Acute Hypoglycemia Presenting as Methamphetamine psychosis

[Quercetin]

Glucose Regulation

Glucose is the principal brain fuel. Most other cells and organs of the body are able to "burn" fat as well as glucose to produce ATP bioenergy, but brain neurons can only burn glucose under normal, non-starvation/ketogenic conditions. The brain is only 2% of the body mass, yet typically consumes 15-20% of total body ATP energy. The brain is dependent on a second-by-second delivery of glucose from the bloodstream, as neurons can only store about a 2-minute supply of glucose (as glycogen) at any given time. The brain must routinely have access to a large portion of the glucose flowing through the bloodstream.

Unlike most other body tissues, the brain does not require insulin to absorb glucose from the blood. The effect of insulin on the brain is less well defined. Elevations of circulating insulin can alter brain function, augmenting the counterregulatory response to hypoglycemia, altering feeding behavior. Thus, the optimal blood status for the brain to acquire its disproportionately large share of blood sugar is a normal blood sugar level, combined with low blood insulin. When insulin is low or absent in the bloodstream, the rest of the body will ignore the blood sugar and burn fat or amino acids for their fuel.

The chief stimulant for insulin release is carbohydrate. A surge in blood sugar (glucose) from rapidly absorbed dietary sugar/refined starch may increase insulin levels 10-fold within minutes, and keep on increasing insulin to even higher levels for 2-3 hours. This will cause a rapid glucose uptake by almost all body tissues, leaving far less than optimal supplies for the brain. Methamphetamine is known to stimulate production of insulin, leaving the brain with less then adequate amount of glucose.

Vinpocetine

Vinpocetine is a slightly altered form of vincamine, an alkaloid extracted from the Periwinkle plant, vinca minor. In use for almost 30 years, research has gradually shown vinpocetine to be the superior vinca alkaloid, having few and minor if any side effects, with a greater range of metabolic and clinical benefits than vincamine. Vinpocetine has been shown to be a cerebral metabolic enhancer and a selective cerebral vasodilator (i.e. one which increases blood flow only to brain regions where it is compromised). Vinpocetine has been shown to enhance oxygen and glucose uptake from blood by brain neurons, and to increase neuronal ATP energy production, even under hypoxic (low oxygen) conditions. Both animal and human research has shown vinpocetine to restore impaired brain carbohydrate/energy metabolism.

Vinpocetine inhibits glutamate release induced by the convulsive agent 4-aminopyridine more potently than several antiepileptic drugs.
4-Aminopyridine (4-AP) is a convulsing agent that in vivo preferentially releases Glu, the most important excitatory amino acid neurotransmitter in the brain. Here the ionic dependence of 4-AP-induced Glu release and the effects of several of the most common antiepileptic drugs (AEDs) and of the new potential AED, vinpocetine on 4-AP-induced Glu release were characterized in hippocampus isolated nerve endings pre-loaded with labelled Glu ([3H]Glu). 4-AP-induced [3H]Glu release was composed by a tetrodotoxin (TTX) sensitive and external Ca2+ dependent fraction and a TTX insensitive fraction that was sensitive to the excitatory amino acid transporter inhibitor, TBOA. The AEDs: carbamazepine, phenytoin, lamotrigine and oxcarbazepine at the highest dose tested only reduced [3H]Glu release to 4-AP between 50-60%, and topiramate was ineffective. Vinpocetine at a much lower concentration than the above AEDs, abolished [3H]Glu release to 4-AP. We conclude that the decrease in [3H]Glu release linked to the direct blockade of presynaptic Na+ channels, may importantly contribute to the anticonvulsant actions of all the drugs tested here (except topiramate); and that the significantly greater vinpocetine effect in magnitude and potency on [3H]Glu release when excitability is exacerbated like during seizures, may involve the increase additionally exerted by vinpocetine in some K+ channels permeability.

Excitability linked to glutamate modulation is exacerbated by methamphetamine administration. Glutamate signaling plays a significant role in regards to DAergic deficits. Glutamate also contributes to the persistent deficits, as suggested by the inhibition of these deficits when NMDA antagonist are administered. Dopaminergic cells within the striatum possess AMPA and NMDA receptors. Glutamate-induced activation of these receptors promotes Ca 2+ influx into the DAergic neuron. This effect, when excessive, can result in mitochondrial damage and neurotoxicity.

Reversing brain damage in former NFL players: implications for traumatic brain injury and substance abuse rehabilitation.
Brain injuries are common in professional American football players. Finding effective rehabilitation strategies can have widespread implications not only for retired players but also for patients with traumatic brain injury and substance abuse problems. An open label pragmatic clinical intervention was conducted in an outpatient neuropsychiatric clinic with 30 retired NFL players who demonstrated brain damage and cognitive impairment. The study included weight loss (if appropriate); fish oil (5.6 grams a day); a high-potency multiple vitamin; and a formulated brain enhancement supplement that included nutrients to enhance blood flow (ginkgo and vinpocetine), acetylcholine (acetyl-l-carnitine and huperzine A), and antioxidant activity (alpha-lipoic acid and n-acetyl-cysteine). The trial average was six months. Outcome measures were Microcog Assessment of Cognitive Functioning and brain SPECT imaging. In the retest situation, corrected for practice effect, there were statistically significant increases in scores of attention, memory, reasoning, information processing speed and accuracy on the Microcog. The brain SPECT scans, as a group, showed increased brain perfusion, especially in the prefrontal cortex, parietal lobes, occipital lobes, anterior cingulate gyrus and cerebellum. This study demonstrates that cognitive and cerebral blood flow improvements are possible in this group with multiple interventions.

Vinpocetine impact on blood flow may decrease neurotoxicity cause by BBB permeability. Significant increases in blood pressure is often experienced post-admisnistration. Vasodilatation and (PDE) type-1 inhibition may cause the effect on smooth muscle tissue.

 

[Epsilon Alpha]

Its not so much hypoglycemia alone. Neuroglycopenia is the problem, and it is caused by desensitization of GLUT1 and GLUT3 glucose uptake transporter at some specific location in the brain. Desensitization occur when hypoglycemic episode are frequent.

Adaptation in brain glucose uptake following recurrent hypoglycemia
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC44810/

This is extremely relevant to my interests. Mind posting a summery of your findings or a link to this thread in "Amphetamine neurotoxicity and tolerance reduction/prevention II"?

Also, any idea about what plasma concentrations of amphetamine are necessary for this to happen? If memory serves human ADHD patients have around 124 ng/dL (its in the GA Ricaurte study).

 

[Quercetin]

This is extremely relevant to my interests. Mind posting a summery of your findings or a link to this thread in "Amphetamine neurotoxicity and tolerance reduction/prevention II"?

Also, any idea about what plasma concentrations of amphetamine are necessary for this to happen? If memory serves human ADHD patients have around 124 ng/dL (its in the GA Ricaurte study).

Methamphetamine inhibits the glucose uptake by human neurons and astrocytes: stabilization by acetyl-L-carnitine.
Methamphetamine (METH), an addictive psycho-stimulant drug exerts euphoric effects on users and abusers. It is also known to cause cognitive impairment and neurotoxicity. Here, we hypothesized that METH exposure impairs the glucose uptake and metabolism in human neurons and astrocytes. Deprivation of glucose is expected to cause neurotoxicity and neuronal degeneration due to depletion of energy. We found that METH exposure inhibited the glucose uptake by neurons and astrocytes, in which neurons were more sensitive to METH than astrocytes in primary culture. Adaptability of these cells to fatty acid oxidation as an alternative source of energy during glucose limitation appeared to regulate this differential sensitivity. Decrease in neuronal glucose uptake by METH was associated with reduction of glucose transporter protein-3 (GLUT3). Surprisingly, METH exposure showed biphasic effects on astrocytic glucose uptake, in which 20 µM increased the uptake while 200 µM inhibited glucose uptake. Dual effects of METH on glucose uptake were paralleled to changes in the expression of astrocytic glucose transporter protein-1 (GLUT1). The adaptive nature of astrocyte to mitochondrial β-oxidation of fatty acid appeared to contribute the survival of astrocytes during METH-induced glucose deprivation. This differential adaptive nature of neurons and astrocytes also governed the differential sensitivity to the toxicity of METH in these brain cells. The effect of acetyl-L-carnitine for enhanced production of ATP from fatty oxidation in glucose-free culture condition validated the adaptive nature of neurons and astrocytes. These findings suggest that deprivation of glucose-derived energy may contribute to neurotoxicity of METH abusers.

I haven't found any study covering your question. I would believe that it is dose dependent.

 

[Quercetin]

Neuroendocrine Responses to Hypoglycemia

The opioid signaling system has also been hypothesized to contribute to the development of hypoglycemia unawareness by attenuating the counterregulatory response. Studies have shown that β-endorphin levels are increased after hypoglycemic stress in humans. Subsequent human studies of insulin-induced hypoglycemia with and without blockade of opiates by naloxone in well-controlled subjects with type 1 diabetes with defective counterregulation and in healthy controls showed augmentation in the counterregulatory response with use of naloxone—with naloxone resulting in increased epinephrine and cortisol response in controls and increased epinephrine, growth hormone, and cortisol response in the subjects with diabetes during hypoglycemia. Most recently, Leu et al. reported that opioid receptor blockade with naloxone during antecedent hypoglycemia prevented blunting of the counterregulatory response to subsequent hypoglycemia, suggesting that the opioid signaling system may indeed play a role in defective counterregulation.

In summary, the potential mechanisms for the development of hypoglycemia unawareness are numerous. Impaired sensing of hypoglycemia by the brain is likely the primary contributor to hypoglycemia unawareness. This may occur as a result of structural changes in glucose sensing neurons, alterations in neurotransmission or the availability of alternate fuels for brain metabolism. Defective coordination of counterregulation may also have a role in the development of hypoglycemia unawareness. To date, cortisol and the opioid signaling system have been studied as possible causes of defective counterregulation that could contribute to hypoglycemia unawareness. Future research is needed to understand the complex sequence of events that is necessary to develop hypoglycemia-induced autonomic failure.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2991551/

 

[Quercetin]

Physiologic response to hypoglycemia

The physiologic response to hypoglycemia is a complex and well-coordinated process. In healthy humans, there is an ordered, failsafe response system that begins with a reduction in insulin secretion while blood glucose concentration is still in the physiologic range. As blood glucose concentration declines further, peripheral and central glucose sensors relay this information to central integrative centers to coordinate the secretion of counterregulatory hormones (glucagon, epinephrine, norepinephrine, growth hormone and cortisol, respectively) and avert the progression of hypoglycemia. Type 1 diabetes perturbs these counterregulatory responses: circulating insulin levels cannot be reduced (due to exogenous insulin); glucagon secretion is blunted or absent; and epinephrine secretion is blunted and shifted to a lower plasma glucose concentration. It is also observed in methamphetamine induced hyperinsulinemia.

Counterregulation has also been shown to be impaired in type 2 diabetes. In this setting, the glucagon response to hypoglycemia may be normal or blunted, while epinephrine response remains intact, if not augmented. Patients affected by type 1 and type 2 diabetes can develop the syndrome of hypoglycemia unawareness.

Hypoglycemia unawareness develops as recurrent iatrogenic hypoglycemia shifts the glycemic threshold for counterregulation and development of hypoglycemic symptoms to lower plasma glucose concentrations. In this setting, neurogenic symptoms, which are usually the initial warning symptoms of hypoglycemia, are blunted and the first manifestation of hypoglycemia becomes neuroglycopenia. The mechanisms underlying the development of hypoglycemia unawareness may be related to both altered central sensing of hypoglycemia and impaired coordination of responses to hypoglycemia.

Methamphetamine-induced insulin release.
Administration of methamphetamine or amphetamine to rats and mice produces a rapid increase in the level of immunoassayable plasma insulin not attributable to hyperglycemia. While in the mouse this release of insulin is followed consistently by a profound hypoglycemia, in the rat this response is variable. Studies in vitro demonstrate that insulin is released by a direct effect of methamphetamine on the pancreas.

 

[Quercetin]

Dentate gyrus, stress, psychosis and depression
The dentate gyrus is part of the hippocampal formation. It is thought to contribute to the formation of new memories, as well as possessing other functional roles. It may also have a functional role in stress and depression. However, the physiological effects of stress, often characterized by release of glucocorticoids such as cortisol, as well as activation of the sympathetic division of the autonomic nervous system, have been shown to inhibit the process of neurogenesis in primates. Both endogenous and exogenous glucocorticoids are known to cause psychosis and depression, implying that neurogenesis in the dentate gyrus may play an important role in modulating symptoms of stress and depression. Recent studies indicate that poor glucose control can lead to deleterious effects on the dentate gyrus.

Diabetes increases brain damage caused by severe hypoglycemia.
Insulin-induced severe hypoglycemia causes brain damage. The hypothesis to be tested was that diabetes portends to more extensive brain tissue damage following an episode of severe hypoglycemia. Nine-week-old male streptozotocin-diabetic (DIAB; n = 10) or vehicle-injected control (CONT; n = 7) Sprague-Dawley rats were subjected to hyperinsulinemic (0.2 U.kg(-1).min(-1)) severe hypoglycemic (10-15 mg/dl) clamps while awake and unrestrained. Groups were precisely matched for depth and duration (1 h) of severe hypoglycemia (CONT 11 +/- 0.5 and DIAB 12 +/- 0.2 mg/dl, P = not significant). During severe hypoglycemia, an equal number of episodes of seizure-like activity were noted in both groups. One week later, histological analysis demonstrated extensive neuronal damage in regions of the hippocampus, especially in the dentate gyrus and CA1 regions and less so in the CA3 region (P < 0.05), although total hippocampal damage was not different between groups. However, in the cortex, DIAB rats had significantly (2.3-fold) more dead neurons than CONT rats (P < 0.05). There was a strong correlation between neuronal damage and the occurrence of seizure-like activity (r(2) > 0.9). Separate studies conducted in groups of diabetic (n = 5) and nondiabetic (n = 5) rats not exposed to severe hypoglycemia showed no brain damage. In summary, under the conditions studied, severe hypoglycemia causes brain damage in the cortex and regions within the hippocampus, and the extent of damage is closely correlated to the presence of seizure-like activity in nonanesthetized rats. It is concluded that, in response to insulin-induced severe hypoglycemia, diabetes uniquely increases the vulnerability of specific brain areas to neuronal damage.

Withdrawal from chronic amphetamine produces persistent anxiety-like behavior but temporally-limited reductions in monoamines and neurogenesis in the adult rat dentate gyrus.
Acute amphetamine administration activates monoaminergic pathways and increases systemic corticosterone, both of which influence anxiety states and adult dentate gyrus neurogenesis. Chronic amphetamine increases anxiety states in rats when measured at 24 h and at 2 weeks of withdrawal. However, the effects of chronic amphetamine exposure and withdrawal on long term anxiety-like behavior and adult neurogenesis in the dentate gyrus are unknown. Adult male rats were administered amphetamine (2.5 mg/kg, ip.) daily for two weeks. Anxiety-like behaviors were increased markedly in amphetamine-treated rats following four weeks of withdrawal from amphetamine. Plasma corticosterone level was unaltered by amphetamine treatment or withdrawal. However, norepinephrine and serotonin concentrations were selectively reduced in the dentate gyrus 20 h following amphetamine treatment. This effect did not persist through the four week withdrawal period. In separate experiments, rats received bromodeoxyuridine to label cells in S-phase, prior to or immediately following amphetamine treatment. Newly generated cells were quantified to measure extent of progenitor cell proliferation and neurogenesis following treatment or withdrawal. Progenitor cell proliferation and neurogenesis were not significantly affected by amphetamine exposure when measured 20 h following the last amphetamine treatment. However, neurogenesis in the dentate gyrus was reduced after four weeks of withdrawal when compared to saline-pretreated rats. Overall, our findings indicate that withdrawal from chronic amphetamine leads to persistent anxiety-like behavior which may be maintained by reduced neurogenesis in the dentate gyrus at this protracted withdrawal time point. However, neurogenesis is unaffected at earlier withdrawal time points where anxiety states emerge, suggesting different mechanisms may underlie the emergence of anxiety states during amphetamine withdrawal.

Hypothesis
Methamphetamine induced hypoglycemia, caused by insulin secretion have deleterious impact on the dentate gyrus, part of the hippocampus, which is also observed with diabetic experiencing hypoglycemia from exogenous insulin. The Functional role in stress and depression play an important role in modulating symptoms causing relapse. An educated guess tend to make me believe that a dysfunctional dentate gyrus, could potentially explain poor emotional intelligence often observed with methamphetamine abuser.

 

[Quercetin]

N-Acetylcysteine prevent metabolic changes

N-Acetylcysteine (NAC) Prevents the Impairment of the Counter-Regulatory Response Following Recurrent Hypoglycemia
Hypoglycemia is a severe side effect of intensive insulin therapy. Recurrent hypoglycemia (RH) impairs the counter-regulatory response (CRR) which restores euglycemia. The ventromedial hypothalamus (VMH) detects hypoglycemia and initiates the CRR. VMH nitric oxide (NO) production and activation of it's receptor soluble guanylyl cyclase (sGC) is necessary for the CRR. When NO is produced in the presence of reactive oxygen species (ROS) protein S-nitrosylation occurs. S-nitrosylation of sGC impairs its function and desensitizes NO signaling. We hypothesize that during hypoglycemia, the interaction between NO and ROS increases S-nitrosylation levels. This reduces NO activation of sGC and impairs the CRR. In support of this, insulin-hypoglycemia increases VMH ROS levels by 49.66 ± 18.37% (P<0.05). Moreover, 3 consecutive daily episodes of insulin-hypoglycemia (RH model) increase VMH sGC S-nitrosylation. We then determined whether preventing ROS production, and consequently S-nitrosylation of sGC prevents the impaired CRR after RH by treating rats with the antioxidant N-acetylcysteine (NAC) in their drinking water (5 g/l) for 9 days before and during RH (NAC pre-treatment). After RH, glucose levels fell further and epinephrine production was reduced by 50% in response to insulin-hypoglycemia compared to controls (glucose nadir RH: 39.3 ± 1.1 mg/dl; single hypoglycemia [SH]: 53.5 ± 1.8 mg/dl; epinephrine 120 min RH: 611.2 ± 108.3 ng/l; SH: 1350.6 ± 95 ng/l; p<0.05). After NAC pre-treatment there were no significant differences in glucose nadir between RH and SH animals (glucose nadir RH + NAC: 39.6 ± 3 mg/dl; SH + NAC: 35 ± 3 mg/dl). Moreover, after NAC pre-treatment the RH epinephrine response was restored to that of the SH group (RH + NAC: 1390 ± 148.4 ng/l vs SH, p>0.05). NAC also reversed sCG S-nitrosylation. Next we determined whether NAC reverses the impaired CRR by injecting NAC (200mg/kg; i.p). into RH rats 4 hours after the 3rd episode of insulin hypoglycemia. NAC significantly increased glucagon production following RH (RH+NAC: 140 ± 9.2 vs RH: 102.4 ± 8.4; p<0.05). Interestingly, following RH insulin-hypoglycemia produced no further increase in ROS production suggesting that ROS–induced S-nitrosylation is sustained in the absence of further ROS production. These data suggest that NAC prevention of ROS production during hypoglycemia may be clinically useful in preventing impaired CRR in patients undergoing intensive-insulin therapy.

After recurrent insulin-hypoglycemia, NAC significantly increased glucagon secretion and epinephrine response was restored. NAC prevention of ROS production during hypoglycemia may prevent metabolic changes causing dysfunction in counter-regulatory response. During hypoglycemia, the interaction between NO and ROS increases S-nitrosylation levels. This reduces NO activation of sGC and impairs the counter-regulatory response. Soluble guanylate cyclase (sGC) is a mammalian nitric oxide (NO) sensor. When NO binds to the sGC heme, its GTP cyclase activity markedly increases, thus generating cyclic GMP, which serves to regulate several cell signaling functions. A good deal is known about the kinetics and equilibrium of binding of NO to sGC, leading to a proposed multistep mechanism of sGC activation that involves at least two NO-binding sites.

Clinical, endocrine and metabolic effects of metformin vs N-acetyl-cysteine in women with polycystic ovary syndrome.
To evaluate the clinical, endocrine and metabolic effects of metformin and N-acetyl-cysteine (NAC) in patients with polycystic ovary syndrome (PCOS). In this prospective trial, 100 women with PCOS were randomly divided to receive metformin (500 mg p.o. three times daily) or NAC (600 mg p.o. three times daily) for 24 weeks. Hyperandrogenism, lipid profiles, hirsutism scores, menstrual irregularity, insulin sensitivity and tumour necrosis factor-α (TNF-α) levels were measured at baseline and after the treatment period. Both treatments resulted in a significant decrease in fasting insulin, body mass index, hirsutism score, HOMA index, free testosterone and menstrual irregularity compared with baseline values, and both treatments had equal efficacy. NAC led to a significant decrease in both total cholesterol and low-density lipoprotein levels, whereas metformin only led to a decrease in total cholesterol level. Although TNF-α levels increased following treatment for both groups, the difference from baseline was not significant. Metformin and NAC appear to have comparable effects on hyperinsulinaemia, hyperandrogenismand menstrual irregularity in women with PCOS. The effects of metformin and NAC on insulin sensitivity are not associated with TNF-α.

Polycystic ovary syndrome is one of the most common female endocrine disorders with insulin resistance, hyperinsulinaemia for symptoms.

Effect of antioxidant N-acetyl-L-cysteine on behavioral changes and neurotoxicity in rats after administration of methamphetamine.
http://www.ncbi.nlm.nih.gov/pubmed/15234256

Several lines of evidence suggest that oxidative stress may play a role in the behavioral changes and neurotoxicity in rats after administration of methamphetamine (MAP). N-acetyl-L-cysteine (NAC) is a precursor of glutathione, and it also exerts as an antioxidant. In this study, we investigated the effects of NAC on the behavioral changes (hyperlocomotion and development of sensitization) and neurotoxicity in male Wistar rats after administration of MAP. Pretreatment with NAC (30, 100 or 300 mg/kg, i.p.) attenuated significantly hyperlocomotion in rats induced by a single administration of MAP (2 mg/kg, i.p.), in a dose-dependent manner. Furthermore, pretreatment with NAC (100 mg/kg, i.p., 15 min before MAP injection, once daily for 5 consecutive days) blocked significantly the development of behavioral sensitization in rats after repeated administration of MAP (2 mg/kg, once daily for 5 consecutive days), whereas the behaviors in rats after repeated administration of NAC plus saline groups were not different from those of control (vehicle plus saline) groups. One week after administration of MAP (7.5 mg/kg x 4, 2-h intervals), levels of dopamine (DA) in rat striatum were significantly decreased as compared with control groups. Pretreatment with NAC (1, 3, 10 or 30 mg/kg, i.p., 30 min before each MAP injection) attenuated significantly the MAP-induced reduction of DA in rat striatum, in a dose-dependent manner. These results suggest that NAC could prevent the behavioral changes (acute hyperlocomotion and development of behavioral sensitization) in rats and neurotoxicity in rat striatum after administration of MAP, and that NAC would be a useful drug for treatment of several symptoms associated with MAP abuse.

 

[Quercetin]

Hippocampal leptin suppresses methamphetamine-induced hyperlocomotion.
genic peptide which is synthesized in white adipose tissue. The actions of leptin are mediated by the leptin receptor which is abundantly localized in the hypothalamus and is involved in energy regulation and balance. Recently, there has been evidence suggesting that the leptin receptor is also present in the hippocampus and may be involved with hippocampal excitability and long-term depression. To investigate the physiological function of leptin signalling in the hippocampus, we studied the effects of leptin on methamphetamine-induced ambulatory hyperactivity by utilizing intra-hippocampal infusion (i.h.) in mice. Our results show that the infusion of leptin (5 ng each bilaterally i.h.) does not affect the basal ambulatory activity but significantly suppresses methamphetamine-induced ambulatory hyperactivity as compared to saline-infused controls. Interestingly, higher dose of leptin increases the suppression of the methamphetamine-induced ambulatory hyperactivity. The i.h. infusion of leptin did not activate the JAK-STAT pathway, which is the cellular signalling pathway through which leptin acts in the hypothalamus. The infusion of leptin also did not affect activation of p42/44 MAPK which is known to be another leptin-induced signalling pathway in the brain. These results demonstrate that leptin has a novel potential suppressive effect on methamphetamine-induced hyperlocomotion and also suggest that there must be an alternative pathway in the hippocampus through which leptin signalling is being mediated.

Leptin increases circulating glucose, insulin and glucagon via sympathetic neural activation in fasted mice
OBJECTIVE: A number of recent studies suggest that leptin has effects on glucose metabolism and pancreatic hormone secretion. Therefore, the effect of leptin administration on circulating glucose, insulin and glucagon in fed and fasted mice was investigated. The potential contribution of the sympathetic nervous system to the effects of leptin was also examined. DESIGN: Recombinant human or murine leptin was administered intraperitoneally (300 μg/mouse per 12 h over 24 h) to fed or fasted, normal or chemically sympathectomized NMRI mice. Blood samples were collected at baseline and after 24h. MEASUREMENTS: Plasma concentrations of glucose, insulin and glucagon. RESULTS: In the fed state (n=24), leptin administration did not affect glucose, insulin or glucagon concentrations after 24h. Fasting (n=24) reduced body weight by 2.2±0.4 g, plasma glucose by 3.7±0.4 mmol/l, plasma insulin by 138±35 pmol/l, and plasma glucagon by 32±7 pg/ml. In fasted mice, human leptin (n=24) increased plasma glucose by 1.5±0.2mmol/l (P=0.041), plasma insulin by 95±22pmol/l (P=0.018), and plasma glucagon by 16±3pg/ml (P= 0.025), relative to saline-injected control animals. Murine leptin exerted similar stimulating effects on circulating glucose (+ 1.0±0.2 mmol/l, P=0.046), insulin (+58±17 pmol/l, P=0.038) and glucagon (+24±9 pg/ml, P=0.018) as human leptin in fasted mice (n = 12) with no significant effect in fed mice (n = 12). Human leptin did not affect circulating glucose, insulin or glucagon in fasted mice after chemical sympathectomy with 6-hydroxydopamine (40 mg/kg iv 48h prior to fasting; n = 12). CONCLUSION: Leptin increases circulating glucose, insulin and glucagon in 24 h fasted mice by a mechanism requiring intact sympathetic nerves.

Leptin: a potent inhibitor of insulin secretion.
The hormone leptin is expressed and secreted by the adipose tissue and impacts on the central nervous system. Leptin is involved in the regulation of energy balance, satiety, and body composition. The lack of active leptin results in obesity, high food intake, hyperglycemia, and hyperinsulinemia. We present data supporting effects of leptin on the endocrine pancreas. We found the leptin receptor to be expressed in insulin- and glucagon-secretin cells derived from mouse, hamster, and rat pancreas. In the isolated perfused rat pancreas leptin is a potent inhibitor of basal and glucose-induced insulin secretion, especially during the first phase of the insulin response. At isolated mouse islets and insulin-secreting INS-1 cells leptin reduced promptly and persistently the intracellular Ca2+ levels. Cytoplasmic Ca2+ oscillation amplitude was decreased and the oscillation frequency increased. These findings suggest functional active receptors for leptin on insulin-secreting B-cells. Therefore, leptin is a metabolic hormone and not only a signal to the brain indicating filled fat stores. Our data suggest that leptin is also a signal back to the endocrine pancreas that no more insulin is required to replenish fat stores. Thus, an "adipo-insular axis" operating with two arms exists: insulin and glucagon are signals to the adipocyte. This releases leptin, which could be the mediator of the respective feedback to the pancreas. A defective leptin suppression of insulin secretion could contribute to hyperinsulinemia and disturbances of glucose metabolism.

Differential impairment of glucagon responses to hypoglycemia, neuroglycopenia, arginine, and carbachol in alloxan-diabetic mice.
To gain insight into the mechanisms responsible for the loss of the glucagon response to insulin-induced hypoglycemia in type 1 diabetes, glucagon responses to 4 different stimuli were examined over 3 months of diabetes in alloxan-treated mice. At 1, 6, and 12 weeks after alloxan (60 mg/kg), phloridzin (0.1 g/kg) was administered to overnight fasted diabetic mice to match the glucose levels of those in nondiabetic control mice before administration of the acute stimuli. Despite the elevation of baseline glucagon levels produced by the phloridzin treatment, the glucagon responses to insulin (2 U/kg intraperitoneally [IP])-induced hypoglycemia was not impaired at 1 week. However, the response was reduced by greater than 60% after 6 and 12 weeks of diabetes (P <.05). In contrast, the glucagon response to arginine (0.25 g/kg intravenously [IV]) was not reduced after 1, 6, or 12 weeks of diabetes, ruling out a generalized impairment of the A-cell responses. The glucagon response to the neuroglucopenic agent, 2-deoxyglucose (2-DG; 500 mg/kg IV) was impaired, like that to insulin-induced hypoglycemia, after 6 and 12 weeks of diabetes (P <.05), suggesting that supersensitivity to the potential inhibitory effects of exogenous insulin is not the mechanism responsible for the impairment. Finally, the glucagon response to the cholinergic agonist, carbachol (0.53 micromol/kg IV), was not impaired in the diabetic animals, arguing against a defect in the A-cell's responsiveness to autonomic stimulation. The data suggest that the impairment of the glucagon response to insulin-induced hypoglycemia in alloxan diabetic mice is not due to a generalized impairment of A-cell responsiveness, to desensitization by a suppressive action of insulin, or to impairment of the A-cell response to autonomic stimuli. The remaining mechanisms which are likely to explain the late loss of the glucagon response to insulin-induced hypoglycemia include (1) a defect in the A-cell recognition of glucopenic stimuli, or (2) a defect in the autonomic inputs to the A cell that are known to be activated by glucopenic stimuli.

 

[humbleambition]

Hi, Definitely an interesting thought.

I think a lot of it depends on how you are wanting to define "psychosis". The definitions that we use focus more on the existence of delusions and hallucinations, rather than aggression or "combative" behaviour as above. Also, there are many most common hypoglycaemic symptoms like disorientation and dissyness that certainly do not go un-noticed when one presents with methamphetamine induced psychosis.

I do find this hypoglycaemia to psychosis link very interesting though, because I'm convinced that the psychosis happens due to decreased GABA - i don't think there are many in this camp just yet, I'm still busy with my paper... Point is, low glucose levels have been linked with low GABA levels... which causes mood swings, and with just a bit of delusion in that mix and you end up with a diagnosis of schizaffective disorder.

I didn't think to look in this direction at all, but you seem to be backing up my point of low GABA in meth psychosis.
Thanks!! :D

 

[humbleambition]

One other question:

What about chronic meth psychosis? those guys who end up with the diagnosis of schizophrenia, because they have persistent episodes even after long-term abstinence.
I think the hypoglycaemia might occur concurrently with, or be part of the physiological circuit, but not the cause of the problem. It is too transient, although perhaps this could be tested by whether they are less psychotic after having meals and desserts?

 

[Quercetin]

Metabolite alterations in basal ganglia -- connected to chronic psychosis

Metabolite alterations in basal ganglia associated with methamphetamine-related psychiatric symptoms. A proton MRS study.
Following the chronic use of methamphetamine, some individuals experience psychosis and anxiety. One reason may be the persistence of metabolite abnormalities in the brain of currently abstinent former methamphetamine users. In this study, N-acetylaspartate (NAA), creatine plus phosphocreatine (Cr+PCr), and choline-containing compound (Cho) levels were measured in the left and right basal ganglia using proton magnetic resonance spectroscopy (MRS) in 13 abstinent methamphetamine users and 11 healthy comparison subjects with no history of illicit drug use. The methamphetamine users showed a significantly reduced Cr+PCr/Cho ratio in the bilateral basal ganglia compared with the healthy comparison subjects. Furthermore, the reduction in the Cr+PCr/Cho ratio was significantly correlated with the duration of methamphetamine use and with the severity of residual psychiatric symptoms. NAA/Cho ratios in the bilateral basal ganglia did not significantly differ between methamphetamine users and comparison subjects. These findings suggest that protracted use of methamphetamine may cause metabolite alterations in the basal ganglia. Furthermore, residual psychiatric symptoms may be attributable to the metabolite alterations in the basal ganglia.

Schizophrenia, psychosis, and the basal ganglia.
Schizophrenia is one of the most common and perhaps the most disabling of mental disorders, for which effective forms of treatment have not yet been established definitively. The findings reviewed in this article strongly suggest that basal ganglia abnormalities are involved in the pathophysiology of psychotic syndromes in general, and schizophrenia in particular.

 

[Quercetin]

Magnesium sulfate attenuates increased blood-brain barrier permeability during insulin-induced hypoglycemia in rats.
Kaya M, Küçük M, Kalayci RB, Cimen V, Gürses C, Elmas I, Arican N.
Source

Istanbul Faculty of Medicine, Department of Physiology, University of Istanbul, Capa, Turkey. [email protected]
Abstract

Magnesium probably protects brain tissue against the effects of cerebral ischemia, brain injury and stroke through its actions as a calcium antagonist and inhibitor of excitatory amino acids. The effects of magnesium sulfate on cerebrovascular permeability to a dye, Evans blue, were studied during insulin-induced hypoglycemia with hypothermia in rats. Hypoglycemia was induced by an intramuscular injection of insulin. After giving insulin, each animal received MgSO4 (270 mg/kg) ip, followed by a 27 mg/kg dose every 20 min for 2.5 h. Plasma glucose and Mg2+ levels of animals were measured. Magnesium concentrations increased in the serum following MgSO4 administration (6.05+/-0.57 vs. 2.58+/-0.14 mg/dL in the Mg2+ group, and 7.14+/-0.42 vs. 2.78+/-0.06 mg/dL in the insulin + Mg2+ group, P < 0.01). Plasma glucose levels decreased following hypoglycemia (4+/-0.66 vs. 118+/-2.23 mg/dL in the insulin group, and 7+/-1.59 vs. 118+/-4.84 mg/dL in the insulin + Mg2+ group, P < 0.01). Blood-brain barrier permeability to Evans blue considerably increased in hypoglycemic rats (P < 0.01). In contrast, blood-brain barrier permeability to Evans blue was significantly reduced in treatment of hypoglycemic rats with MgSO4 (P < 0.01). These results indicate that Mg2+ greatly reduced the passage of exogenous vascular tracer bound to albumin into the brain during hypoglycemia with hypothermia. Mg2+ could have protective effects on blood-brain barrier permeability against insulin-induced hypoglycemia.

Hypoglycemia induced behavioural deficit and decreased GABA receptor, CREB expression in the cerebellum of streptozoticin induced diabetic rats.
Sherin A, Peeyush KT, Naijil G, Chinthu R, Paulose CS.
Source

Molecular Neurobiology and Cell Biology Unit, Centre for Neuroscience, Department of Biotechnology, Cochin University of Science and Technology, Cochin 682 022, Kerala, India.
Abstract

Intensive glycemic control during diabetes is associated with an increased incidence of hypoglycemia, which is the major barrier in blood glucose homeostasis during diabetes therapy. The CNS neurotransmitters play an important role in the regulation of glucose homeostasis. In the present study, we showed the effects of hypoglycemia in diabetic and non- diabetic rats on motor functions and alterations of GABA receptor and CREB expression in the cerebellum. Cerebellar dysfunction is associated with seizure generation, motor deficits and memory impairment. Scatchard analysis of [(3)H]GABA binding in the cerebellum of diabetic hypoglycemic and control hypoglycemic rats showed significant (P<0.01) decrease in B(max) and K(d) compared to diabetic and control rats. Real-time PCR amplification of GABA receptor subunit GABA(Aα1) and GAD showed significant (P<0.001) down-regulation in the cerebellum of hypoglycemic rats compared to diabetic and control rats. Confocal imaging study confirmed the decreased GABA receptors in hypoglycemic rats. CREB mRNA expression was down-regulated during recurrent hypoglycemia. Both diabetic and non-diabetic hypoglycemic rats showed impaired performance in grid walk test compared to diabetic and control. Impaired GABA receptor and CREB expression along with motor function deficit were more prominent in hypoglycemic rats than hyperglycemic which showed that hypoglycemia is causing more neuronal damage at molecular level. These molecular changes observed during hypo/hyperglycemia contribute to motor and learning deficits which has clinical significance in diabetes treatment.

 

[Quercetin]

I am going to re-edit everything. I now believe that hypoglycemia trigger glutamatergic pathways and gaba. Which is the cause of psychosis.

GAD67: the link between the GABA-deficit hypothesis and the dopaminergic- and glutamatergic theories of psychosis
http://www.ncbi.nlm.nih.gov/pubmed/12811640
Decreases in the 67 kDa isoenzyme of brain glutamic acid decarboxylase (GAD67) expression have been consistently found in patients with bipolar disorder and schizophrenia. In animals GAD67 expression is diminished by chronic, but not acute stimulation of dopamine D2 receptors and by short-term blockade of NMDA receptors. In contrast, chronic treatment with D2 receptor antagonists enhances GAD67 expression. Thus, antipsychotic treatment cannot explain the reduction in GAD67 levels in patients with psychotic disorders. Rather, pathophysiological findings such as reduced viability of cortical glutamatergic neurones (in schizophrenia) or enhanced dopamine sensitivity (in bipolar disorder) might explain the observed reduction in GAD67. Since reduction in GAD67 expression leads to reduced levels of GABA, the GABAergic inhibitory control over glutamatergic cells is reduced.Psychosis could result from AMPA receptor activation caused by overactivity of the glutamatergic system. GAD67 levels would thus be a surrogate marker for psychosis liability. Pharmacological principles that raise GAD67 expression levels could represent novel targets for antipsychotic therapy.

Glutamic acid decarboxylase (GAD) is an enzyme that catalyzes the decarboxylation of glutamate to GABA and CO2.
Extracts from Centella asiatica (gotu kola) and Valeriana officinalis (valerian) stimulated GAD activity.

MAO-B is an enzyme that metabolises the dopamine neurotransmitter.
Monoamine Oxidase B inhibitors are used in the treatment of Parkinson's Disease.

Down-Regulated GABAergic Expression in the Olfactory Bulb Layers of the Mouse Deficient in Monoamine Oxidase B and Administered With Amphetamine
http://rd.springer.com/article/10.1007/s10571-009-9475-2
This study explores primarily the role of the activity of monoamine oxidase B (MAOB) in the regulation of glutamic acid decarboxylase67 (GAD67) expression in distinct layers of main olfactory bulb (OlfB), which links the limbic system. Moreover, the response of GAD67 was investigated to amphetamine perturbation in the absence of MAOB activity. Immunocytochemical analysis was performed on OlfB sections prepared from the adult wild type (WT) and the MAOB gene-knocked-out (KO) mice after receiving repeated intraperitoneal injections (two doses per day, total seven doses) of saline or amphetamine, 5 mg/kg. The levels of the GAD67 immunoreactivity were approximate 25 and 38% lower in respective glomerular (GloL) and mitral cell layers (ML) of saline-treated KO mice than that of WT, whereas similar in the external plexiform or granule cell layers (GraL) of the KO and WT. In the GloL, the level of tyrosine hydroxylase was 39% lower in the KO mice than WT, implicating different dopamine content in the KO from WT. The amphetamine exposure down-regulated the levels of GAD67 in the WT layers by 46 to 52%, and in KO layers 65 to 71%, except ML. The GraL GAD67 level may be regulated by the activation of CREB, as the phosphorylated (p) CREB coexisted with GAD67, and the percentage of GAD67-expressing pCREB neurons was decreased by the amphetamine exposure. The data indicate that the activity of MAOB could modulate the regular and amphetamine-perturbed expression of GAD67 and pCREB. Thus, interactions are suggested among the MAOB activity, GABA content of OlfB, and olfaction.