Carlos Castillo

Effects of aging and hypertension on learning, memory, and activity in rats

A comparison between behavioral alterations induced by hypertension and aging was made in spontaneously hypertensive (SHR) and Wistar-Kyoto rats (WKY) of different ages (3-24 months old), trained to perform autoshaping learning and activity tasks. Food-deprived rats received autoshaping training sessions during 6 days; the animals were retrained 1 month later. Two weeks after autoshaping training, the animals were evaluated in the spontaneous activity task during 2 consecutive days. The results show an age-related decrease in learning, memory, and spontaneous activity. Independently of the age group compared, WKY, though showing lower activity, learned and retrieved more than SHR. Accordingly, the reductions in learning and memory were correlated with both aging and hypertension. The combined influence of these two factors had synergistic detrimental effects on cognitive functions.

5-HT6 Receptor Memory and Amnesia: Behavioral Pharmacology – Learning and Memory Processes

Growing evidence indicates that antagonists of the 5-hydroxytryptamine (serotonin) receptor6 (5-HT6) improve memory and reverse amnesia, although the mechanisms involved are poorly understood. Hence, in this paper an attempt was made to summarize recent findings. Available evidence indicates that diverse 5-HT6 receptor antagonists produce promnesic and/or antiamnesic effects in diverse conditions, including memory formation, age-related cognitive impairments, memory deficits in diseases such as schizophrenia, Parkinson, and Alzheimers disease (AD). Notably, some 5-HT6 receptor agonists seem to have promnesic and/or antiamnesic effects. At the present, it is unclear why 5-HT6 receptor agonists and antagonists may facilitate memory or may reverse amnesia in some memory tasks. Certainly, 5-HT6 drugs modulate memory, which are accompanied with neural changes. Likewise, memory, aging, and AD modify 5-HT6 receptors and signaling cascades. Further investigation in different memory tasks, times, and amnesia models together with more complex control groups might provide further clues. Notably, human studies suggest a potential utility of 5-HT6 receptor antagonists in mild-to-moderate AD patients. Even individuals with mild cognitive impairment (MCI) offer a great opportunity to test them.

Memory consolidation and amnesia modify 5-HT6 receptors expression in rat brain: An autoradiographic study

Traditionally, the search for memory circuits has been centered on examinations of amnesic and AD patients, cerebral lesions and, neuroimaging. A complementary alternative might be the use of autoradiography with radioligands. Indeed, ex vivo autoradiographic studies offer the advantage to detect functionally active receptors altered by pharmacological tools and memory formation. Hence, herein the 5-HT(6) receptor antagonist SB-399885 and the amnesic drugs scopolamine or dizocilpine were used to manipulate memory consolidation and 5-HT(6) receptors expression was determined by using [(3)H]-SB-258585. Thus, memory consolidation was impaired in scopolamine and dizocilpine treated groups relative to control vehicle but improved it in SB-399885-treated animals. SB-399885 improved memory consolidation seems to be associated with decreased 5-HT(6) receptors expression in 15 out 17 brain areas. Scopolamine or dizocilpine decreased 5-HT(6) receptors expression in nine different brain areas and increased it in CA3 hippocampus or other eight areas, respectively. In brain areas thought to be in charge of procedural memory such basal ganglia (i.e., nucleus accumbens, caudate putamen, and fundus striate) data showed that relative to control animals amnesic groups showed diminished (scopolamine) or augmented (dizocilpine) 5-HT(6) receptor expression. SB-399885 showing improved memory displayed an intermediate expression in these same brain regions. A similar intermediate expression occurs with regard to amygdala, septum, and some cortical areas in charge of explicit memory storage. However, relative to control group amnesic and SB-399885 rats in the hippocampus, region where explicit memory is formed, showed a complex 5-HT(6) receptors expression. In conclusion, these results indicate neural circuits underlying the effects of 5-HT(6) receptor antagonists in autoshaping task and offer some general clues about cognitive processes in general.

Expression of the 5-HT receptors in rat brain during memory consolidation

Serotonin (5-hydroxytryptamine, 5-HT) system displays more than 14 receptors subtypes on brain areas involved in learning and memory processes, and pharmacological manipulation of specific receptors selectively affects memory formation. In order to begin the search of 5-HT receptors expression during memory formation, in this work, we aimed to determine, by autoradiography (using 3H 5-HT as ligand, 2 nM, specific activity 123 Ci/mmol), 5-HT receptors (5-HTR) expression in passive (untrained) and autoshaping trained (3 sessions) adult (3 months) and old (9 months) male rats. Thus, trained adult rats had better retention than old animals. Raphe nuclei of adult and old trained rats expressed less receptors on medial and dorsal, respectively. Hippocampal CA1 area and dentate gyrus of adult trained rats expressed less 5-HTR, while dentate gyrus of old increased them. Basomedial amygdaloid nucleus in old trained rats expressed more 5-HTR; while in the basolateral amygdaloid nucleus they were augmented in both groups. Training decreased or did not change 5-HTR in caudate-putamen of adult or old animals. The above profile of 5-HTR expression is consistent with previous reports, and suggests that memory formation and aging modulates 5-HTR expression in brain areas relevant to memory systems.

Pharmacological profile of the receptors that mediate external carotid vasoconstriction by 5-HT in vagosympathectomized dogs.

1 5‐Hydroxytryptamine (5‐HT) can produce vasodilatation or vasoconstriction of the canine external carotid bed depending upon the degree of carotid sympathetic tone. Hence, external carotid vasodilatation to 5‐HT in dogs with intact sympathetic tone is primarily mediated by prejunctional 5‐HT1‐like receptors similar to the 5‐HT1D subtype, which inhibit the carotid sympathetic outflow. The present investigation is devoted to the pharmacological analysis of the receptors mediating external carotid vasoconstriction by 5‐HT in vagosympathectomized dogs. 2 Intracarotid (i.c.) infusions for 1 min of 5‐HT (0.3, 1, 3, 10, 30 and 100 μg) resulted in dose‐dependent decreases in both external carotid blood flow and the corresponding conductance; both mean arterial blood pressure and heart rate remained unchanged during the infusions of 5‐HT. These responses to 5‐HT were resistant to blockade by antagonists at 5‐HT2 (ritanserin) and 5‐HT3/5‐HT4 (tropisetron) receptors, but were partly blocked by the 5‐HT1‐like and 5‐HT2 receptor antagonist, methiothepin (0.3 mg kg−1); higher doses of methiothepin (1 and 3 mg kg−1) caused little, if any, further blockade. These methiothepin (3 mg kg−1)‐resistant responses to 5‐HT were not significantly antagonized by MDL 72222 (0.3 mg kg−1) or tropisetron (3 mg kg−1). 3 The external carotid vasoconstrictor effects of 5‐HT were mimicked by the selective 5‐HT1‐like receptor agonist, sumatriptan (3, 10, 30 and 100 μg during 1 min, i.c.), which produced dose‐dependent decreases in external carotid blood flow and the corresponding conductance; these effects of sumatriptan were dose‐dependently antagonized by methiothepin (0.3, 1 and 3 mg kg‐1), but not by 5‐HT1D‐like receptor blocking doses of metergoline (0.1 mg kg−1). 4 The above vasoconstrictor effects of 5‐HT remained unaltered after administration of phentolamine, propranolol, atropine, hexamethonium, brompheniramine, cimetidine and haloperidol, thus excluding the involvement of α‐ and β‐adrenoceptors, muscarinic, nicotinic, histamine and dopamine receptors. Likewise, inhibition of either 5‐HT‐uptake (with fluoxetine) or cyclo‐oxygenase (with indomethacin), depletion of biogenic amines (with reserpine) or blockade of calcium channels (with verapamil) did not modify the effects of 5‐HT. 5 Taken together, the above results support our contention that the external carotid vasoconstrictor responses to 5‐HT in vagosympathectomized dogs are mainly mediated by activation of sumatriptan‐sensitive 5‐HT1‐like receptors. It must be emphasized, notwithstanding, that other mechanisms of 5‐HT, including an interaction with a novel 5‐HT receptor (sub)type and/or an indirect action that may lead to the release of a known (or even unknown) neurotransmitter substance cannot be categorically excluded.

Acute lead exposure induces renal haeme oxygenase-1 and decreases urinary Na excretion

The effects of acute lead exposure on renal function, lipid peroxidation and the expression of haeme oxygenase (HO) in rat kidney were determined. A single injection of lead acetate (50 mg Pb/kg) was given to rats. Changes in renal function, characterized by a significant reduction in the Na excretion was observed six hours after Pb exposure; this effect persisted for 24 hours. TBARS levels increased in kidney cortex 24 hours after Pb administration. In kidney cortex, Pb exposure affected the expression of HO-1, a renal protein associated with oxidative stress. HO-1 mRNA increased 2.3-fold, three hours after Pb administration and remained increased for six, 12 and 24 hours. HO enzymatic activity and HO-1 protein increased six and three hours after Pb administration, respectively, and remained increased at 24 hours. HO inhibition by tin-protoporphyrin, potentiated Pb-induced increase in TBARS and prevented the Pb-induced reduction in Na excretion. Our data suggest that Pb may be acting through the generation of oxidant products and induction of HO.

Spontaneously hypertensive rat (SHR) as an animal model for ADHD: a short overview.

Abstract Diverse studies indicate that attention-deficit hyperactivity disorder (ADHD) is associated with alterations in encoding processes, including working or short-term memory. Some ADHD dysfunctional domains are reflected in the spontaneously hypertensive rat (SHR). Because ADHD, drugs and animal models are eliciting a growing interest, hence the aim of this work is to present a brief overview with a focus on the SHR as an animal model for ADHD and memory deficits. Thus, this paper reviews the concept of SHR as a model system for ADHD, comparing SHR, Wistar-Kyoto and Sprague-Dawley rats with a focus on the hypertension level and working, short-term memory and attention in different behavioral tasks, such as open field, five choice serial reaction time, water maze, passive avoidance, and autoshaping. In addition, drug treatments (d-amphetamine and methylphenidate) are evaluated.

Pharmacological evidence for interactions between 5-HT1A receptor agonists and subtypes of α1-adrenoceptors on rabbit aorta

This study was designed to determine if alpha 1-adrenoceptors are involved in the vascular responses to 5-HT1A receptor agonists. Buspirone (3.1 x 10(-7)-3.1 x 10(-5) M) and 8-hydroxy-2(di-N-propylamino)tetralin (8-OH-DPAT; 3.1 x 10(-6)-10(-4) M) elicited contractions of rabbit aorta rings which were blocked by prazosin (10(-9)-5.6 x 10(-9) M), but which were unaffected by reserpine pretreatment (1 mg/kg i.p.). 5-Methylurapidil (10(-7) and 10(-6) M) blocked contractions elicited by 8-OH-DPAT and by buspirone, whereas chloroethylchonidine (10(-5) and 10(-4) M) inhibited only the effect of buspirone. In addition, these 5-HT1A receptor agonists relaxed arteries precontracted with alpha-adrenoceptor agonists in a similar range of concentrations in which they elicited contraction. Moreover, 8-OH-DPAT and buspirone protected the alpha-adrenoceptors from the irreversible blockade provoked by phenoxybenzamine (10(-7) M), as judged by the norepinephrine contraction and stimulated phosphatidylinositol labeling. According to these results the contractile and relaxant effects elicited by 5-HT1A receptor agonists are a consequence of a direct interaction with alpha 1-adrenoceptors. The contraction elicited by 8-OH-DPAT may be mediated by alpha 1A-adrenoceptors, whereas both alpha 1A- and alpha 1B-adrenoceptors may mediate the effect of buspirone in rabbit aorta.

Characterization of prejunctional 5-HT receptors mediating inhibition of sympathetic vasopressor responses in the pithed rat.

1 It has recently been shown that continuous infusions of 5‐hydroxytryptamine (5‐HT) are able to inhibit, in a dose‐dependent manner, the pressor responses induced by preganglionic (T7‐T9) sympathetic stimulation in pithed rats pretreated with desipramine (50 μg kg−1, i.v.). This inhibitory effect, besides being significantly more pronounced at lower frequencies of stimulation (0.03‐1 Hz) and devoid of tachyphylaxis, is reversible after interrupting the infusions of 5‐HT (up to 5.6 μg kg−1 min−1). In the present study we have characterized the pharmacological profile of the receptors mediating the above inhibitory effect of 5‐HT. 2 The inhibition induced by 5.6 μg kg−1 min−1 of 5‐HT on sympathetically‐induced pressor responses was not blocked after i.v. treatment with physiological saline (1 ml kg−1), ritanserin (0.1 mg kg−1), MDL 72222 (0.15 mg kg−1) or tropisetron (3 mg kg−1), which did not modify the sympathetically‐induced pressor responses per se, but was significantly antagonized by the 5‐HT1‐like and 5‐HT2 receptor antagonist, methysergide (0.3 mg kg−1), which also produced a slight attenuation of the pressor responses to 0.03 and 0.1 Hz per se. 3 Unexpectedly and contrasting with methysergide, the 5‐HT1‐like and 5‐HT2 receptor antagonists, methiothepin (0.01, 0.03 and 0.1 mg kg−1) and metergoline (1 and 3 mg kg−1), apparently failed to block the above 5‐HT‐induced inhibition. Nevertheless, it is noteworthy that these antagonists also blocked the electrically‐induced pressor responses per se, presumably by blockade of vascular α1‐adrenoceptors and, indeed, this property might have masked their potential antagonism at the inhibitory 5‐HT1‐like receptors. 4 Consistent with the above findings, 5‐carboxamidotryptamine (5‐CT, a potent 5‐HT1‐like receptor agonist), metergoline and methysergide mimicked the inhibitory action of 5‐HT with the following rank order of agonist potency: 5CT> > 5‐HT > metergoline ≥ methysergide. 5 Taken together, the above results suggest that the inhibitory action of 5‐HT on the electrically‐induced pressor responses is primarily mediated by an action on inhibitory prejunctional 5‐HT1‐like receptors leading to a decrease in the sympathetic nerve discharge. Interestingly, 5‐HT‐induced excitatory mechanisms could be made manifest once the inhibitory action of 5‐HT had been antagonized.

Autoradiographic study of serotonin transporter during memory formation

Serotonin transporter (SERT) has been associated with drugs of abuse like d-methamphetamine (METH). METH is well known to produce effects on the monoamine systems but it is unclear how METH affects SERT and memory. Here the effects of METH and the serotonin reuptake inhibitor fluoxetine (FLX) on autoshaping and novel object recognition (NOR) were investigated. Notably, both memory tasks recruit different behavioral, neural and cognitive demand. In autoshaping task a dose-response curve for METH was determined. METH (1.0mg/kg) impaired short-term memory (STM; lasting less of 90min) in NOR and impaired both STM and long-term memory (LTM; lasting 24 and 48h) in autoshaping, indicating that METH had long-lasting effects in the latter task. A comparative autoradiography study of the relationship between the binding pattern of SERT in autoshaping new untrained vs. trained treated (METH, FLX, or both) animals was made. Considering that hemispheric dominance is important for LTM, hence right vs. left hemisphere of the brain was compared. Results showed that trained animals decreased cortical SERT binding relative to untrained ones. In untrained and trained treated animals with the amnesic dose (1.0mg/kg) of METH SERT binding in several areas including hippocampus and cortex decreased, more remarkably in the trained animals. In contrast, FLX improved memory, increased SERT binding, prevented the METH amnesic effect and re-established the SERT binding. In general, memory and amnesia seemed to make SERT more vulnerable to drugs effects.