Mona M. McConnaughey

Long-term consequences of prenatal exposure to cocaine or related drugs: Effects on rat brain monoaminergic receptors ☆

Reports from both this laboratory and others indicate that prenatal exposure of rats to cocaine can produce alterations in development, activity and responses to environmental stimuli. In order to determine a biochemical basis for these effects, radioligand receptor-binding assays for different monoaminergic receptors were performed on rat brain tissues obtained from offspring of dams treated SC with saline, cocaine (15 mg/kg b.i.d.), amitriptyline (10 mg/kg) or amfonelic acid (AFA, 1.5 mg/kg). Male rat pups were fostered by surrogate dams and one rat per litter taken at 30, 60 or 180 days postnatal for determination of striatal and prefrontal cortical D2 receptors, prefrontal cortical 5HT2 receptors, cortical alpha 1-, alpha 2-, beta 1- and beta 2-adrenoceptors. Across all drug treatments and times, the only significant change was at 30 days of age when beta 1-adrenoceptors were increased 68% in the cocaine exposed pups--a time when these rats show hyperactivity--and at 180 days postnatal when a 20% decrease in DA2 receptor Bmax was observed. Also, cortical membrane Mg(2+)-dependent Na+, K(+)-ATPase activities and basal ATPase activities were unaltered by any of the treatments at any of the times. These results suggest that few changes have occurred in monoaminergic receptor sensitivity as a result of the exposure to these drugs during gestation. The behavioral changes that are known to occur following prenatal exposure to cocaine may be due to presynaptic alterations in neurotransmitter function rather than changes in postsynaptic receptors.

Practical Considerations of the Pharmacology of Angiotensin Receptor Blockers

A review of the drug class of angiotensin receptor blockers (ARBs) as well as the ARBs currently available by prescription in the United States is presented. The importance of angiotensin II production by non‐angiotensin‐converting enzyme (non‐ACE) pathways, particularly human chymase, is discussed. Emphasis is placed on the mechanism of action of ARBs and the different binding kinetics of these agents. Although all ARBs, as a group, block the AT1 receptor, they may differ in the pharmacological characteristics of their binding and be classified as either surmountable or insurmountable antagonists. Mechanisms of surmountable and insurmountable antagonism as well as possible benefits of these blocking characteristics are discussed in relation to the various ARBs. The cardiovascular effects of activation of the two main subtypes of angiotensin receptors (AT1 and AT2) are presented. In addition to their treatment of hypertension, ACE inhibitors are recognized as being effective in the management of heart failure, left ventricular hypertrophy, recurrent myocardial infarctions, and renal disease. ARBs are currently indicated only for the treatment of hypertension; however, in vitro and in vivo pharmacological studies as well as preliminary clinical data suggest that ARBs, like ACE inhibitors, may also provide effective protection against end‐organ damage in these conditions.

Chronic aspartame affects T-maze performance, brain cholinergic receptors and Na+,K+-ATPase in rats

This study demonstrated that chronic aspartame consumption in rats can lead to altered T-maze performance and increased muscarinic cholinergic receptor densities in certain brain regions. Control and treated rats were trained in a T-maze to a particular side and then periodically tested to see how well they retained the learned response. Rats that had received aspartame (250 mg/kg/day) in the drinking water for 3 or 4 months showed a significant increase in time to reach the reward in the T-maze, suggesting a possible effect on memory due to the artificial sweetener. Using [(3)H]quinuclidinyl benzilate (QNB) (1 nM) to label muscarinic cholinergic receptors and atropine (10(-6) M) to determine nonspecific binding in whole-brain preparations, aspartame-treated rats showed a 31% increase in receptor numbers when compared to controls. In aspartame-treated rats, there was a significant increase in muscarinic receptor densities in the frontal cortex, midcortex, posterior cortex, hippocampus, hypothalamus and cerebellum of 80%, 60%, 61%, 65%, 66% and 60%, respectively. The midbrain was the only area where preparations from aspartame-treated rats showed a significant increase in Na(+),K(+)-ATPase activity. It can be concluded from these data that long-term consumption of aspartame can affect T-maze performance in rats and alter receptor densities or enzymes in brain.

Effects of microgravity on brain neurotransmitter receptors

Neurotransmitter receptor binding and Na+, K+-ATPase activity were examined in the brains of six rats exposed to 7 days of microgravity during the flight of Spacelab 3. The same variables were examined in a group of six ground control rats. 5-HT1 receptor number in the hippocampus was significantly elevated by exposure to the microgravity environment, and cortical sodium-potassium pump activity was significantly depressed. A marginal depression in dopamine D-2 binding in the striatum was noted. Dopamine and 5-HT binding in a wide variety of other central regions, in addition to GABAA, muscarinic acetylcholine, adenosine A1, and opiate receptor binding, and adrenoceptor binding, was unaffected by microgravity exposure.

Dynorphin Receptor Changes in Hippocampus of the Spontaneously Hypertensive Rat

Dynorphin receptor binding sites in hippocampal membrane preparations were assessed in spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats at 4, 8, 12 and 16 weeks of age. At 4 weeks of age, before hypertension is manifested, SHRs had significantly more hippocampal dynorphin receptor binding sites than WKY controls. At 8, 12 and 16 weeks of age, however, when hypertension is seen, SHRs showed significantly fewer hippocampal binding sites than WKY rats. No receptor affinity changes for dynorphin were seen between the two strains of rats at any age. These results suggest that hippocampal receptor changes involving the opioid system may play a role in the central component of blood pressure control.

The effects of estradiol and mestranol on alpha-adrenoceptors in select regions of the rat brain.

The role of estrogens in modulating the concentration of CNS alpha-adrenoceptors has not been elucidated nor has it been determined how different estrogenic compounds affect these receptors. In this study brain alpha-1 and alpha-2-adrenoceptor binding was measured in female rats treated with estradiol and/or the synthetic estrogen mestranol. Rats treated biweekly for 12 weeks with mestranol (50 micrograms/100 g b.wt.) had a significant reduction in the apparent number of alpha-2-adrenoceptors in the frontal cortex and nucleus tractus solitarius (NTS), while apparent numbers of both alpha-1 and alpha-2-adrenoceptors were depressed in the locus coeruleus. Estradiol treatment (50 micrograms/100 g b.wt.) caused a significant elevation in apparent alpha-1-adrenoceptor numbers in the NTS relative to control. Alpha-adrenoceptor numbers in the rostral and caudal hypothalamus were not affected by either steroid treatment. These results suggest that regulation of apparent numbers of alpha-1 and alpha-2-adrenoceptors in the CNS depends on the type of estrogen used for treatment.

κ-Opioid receptor antisense oligonucleotide injected into rat hippocampus causes hypertension

Bi-hippocampal microinjection treatment (1 microg per side, twice a day for 5 days) with an antisense phosphorothioate oligodeoxynucleotide antisense oligodeoxynucleotide to the rat kappa-opioid receptor, caused hypertension in normotensive Wistar Kyoto (WKY) rats and increased the blood pressure of spontaneously hypertensive rats (SHR). Systolic blood pressure in WKY rats increased from 121+/-4 to 153+/-6 mm Hg, and in SHR systolic blood pressure increased from 153+/-4 to 183+/-5 mm Hg. Similar results were observed with mean blood pressure, however, there were no changes in heart rate. No significant responses were seen with either vehicle or missense injections. Radioligand binding studies indicated that there was a significant decrease in apparent kappa-opioid receptor density due to antisense oligodeoxynucleotide treatment. The results are in accord with our earlier suggestions that the kappa-opioid system in the hippocampus may have a role in the neural control of blood pressure.

Characterization of adenosine binding sites in bovine testicular tissue using 8-cyclopentyl-1,3-[3H]dipropylxanthine☆

The existence of specific adenosine binding sites in bovine testicular tissue was evaluated using the novel antagonist radioligand 8-cyclopentyl-1,3-[3H]dipropylxanthine ([3H]DPCPX). Saturation analysis revealed specific binding that was saturable at approximately 1 nM. Scatchard analysis indicated a single class of binding sites with a KD = 0.26 nM and a Bmax = 0.37 pmol/mg protein. Affinity profiles suggest an A1 subtype recognition site that is different from the classical A1 adenosine receptor. The results presented should prove useful in subsequent studies concerning heterogeneity among adenosine receptors and also aid in discerning the role of adenosine in reproduction.

Influence of environment on GABA receptors in muricidal rats

The influence of environment (isolation) on GABA receptor numbers ( [3H]-muscimol binding sites) and affinities was investigated in specific limbic areas known to be involved with the development of muricide. Olfactory bulbs of isolated rats were found to have identical numbers of [3H]-muscimol binding sites whether or not they were muricidal. However, in the olfactory bulbs of the aggregated animals a greater than two-fold increase was found in numbers of [3H]-muscimol binding sites in those rats that were muricidal. In the amygdala muricidal rats had a 32-34% increase in [3H]-muscimol binding sites over non-muricidal rats regardless of environment. In the septum non-muricidal rats had fewer [3H]-muscimol binding sites than muricidal rats and although the trend was evident, statistical vigor was seen only in the aggregated animals. Neither muricide nor isolation significantly influenced [3H]-muscimol binding numbers in the hypothalamus. GABA Ki values were examined in all brain regions and found to be the same in the isolated and aggregated animals whether or not they were muricidal. We concluded that environment appears to influence apparent GABA receptor numbers in the olfactory bulbs and septum whereas muricidal behavior correlates well with an increase in apparent number of GABA receptors in the amygdala. GABA receptors in the hypothalamus were not influenced by either environment or aggression.

Neuropharmacology: Effects on Rat Brain K1- and K2-Opioid Receptors after Chronic Treatment with Non-peptide K-Agonists

Injection of K‐agonist dynorphins and non‐peptide K‐agonists into the hippocampus induces a reduction in blood pressure. It has been postulated that K‐opioid agonists and K‐receptors are important in one mechanism of antihypertension and might have clinical potential for the treatment of hypertension. We have investigated whether chronic treatment with U‐50488H and U‐62066E, two non‐peptide K‐agonists, effects brain K1‐ or K2‐receptor numbers or affinities in areas that might correlate with changes in blood pressure.