in different conditions, evoked from the same baseline of −50 mV (∗∗∗ = p < 0.001; n.s. = p = 0.24).

 

(G) Left, effect of switching from “low AA mix” to “AA mix” (see Table S1) on orx/hcrt cells (n = 6, quantified in F). Right, dose-response (means ± SEM) of AA-induced depolarization. Total concentration of AA mix was changed while proportions of AAs were kept same as in “AA mix” in Table S1. EC50 value (see Experimental Procedures) = 438.2 μM (equivalent to 0.66-fold of “AA mix” in Table S1).

(H) Effects of AAs in cell-attached recording mode (left, frequency histogram; right, raw trace, n = 6). Firing rate was higher in AA (6.6 ± 0.5 Hz) than in low AA (3.0 ± 0.3 Hz, p < 0.001).

Effects of Individual Amino Acids

To explore whether orx/hcrt cells are more sensitive to particular AAs, we first examined their membrane current responses to individual AAs applied at high concentration (5 mM). In this voltage-clamp assay, nonessential AAs elicited large responses, with a relative potency order glycine > aspartate > cysteine > alanine > serine > asparagine > proline > glutamine, while essential AAs were much less effective (Figures 3A and 3B). Because leucine has been suggested previously to be sensed in the hypothalamus (Cota et al., 2006), we investigated its effect across a broad concentration range in comparison with alanine (Figure 3C). Across all concentrations tested, leucine (0.02–10 mM) did not induce any detectable membrane currents, whereas alanine dose-dependently stimulated currents with an EC50 of 3.19 mM (Figure 3C).

Source: http://www.sciencedirect.com/science/article/pii/S0896627311007823

Amino acid Alanine food sources: Good sources of alanine include. Animal sources: meat, seafood, caseinate, dairy products, eggs, fish, gelatin, lactalbumin. Vegetarian sources: beans, nuts, seeds, soy, whey, brewer’s yeast, brown rice, bran, corn, legumes, whole grains.

Note that per gram of protein, eggs and egg whites provide the highest levels of BCAAs. Eggs again are also marginally superior when it comes to leucine content. This should be of interest to you because leucine is the main driver of muscle protein synthesis.
Leucine food sources Leucine content (grams/ 100 grams food)
Soybeans, mature seeds, raw
2.97
lentils, raw
2.03
cowpea, catjang, mature seeds, raw
1.83
Beef, round, top round, separable lean and fat, trimmed to 1/8″ fat, select, raw
1.76
Beef, top sirloin, separable lean only, trimmed to 1/8″ fat, choice, raw
1.74
Peanuts, all types, raw
1.67
Salami, Italian, pork
1.63
Fish, salmon, pink, raw
1.62
Crustaceans, shrimp, mixed species, raw
1.61
Chicken, broilers or fryers, thigh, meat only, raw
1.48
Nuts, almonds
1.47
Egg, yolk, raw, fresh
1.40
Chickpeas (garbanzo beans, bengal gram), mature seeds, raw
1.37
Seeds, sesame butter, tahini, from raw and stone ground kernels
1.36
Chicken, broilers or fryers, wing, meat and skin, raw
1.29
flax seed, raw
1.24
Nuts, walnuts, english
1.17
Egg, whole, raw, fresh
1.09
Egg, white, raw, fresh
1.02
Sausage, Italian, pork, raw
0.96
Milk, sheep, fluid
0.59
Pork, fresh, separable fat, raw
0.40
Hummus
0.35
Milk, goat, fluid
0.31
Milk, whole, 3.25% milkfat
0.27
Soy milk, fluid
0.24
asparagus
0.13

Habits of highly effective brain by Alvaro Fernandez

Let’s review some good lifestyle options we can all follow to maintain, and improve, our vibrant brains.

  • 1. Learn more about the “It” in “Use It or Lose It“. A basic understanding will serve you well to appreciate your brain’s beauty as a living and constantly-developing dense forest with billions of neurons and synapses.
  • 2. Take care of your nutrition. Did you know that the brain only weighs 2% of body mass but consumesgood brain food over 20% of the oxygen and nutrients we intake? As a general rule, you don’t need expensive ultra-sophisticated nutritional supplements, just make sure you don’t stuff yourself with the “bad stuff”.
  • 3. Remember that the brain is part of the body. Things that exercise your body can also help sharpen your brain: physical exercise enhances neurogenesis, at any age!
  • 4. Practice positive, action-oriented thoughts until they become your default mindset and you look forward to creating something beautiful every new day. Too much stress and anxiety–either induced by external events or by your own thoughts–actually kills neurons and prevent the creation of new ones. physical exercise for brain health
  • 5. Thrive on Learning and Mental Challenges. The point of having a brain is precisely to learn and to adapt to challenging new environments. Once new neurons appear in your brain, where they migrate and how long they survive depends on how you use them. “Use It or Lose It” does not mean “do crossword puzzle number 1,234,567”. It means, “challenge your brain, and often, with novel activities”.
  • 6. We are (as far as we know) the only self-directed organisms in this planet. Aim high. Once you graduate from college, keep learning. Once you become too comfortable in one job, find a new one. The brain keeps developing ALWAYS, reflecting what you do with it.
  • 7. Explore, travel. Adapting to new locations forces you to pay more attention to your environment. Make new decisions, use your brain.
  • 8. Don’t Outsource Your Brain. Not to media personalities, not to politicians, not to your smart neighbour… Make your own decisions, and mistakes. That way, you are training your brain, not your neighbour’s.
  • 9. Develop and maintain stimulating friendships. We are social animals, and need social interaction. Which, by the way, is why ‘Baby Einstein’ or all those educational apps have been shown not to be the panacea for children development.
  • 10. Laugh. Often. Especially to cognitively complex humor, full of twists and surprises. Better, try to become the next Jon Stewart

Now, remember that what counts is not reading this article–or any other– but practicing a bit every day until small steps snowball into unstoppable, internalized habits…”cells that fire together wire together”…so, start improving one of these 10 habits today. Revisit the habit above that really grabbed your attention, and make a decision to try something different today and tomorrow.


Connie’s comments: As we learn to dance and instruct our limbs to move, we are growing neurons. Do take acidophilus capsules, eat pickled veggies and have a strong immune system to detox our brain (also with good sleep – take melatonin and calcium and magnesium when over 40 yrs of age). Powerful whole foods rich in sulfur and resveratrol and fish are good for our brain. Add coconut oil, walnut and avocado in your dish always.

Be happy and move often (be in the sun before 9am and after 5pm).

10 proven ways to grow your brain by Thai Nguyen

 1.      Intermittent Fasting

Calorie-restriction/fasting increases synaptic plasticity, promotes neuron growth, decreases risk of neurodegenerative diseases, and improves cognitive function according to the Society for Neuroscience.

During fasting, a metabolic shift lowers the body’s leptin levels, a hormone produced by fat. As a result, the brain receives a chemical signal for neurons to produce more energy.

Popular methods include: fasting one day per week, for an entire 24-hour period; a 16-hour fast — having your last meal at 8pm and breaking your fast at lunch (12pm) the next day; the “5-2” model — five days of regular eating and two days (non-consecutive) of calorie-restricted eating in a week (between 400-600 calories).

2. Travel

Traveling promotes neurogenesis by exposing your brain to new, novel, and complex environments. Paul Nussbaum, a neuropsychologist from the University of Pittsburgh explains, “Those new and challenging situations cause the brain to sprout dendrites.”

You don’t need to travel across the world to reap these benefits either; taking a weekend road trip to a different city gives your brain the same stimulation.

3. Use Mnemonic Devices

Memory training promotes connectivity in your brain’s prefrontal parietal network and can slow memory loss with age. Mnemonic devices are a form of memory training that combines visualization, imagery, spatial navigation, and rhythm and melody.

A popular technique is known as the Method of Loci (MoL). Explained by Scientific American: It involves visualizingfamiliar route — through a building, your home, or your way to work — and placing items to be remembered at attention-grabbing spots along the way. The more bizarre you make these images, the better you will recall them later. By simply retracing your steps, like a fishing line, you will “pull up” items to the surface. Along with objects, numbers, and names, this method has helped people with depression store happy memories that they can retrieve in times of stress.

Begin using mnemonic techniques and engage in memory training; start working on remembering names, scriptures, or poems. Here are some mnemonic techniques to get you started.

4. Learn an Instrument

Brain scans on musicians show heightened connectivity between brain regions. Neuroscientists explain that playing a musical instrument is an intense, multi-sensory experience. The association of motor actions with specific sounds and visual patterns leads to the formation of new neural networks.

If you’ve always wanted to learn an instrument, consider brain growth as a motivator to get you started.

5. Non-Dominant Hand Exercises

Using your non-dominant hand to do simple tasks such as brushing your teeth, texting, or stirring your coffee/tea can help you form new neural pathways. These cognitive exercises, also known as “neurobics,” strengthen connectivity between your brain cells. “It’s like having more cell towers in your brain to send messages along. The more cell towers you have, the fewer missed calls,” explains Dr. P. Murali Doraiswamy, chief of biological psychiatry at Duke University Medical Center.

Studies have also shown that non-dominant hand activities improves your emotional health and impulse control. Switch hands with simple tasks to give you brain a workout.

6. Read Fiction

A study conducted over 19 consecutive days by Emory University showed increased and ongoing connectivity in the brains of participants after they all read the same novel. Researcher Gregory Berns, noted, “Even though the participants were not actually reading the novel while they were in the scanner, they retained this heightened connectivity.”

Enhanced brain activity was observed in the region that controls physical sensations and movement systems. Berns explains that reading a novel “can transport you into the body of the protagonist.” This ability to shift into another mental state is a crucial skill for mastering the complex social relationships. Add some novels to your reading list for these extra brain benefits.

7. Expand your Vocabulary

Learning new words activates the brain’s visual and auditory processes (seeing and hearing a word) and memory processing. A small vocabulary is linked with poor cognitive efficiency in children, while an expansive vocabulary is an indicator of student success.

Learn one new word each day to expand your vocabulary and give your brain a workout. Use apps or online courses to make it fun.

8. Create Artwork

In a journal article titled, “How Art Changes Your Brain,” participants in a 10-week art course (a two hour session, one day per week) showed enhanced connectivity of the brain at a resting state known as the “default mode network” (DMN). The DMN influences mental processes such as introspection, memory, and empathy. Engaging in art also strengthens the neural pathway that controls attention and focus.

Whether it’s creating mosaics, jewelry, pottery, painting, or drawing, the combination of motor and cognitive processing will promote better brain connectivity. Join a local art class; just once a week will help your brain grow.

9. Hit the Dance Floor

Not many of us would think of dancing as a “decision-making process,” but that’s the reason why it’s healthy for your brain. Especially free-style dancing and forms that don’t retrace memorized paths. Researchers compared the effectiveness of cognitive activities in warding off Alzheimer’s and dementia and found that dancing had the greatest effect (76% risk reduction); higher than doing crossword puzzles at least four days a week (47%) and reading (35%).

Dancing increases neural connectivity because it forces you to integrate several brain functions at once —kinesthetic, rational, musical, and emotional. If you’re dancing with a partner, learning both “Lead” and “Follow” roles will increase your cognitive stimulation.

10. Sleep

Studies from NYU showed that sleep helps learning retention with the growth of dendritic spines, the tiny protrusions that connect brain cells and facilitates the passage of information across synapses.

Aim for 7-8 hours of sleep each night. If you’re struggling to get a consistently good sleep, try creating a nightly ritual; going to bed at the same time; drinking some sleep-inducing tea; or making your room as dark as possible.


Connie’s comments:

For new parents, read and sing the rhymes to your babies. Tell stories without a book to allow the imagination of children to grow.

For adults, teach your body to move and each time you do this new neurons are being developed.

Gettting Vitamin D, sunshine, is important in many cell growths.

For caregivers, massage head and use oil of eucalyptus and apricot oil.  Talk to seniors and ask them stories about their youth.

Email Connie at motherhealth@gmail.com for herbal solutions.

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