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The diminution in cognitive function reported to occur in patients treated with adjuvant cancer chemotherapy (a phenomenon known as 'chemo-fog, 'chemo-brain' or similar designation) is supported with varying degrees of evidence by prospective and retrospective clinical studies. However, the cognitive deficits are often subtle and the methodologies used to measure them not consistent. Additionally, patients might be able to compensate for the deficits, thereby leading to underestimates of the problem by this type of assessment. For these reasons, direct neuroimaging techniques might provide additional insight. The relatively few such studies, and fewer electrophysiological studies, offer an alternative way to evaluate changes that might be related to cognitive deficits in patients treated with cancer chemotherapeutic regimens.

Insulin receptors are known to be located on nerve cells in mammalian brain. The binding of insulin to dimerized receptors stimulates specialized transporter proteins that mediate the facilitated influx of glucose. However, neurons possess other mechanisms by which they obtain glucose, including transporters that are not insulin-dependent. Further, insulin receptors are unevenly distributed throughout the brain (with particularly high density in choroid plexus, olfactory bulb and regions of the striatum and cerebral cortex). Such factors imply that insulin, and insulin receptors, might have functions within the central nervous system in addition to those related to the supply of glucose. Indeed, invertebrate insulin-related peptides are synthesized in brain and serve as neurotransmitters or neuromodulators. The present review summarizes the structure, distribution and function of mammalian brain insulin receptors and the possible implications for central nervous system disorders. It is proposed that this is an under-studied subject of investigation.

1. The present study examined whether LiCl antagonism of morphine-induced antinociception in mice occurs at mu-opioid receptors. 2. The antinociceptive ED50 value of intracerebroventricular morphine was maximally increased compared to controls 18 hr after LiCl (10 mmol/kg, s.c.) and remained significantly less (P < 0.05) 7 and 14 days after once-daily LiCl treatment. 3. There was no significant difference in [3H]-[D-Ala2,N-MePhe4,Gly- ol5]enkephalin affinity or receptor density compared to controls (KD = 0.43 nM, Bmax = 54.8 +/- 9.3 pM). 4. These results suggest that LiCl's effect is not on mu-opioid receptors, but rather on some distal site.

The temperature dependence of the dissociation constant for the interaction of an opioid delta selective ligand and its receptor was evaluated in three tissues. The change in free energy of this interaction was similar in mouse brain, mouse spinal cord, and NG 108-15 mouse neuroblastoma-rat glioma hybrid cells (delta G(o)' = -13.44, -13.34, and -13.66 kcal.mol-1, respectively). However, the reaction was endothermic and occurred with an increase in entropy in mouse brain and NG 108-15 cells, but it was exothermic and occurred with a negligible change in entropy in mouse spinal cord. These data are consistent with the existence of multiple subtypes of opioid delta receptor, and they further suggest that the opioid delta receptor recently cloned from the NG 108-15 cell line is of the brain subtype. Subtypes of opioid delta receptors may mediate analgesia, but not side-effects, of opiates and thus could be targets for future drug design.

The ability of the molluscan neuropeptide Phe-Met-Arg-Phe-NH2 (FMRFamide) to inhibit the binding of opioid-receptor radioligands to mammalian neural tissue was examined. Rabbit brain membrane preparations were exposed to tritiated dihydromorphine and ethylketocyclazocine in the presence of various concentrations of FMRFamide. FMRFamide inhibited the specific binding of both ligands in a dose-related manner, suggesting that the neuropeptide can inhibit binding to at least two subtypes of opioid receptors (mu and kappa). These data are consistent with the recent proposal that FMRFamide, or the immunoreactive FMRFamide-like material in mammalian brain, spinal cord, and gastrointestinal tract, can act as an endogenous opioid antagonist. However, the low binding affinity of FMRFamide might suggest an alternative mechanism for FMRFamide antagonism of opioid action in vivo.

The efficacy and dissociation constant of morphine in naive and morphine-tolerant rats were estimated by the method of partial irreversible blockade of a fraction of the receptor population with buprenorphine. The dissociation constant (KA) of morphine increased from 3.3 x 10(-5) M in naive to 1.4 x 10(-4) M in morphine-tolerant animals, indicating a decrease in the affinity of morphine for its receptor in the tolerant state. The efficacy of morphine (KA/A50 + 1) was constant in naive and tolerant animals (4.23 and 4.46, respectively). When the data were recalculated following conversion of administered dose to brain morphine concentration, the value of KA was 1.7 x 10(-7) M in naive and 7.7 x 10(-7) M in morphine-tolerant rats, while the efficacy was 2.5 and 3.4, respectively. In addition, the stimulus-effect relationship varied in the two states, with the curve in the tolerant animal being of different shape and broader range than in the naive rat. The present results suggest that (a) tolerance to opiate agonists may involve affinity changes and (b) post-receptor events leading to the measured effect may also be affected.

A method was recently developed by Raffa et al (1) for rapid analysis of brain levels of morphine in rats given the drug subcutaneously. The technique combines the extraction procedure of Sprague and Takemori (2) and the HPLC methodology of Peterson et al (3). The purpose of the present work was verification of the accuracy of this technique and its application to an accompanying study in which the dissociation constants of morphine determined in drug-naive and morphine-tolerant rats were compared. Male, Sprague-Dawley rats (180-220 g) were given morphine sulfate s.c. 60 min prior to testing. Each rat in the "tolerant" group received two 75 mg morphine pellets subcutaneously which were removed 96 h later. Brain levels of morphine were measured a further 24 h later. Morphine levels in rat brain ranged from 52 to 1800 ng, corresponding to subcutaneous doses of 2.5 to 320 mg/kg. This range of brain levels agrees well with those obtained using different methods (4,5). We found no significant difference in brain levels of morphine in naive and tolerant rats given the same doses of morphine (10, 20, 40, and 80 mg/kg, s.c.). Thus, in the determination of dissociation constants for morphine, the same relation can be used for both naive and morphine-tolerant rats when converting administered dose to brain level.

Summary What is known and Objective: Fish oils and other essential fatty acids have been purported to ameliorate the symptoms of schizophrenia or the adverse effects of the drugs that are used to manage it. Our objective is to review the basic and clinical evidence regarding replenishment of the reported decreased levels of polyunsaturated essential fatty acids, such as the omega-3 docosahexaenoic acid, the omega-6 linoleic and arachidonic acids, in brains of patients with schizophrenia. Methods: We summarize the literature related to the postulated mechanistic connection between essential fatty acids and schizophrenia and the clinical trials testing fatty acids in patients with schizophrenia. Results and Discussion: Fatty acids play critical roles in cell membranes of neurons, and certain fatty acids appear to be abnormally low in brains of patients with schizophrenia. The attempt to enhance endogenous levels thus seems a rational and worthwhile goal. The value of such intervention awaits the results of ongoing trials. What is new and Conclusion: Despite the limited evidence that supplements ameliorate symptoms of schizophrenia, given the low risk of harm, some clinicians might opt to add omega-3 polyunsaturated fatty acid to current drug regimens in hope of better symptomatic control in schizophrenia. [ABSTRACT FROM AUTHOR]

Summary [ABSTRACT FROM AUTHOR]

Objective: To investigate a possible differential brain uptake of tramadol vs. its major metabolite (O -desmethyl tramadol; M1) in mice and rats. Methods: An extraction and measurement technique (gas chromatograph equipped with a nitrogen phosphorus detector) was used to measure plasma and brain levels of tramadol and M1 at intervals 10–300 min after oral dosing of tramadol hydrochloride to mice and rats. Results: For all doses of tramadol administered (5, 10, 20, or 40 mg/kg), tramadol and M1 plasma levels were greatest 10 min after dosing: in mice, peak tramadol plasma levels were 47·75–736·72 ng/mL and peak M1 levels were 75·30–1084·92 ng/mL; in rats, peak tramadol plasma levels were 185·03–455·81 ng/mL and peak M1 levels were 106·74–455·70 ng/mL. Tramadol brain levels were also greatest 10 min after dosing. In mice, peak tramadol brain levels were 226·42–1847·46 ng/g. Peak M1 levels (72·17–572·97 ng/g) occurred 20–60 min after dosing. In rats, peak tramadol brain levels were 258·50–1777·37 ng/g and peak M1 levels were 80·35–289·60 ng/g. In mice, the ratio of tramadol/M1 in plasma was 0·5–1·0 throughout the measurements, whereas the ratio in brain was about 10 at 10 min and about 2 from 20 to 50 min. In rats, the ratio of tramadol/M1 in plasma was 0·5–1·5, whereas the ratio in brain was about 15 at 10 min and about 4–7 thereafter. Conclusion: In mice and rats, there appears to be preferential brain vs. plasma distribution of tramadol over M1. [ABSTRACT FROM AUTHOR]

The subject of ‘drug addiction’ is multifaceted and many aspects of it (even some of the definitions) are controversial. Collateral medical problems include the spread of HIV and hepatitis C virus secondary to i.v. drug abuse and effects on prenatal brain development (1). Progress in the understanding of the causes of addictions and its treatment has been impeded by the lack of a unifying biochemical theory. However, recent evidence suggests that some common mechanism might underlie addictions to otherwise apparently unrelated drugs. A major hypothesis has emerged suggesting that the neurotransmitter dopamine (DA) might play a central role in the molecular mechanisms of at least some addictions. If so, it would represent an important target for discovery of effective pharmacotherapy and revolutionize the pharmacist’s role in treating addictions. This short overview outlines the status of the theory of a common biochemical mechanism of drug addiction. [ABSTRACT FROM AUTHOR]