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Blockade of M1 muscarinic acetylcholine receptors modulates the methamphetamine-induced psychomotor stimulant effect

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Abstract

Muscarinic acetylcholine receptors (M1-M5) regulate many key functions of the CNS and peripheral nervous system. In the present study, the role of M1 muscarinic receptors (M1R) in the psychomotor stimulant and sensitizing properties of methamphetamine (METH) is investigated using molecular, neurochemical, and behavioral approaches. Acute and repeated treatment with METH increased M1R mRNA expression in the frontal cortex and the CA2 region of the hippocampus. Repeated treatment with METH also increased M1R mRNA expression in the dentate gyrus. Dicyclomine, an M1R antagonist, did not affect the psychomotor effect of METH, but it attenuated METH-induced increases in the dopamine (DA) efflux in the nucleus accumbens (NAc). Dicyclomine enhanced the psychomotor effect of METH after repeated treatment with METH and 8.0 mg/kg of dicyclomine, and also augmented the increase in the NAc DA overflow evoked by repeated METH treatment. These results suggest that M1R plays a role in the METH-induced psychomotor stimulant effect by changing the release of DA in the NAc of mice.

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... Three of the identified compounds from the Prestwick library have been previously identified as efflux inhibitors in bacteria (33-35), thus validating the screen, and a further 40 from the Roche library were characterized as inhibitors of multidrug efflux in Gram-negative bacteria. A further four of the identified compounds from the Prestwick library have been reported to potentiate antibiotic activity but without a mechanism being identified (18,36), while four other compounds identified by our screen are known to inhibit transport in eukaryotic cells (32,(37)(38)(39). ...
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Biogenic amine transport systems in the presynaptic plasma membrane and the synaptic vesicle provide a mechanism for rapidly terminating the action of released transmitters and for recycling neurotransmitters. Alterations in the activity of these transporters, either by endogenous regulatory mechanisms or by drugs, affect the regulation of synaptic transmitter levels. For drugs such as antidepressants and stimulants that interact with these transport systems, the therapeutic and behavioral consequences are profound. Now that the cDNAs encoding the transporters have been isolated, we can expect rapid progress in understanding how the individual proteins work at the molecular level to couple ion gradients to the reuptake and storage of biogenic amine neurotransmitters.
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Microdialysis was used to study the effect of M1 and M2 selective agonists and antagonists on striatal dopamine release and metabolism. Microdialysis probes were implanted, under anesthesia, in the left and the right striatum of the normal rats and in the normal and denervated striatum of the nigral 6-hydroxydopamine-lesioned rats. Dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were determined by liquid chromatography and electrochemical detection. The different drugs were infused through the dialysis probe during 40 min. Pirenzepine (5 microM), a selective M1 antagonist, produced a significant decrease in DA release in the normal and the 6-hydroxydopamine-lesioned rats, with no significant difference between both groups. Methoctramine, a selective M2 antagonist, produced a dose-dependent increase in DA release between 20 and 200 microM in the normal rats, with no significant effect on DOPAC and HVA. Infusing 75 microM methoctramine produced a significant increase in DA release with a more pronounced effect in the intact animals compared to the 6-hydroxydopamine-lesioned animals. The non-selective agonist carbachol produced a decrease in dopamine release after infusion of 50 microM (M2 effect) and an increase in dopamine release after infusion of 50 mM (M1 effect) in the normal rats. Infusing 50 microM carbachol in the denervated striatum, produced a slight increase in DA release. Our data suggest that presynaptic M1-muscarinic receptors enhance and M2-muscarinic receptors inhibit DA release in the striatum of the rat; and that 3 weeks after 6-hydroxydopamine lesioning there may be a normalisation of the number of M1-receptors with a loss of M2-receptors at the denervated side.
Article
In situ hybridization was used to compare the microscopic distribution in the rat brain of cells containing mRNA for choline acetyltransferase (ChAT) (i.e. cholinergic cells) with that of cells containing mRNA for the five subtypes of muscarinic receptors, in an attempt to establish the potential role as autoreceptors (i.e. muscarinic cholinoceptors present in cholinergic cells) of the different muscarinic receptor subtypes. [32P]alpha-dATP-labelled synthetic oligonucleotides were used as hybridization probes in serial sections. Transcripts for all five subtypes of muscarinic receptors were detected in cells co-distributing with ChAT mRNA-containing cells in one or more regions of the brain. Cells containing m2, m3, m4 or m5 mRNAs were observed in the regions of the basal forebrain where cholinergic cells are located (medial septum/diagonal band nuclei, ventral pallidum, basal nucleus of Meynert). m2, m3 and m5 mRNAs were abundant in the parabigeminal nucleus. m2, m3 and m4 transcripts were detected in the pedunculopontine and laterodorsal tegmental nuclei. m1, m2 and m3 mRNAs were present in several cranial nerve nuclei. The present results suggest that muscarinic autoreceptors belonging to the five subtypes cloned to date may exist.
Article
Behavioral sensitization to amphetamine involves the mesoaccumbens dopamine system and is accompanied by cellular changes in this system. Excitatory amino acid antagonists, when co-administered with amphetamine, prevent both behavioral sensitization and associated changes in the mesoaccumbens dopamine system. This suggests that excitatory amino acid-dependent events are critical to the initiation of sensitization. This study sought to identify excitatory amino acid projections required for sensitization, focusing on projections to the nucleus accumbens or ventral tegmental area. The major excitatory projections to the nucleus accumbens originate in the prefrontal cortex, amygdala and hippocampus. The prefrontal cortex and amygdala also send excitatory projections to the ventral tegmental area. Ibotenic acid lesions of the prefrontal cortex or amygdala and electrolytic lesions of the fornix were performed in rats. After one week of recovery, rats were treated with water or 2.5 mg/kg amphetamine for six days and challenged with amphetamine on day 8. Activity was tested in photobeam cages on days 1 and 8. On day 1, control and sham-lesioned rats exhibited stereotyped behaviors followed by a period of post-stereotypy locomotion. On day 8, sensitization was evident as an enhancement of both stereotypy and post-stereotypy locomotion. Co-administration of N-methyl-D-aspartate antagonists [MK-801 (dizocilpine maleate) or CGS 19755] with amphetamine prevented the development of sensitization of both stereotypy and post-stereotypy locomotion. Neither antagonist, however, prevented the expression of sensitization. None of the lesions completely mimicked these effects of N-methyl-D-aspartate antagonists. Lesions of hippocampal projections traveling in the fornix produced a general disinhibition of locomotor activity, but did not prevent sensitization of either stereotypy or post-stereotypy locomotion. Lesions of the prefrontal cortex failed to prevent sensitization of stereotypy was obtained following repeated amphetamine administration. However, like prefrontal cortical lesions, amygdala lesions prevented sensitization of post-stereotypy locomotion. When interpreted in the light of previous studies demonstrating the importance of the ventral tegmental area in the initiation of sensitization, the present results suggest a likely role for neuronal circuits involving the prefrontal cortex, amygdala and ventral tegmental area in the development of sensitization of post-stereotypy locomotion following repeated amphetamine administration. Such circuits may initiate sensitization through a mechanism involving excitatory amino acid regulation of the activity of mesoaccumbens dopamine neurons. Parallel circuits, involving other brain regions, may similarly contribute to sensitization of stereotyped behaviors.
Article
Repeated amphetamine (A) or methamphetamine (M) treatment induces behavioral sensitization and drug conditioning. The present study compared behavioral sensitization and drug conditioning between treatments with M combined with scopolamine (S) and M alone with respect to a reciprocal balance between the dopaminergic and inhibitory cholinergic systems in rats. Repeated treatment with M (4.0 mg/kg i.p.) combined with S (0.5 mg/kg i.p.) (MS) produced progressive enhancement of stereotyped behavior, compared with repeated M treatment alone. Repeated MS treatment induced focussed stereotyped behavior that was elicited by every challenge injection of not only MS and M, but also partially by S. MS- but not M-sensitized rats exhibited conditioned responses to a tone (300 Hz, 100 dB) associated with drug state, suggesting that MS-induced pronounced behavioral sensitization may lead to an enhanced conditioned response to the conditioned stimulus (CS) of a tone. It is suggested that MS-induced behavioral sensitization may be mediated via a reciprocal balance between the dopaminergic and cholinergic systems in favor of a dopaminergic dominance, and that such a balance may be involved in the conditioning to the drug-associated tone CS.
Article
Direct electrical or chemical stimulation of specific brain regions can establish response habits similar to those established by natural rewards such as food or sexual contact. Cocaine, mu and delta opiates, nicotine, phencyclidine, and cannabis each have actions that summate with rewarding electrical stimulation of the medial forebrain bundle (MFB). The reward-potentiating effects of amphetamine and opiates are associated with central sites of action where these drugs also have their direct rewarding effects, suggesting common mechanisms for drug reward per se and for drug potentiation of brain stimulation reward. The central sites at which these and perhaps other drugs of abuse potentiate brain stimulation reward and are rewarding in their own right are consistent with the hypothesis that the laboratory reward of brain stimulation and the pharmacological rewards of addictive drugs are habit forming because they act in the brain circuits that subserve more natural and biologically significant rewards.
Article
Following the molecular cloning of five distinct muscarinic acetylcholine receptor (mAChR) genes, the last decade has witnessed an explosion of new knowledge about how mAChRs function at a molecular level. These studies have been greatly facilitated by the molecular characterization of the many components of the signal transduction pathways activated upon mAChR stimulation. Molecular genetic and biochemical approaches have considerably advanced our knowledge about how mAChRs are assembled, how they bind ligands, and which structural elements on the mAChRs are critical for G protein coupling. In addition, the molecular mechanisms involved in the regulation of mAChR activity (including mAChR sequestration, down-regulation, and phosphorylation) have been explored in great detail. Since the mAChRs are typical members of the superfamily of G protein-coupled receptors, the information gathered with this class of receptors should be of broad general relevance.
Article
It has been known for a long time that cholinergic basal forebrain neurons which project to the cerebral cortex play a role in learning and memory. Behavioral studies following lesions, for example, repeatedly have suggested multiple learning-related roles for these neurons. Apart from behavioral studies, cholinergic neurons have been shown to possess extraordinarily plastic axons. This plasticity has not been related comprehensively to mnemonic devises, even though morphological changes in the CNS are prime candidates for the neural engram. In this paper, I propose a hypothesis that relates these two characteristics of cholinergic neurons. This hypothesis is that plastic cholinergic axon terminals induce structural reorganization in their targets during memory storage. Possible intracellular mechanisms are examined, whereby acetylcholine release in the cerebral cortex could cause postsynaptic structural changes. Finally, the characteristics of the overall cholinergic-cholinoceptive cell "engram" are elaborated with particular attention paid to the encoding of the stimulus properties along with the context and meaning of the stimulus.
Article
The cholinergic innervation of the cerebral cortex has now become one of the most dynamic areas of research and offers exciting opportunities for exploring the chemical neuroanatomy of cognition, age-related memory impairments, and Alzheimer's disease. The cholinergic pathway from the basal forebrain is the most massive of all extra-thalamic corticofugal projections of the cerebral cortex. Developments based on electron microscopy, immunocytochemistry, antibodies to recombinant receptor subtypes, in situ hybridization, single unit recordings, and selective immunotoxic lesioning have introduced a wealth of new information on the organization and function of this pathway in various animal species, including humans. The cholinergic pathway emanating from the basal forebrain constitutes one of the most important modulatory afferents of the mammalian cortex. The initial expectation that the cholinergic deficiency would provide a unifying pathophysiological basis for Alzheimer's disease and that cholinergic therapies would cure the dementia are clearly too optimistic. Nonetheless, the cortical cholinergic denervation remains one of the earliest, most severe, and most consistent transmitter changes in this disease. The cholinergic depletion may provide an important substrate for the neuropsychological features of Alzheimer's disease and may eventually yield important clues to its pathogenesis.
Article
Intrastriatal microdialysis was used to administer muscarinic drugs in freely moving rats for 40 min at a flow rate of 2 microl/min. Administration of the nonselective agonist pilocarpine at 10 mM increased striatal dopamine release and decreased extracellular GABA and glutamate overflow. Perfusion with the muscarinic M2 antagonist methoctramine at 75 microM increased extracellular dopamine and glutamate concentrations but exerted no changes on extracellular GABA levels. Intrastriatal administration of the M1 antagonist pirenzepine at 0.05 microM decreased extracellular dopamine overflow. Application of pirenzepine (0.05 and 5 microM) exerted no effects on the measured GABA or glutamate levels. There are thus important differences in applied doses of muscarinic drugs needed to obtain modulatory effects. High doses of agonists are probably needed to superimpose on the background of tonic influences of striatal acetylcholine, whereas antagonists can block the receptors in small doses. We further suggest that M1 receptors might tonically facilitate striatal dopamine release, that M2 receptors might tonically inhibit striatal glutamate efflux, and that acetylcholine does not exert tonic effects on striatal GABA release. The link with the pilocarpine animal model for temporal lobe epilepsy will be discussed.
Article
1. Male, Sprague-Dawley rats were pretreated with one of several regimens of repeated, intermittent amphetamine or with a single-dose of intra-VTA pertussis toxin (PTX). 2. An amphetamine challenge dose (0.5 mg/kg, i.p.) produced increased locomotor activity in both amphetamine and pertussis toxin-pretreated rats. 3. The magnitude of activity in PTX pretreated rats exceeded 5-fold that of the amphetamine-pretreated rats. 4. There were no significant differences in the levels of sensitized behavior elicited by 4 distinct amphetamine pretreatment protocols. 5. Neither of the drug pretreatments caused significant changes in the ability of 10 microM amphetamine to promote dopamine efflux from nucleus accumbens or striatal tissue in vitro. 6. The sensitized behaviour cannot be explained by in vitro alterations in pre-synaptic dopamine release, which may suggest an up-regulation of post-synaptic activity.
Article
Repeated treatment of rats with ethanol (1 g/kg, once daily for 15 days) enhanced the locomotor effect of morphine, 3 weeks post-treatment. This ethanol-induced long-term behavioural sensitization to morphine was associated with an increase in the electrically evoked release of [3H]dopamine (DA) and [14C]acetylcholine (ACh) from nucleus accumbens slices. A similar enhanced responsiveness of accumbal dopaminergic and cholinergic neurons to depolarization was apparent 3 weeks after repeated morphine, amphetamine or cocaine administration. Prior ethanol exposure also caused a long-term enhancement of electrically evoked release of [3H]DA and [14C]ACh from slices of the caudate-putamen. Unlike the locomotor effect of morphine, that of amphetamine was not enhanced in ethanol-pretreated rats. These data indicate that ethanol administration may cause long-term behavioural sensitization associated with adaptive changes in dopaminergic and cholinergic neurons of rat nucleus accumbens and caudate-putamen. Furthermore, an enhanced reactivity of nucleus accumbens dopaminergic nerve terminals and dopamine-sensitive cholinergic neurons appears to be a common long-term neuroadaptive effect of distinct types of addictive drugs. However, since repeated ethanol exposure did not cause a long-term increase in the locomotor effect of amphetamine, these neuroadaptations may not always be sufficient to cause long-lasting behavioural (cross-)sensitization.
Article
Structural abnormalities in the hippocampal formation and overactive dopamine neurotransmission in the ventral striatum are thought to be key pathologies in schizophrenia. This experiment examined the functional contribution of different hippocampal subfields to locomotion elicited by D-amphetamine (0.32-3.2 mg/kg) and the direct agonists quinpirole (0.025-0.5 mg/kg) and SKF 38393 (2.5-15.0 mg/kg). Male rats served as unoperated controls or received one of six different lesions (hippocampal formation, fimbria-fornix, subiculum, CA3-4, entorhinal cortex or dentate gyrus (DG)). The main results indicated that extensive ibotenic acid-induced lesions of the hippocampal formation, or colchicine-induced lesions of the DG enhanced locomotion elicited by the D2 agonist quinpirole. Electrolytic lesions of the fimbria-fornix, in comparison, had much larger effects and resulted in increases in the locomotor response to amphetamine and quinpirole. These results extend previous demonstrations of hippocampal modulation of the ventral striatum by showing that this modulatory influence is dependent on both the location and total extent of cell loss within the hippocampal formation. The results are discussed in relation to the causes of and neurophysiological mechanisms involved in enhanced drug-induced locomotion and in terms of their implications for mental diseases including schizophrenia.
Article
Neurobiological studies of patients with schizophrenia suggest that abnormalities of both anatomy and function occur in limbic-cortical structures. An anatomical circuit links the functioning of the ventral striatum (i.e., nucleus accumbens) with the hippocampus and other limbic-cortical structures where neurobiological abnormalities have been found. In animals, lesions of limbic-cortical neurons cause decreases in glutamatergic input to the nucleus accumbens and are also associated with decreases in presynaptic dopamine release, increases in the density of D2-like dopamine receptors, and insensitivity to the actions of dopamine antagonists such as haloperidol. These experiments suggest a plausible pathophysiology of schizophrenia, in that schizophrenic symptoms may be caused by an abnormal dopaminergic state brought about by a primary limbic-cortical lesion and deficits in glutamatergic inputs to the ventral striatum.
Article
This is publication number 11130-NP from The Scripps Research Institute. Research was supported by National Institutes of Health grants DA04043, DA04398, and DA08467 from the National Institute on Drug Abuse and AA06420 and AA08459 from the National Institute on Alcohol Abuse and Alcoholism. The authors would like to thank Mike Arends for his valuable assistance with manuscript preparation.
Article
Dopamine transporters (DAT) terminate dopaminergic neurotransmission by Na⁺ and Cl⁻ dependent reaccumulation of dopamine into presynaptic neurons. A number of substantial lines of evidence have suggested that the actions of cocaine in inducing its rewarding and reinforcing properties are largely because of its inhibition of the DAT, especially the transporter expressed on terminals of mesolimbic-mesocortical dopaminergic neurons whose cell bodies lie in the ventral tegmental area (VTA) of the basal midbrain. Reduction in psychostimulant reward after lesions of these VTA neurons, the ability of psychostimulants to enhance dopamine spillover from their terminal areas in nucleus accumbens, the good correlations between the relative potencies of cocaine analogs in tests of behavioral reward and their potencies at the dopamine transporter, and results in transgenic animals in which dopamine transporter is overexpressed in catecholaminergic neurons or deleted—have been interpreted as fitting with the idea that the role of cocaine in reward largely depend on its action at the dopamine transporter. Thus, the chapter explains dopamine transporter mutants, small molecules, and approaches to cocaine antagonist and dopamine transporter disinhibitor development.
Article
Few studies have explored in detail the relation of cognitive deficits in attention, working memory, and semantics to thought disorder. The authors sought to determine whether thought disorder resides in the semantic system or elsewhere. Twenty-three normal comparison subjects and 23 patients with schizophrenia participated in the study. All subjects received tests of executive function and working memory, including the Wisconsin Card Sorting Test and the Letter-Number Span test; a test of deployment of attentional resources; and tests of semantic processing and language comprehension, including the Peabody Picture Vocabulary Test, the Speed and Capacity of Language-Processing Test, the Boston Naming Test, and tests of semantic verbal fluency and phonologic verbal fluency, from which was derived a difference score. All patients were also administered the Scale for the Assessment of Thought, Language, and Communication to assess thought disorder. The normal subjects were compared with the schizophrenic patients who were rated as having mild thought disorder (N=13) or moderate to severe thought disorder (N=10). While differences between the schizophrenic subgroups and the comparison subjects were observed on nearly all tests, a large difference in effect size between the two schizophrenic subgroups was apparent only in the verbal fluency difference score. In a series of multiple regression analyses, two variables made significant contributions to the prediction of positive thought disorder: the verbal fluency difference score and the Peabody Picture Vocabulary Test score. These results suggest that clinically rated thought disorder is associated with and may result from semantic processing abnormalities. In particular, patients with more severe thought disorder may have difficulty accessing semantic items because of disorganization of the semantic systems and, to a more limited degree, may also lack a semantic or conceptual knowledge base.
Article
We examined the effect of methamphetamine on the release of acetylcholine in the striatum of freely moving rats, using an in vivo microdialysis method. The basal level of acetylcholine was 3.67+/-0.47 pmol/30 microl per 15 min in the presence of neostigmine (10 microM). Tetrodotoxin (1 microM), a selective blocker of voltage-dependent Na+ channels, markedly inhibited the release of acetylcholine in the striatal perfusates. Apomorphine (1.0 mg/kg, i.p.), a dopamine receptor agonist, also significantly attenuated acetylcholine release. Methamphetamine (0.1 and 0.5 mg/kg, i.p.) did not immediately affect acetylcholine release in the striatum, but a dose of 1.0 mg/kg (i.p.) induced an increase of acetylcholine release in the striatum at 15-60 min. Striatal infusion of methamphetamine (5 and 10 microM) did not influence acetylcholine release. The increase following intraperitoneal administration of methamphetamine was slightly diminished by haloperidol (0.5 mg/kg). After microinjection of the neurotoxin, 6-hydroxydopamine (6 microg/3 microl), in the substantia nigra 7 days before, the increase of acetylcholine induced by the administration of methamphetamine (1.0 mg/kg) was slightly attenuated, whereas the administration of reserpine (2 mg/kg, i.p.) 24 h before, combined with alpha-methyl-p-tyrosine (300 mg/kg, i.p.) 2.5 h before, completely blocked the increase in release of acetylcholine. These findings suggest that methamphetamine exerts an excitatory influence on striatal acetylcholine release in freely moving rats, and that this excitatory effect involves the dopaminergic system and the catecholaminergic system.
Article
The role of muscarinic receptors in schizophrenia was investigated using the muscarinic agonist PTAC. PTAC was highly selective for muscarinic receptors, was a partial agonist at muscarinic M2/M4 receptors and an antagonist at M1, M3 and M5 receptors. PTAC was highly active in animal models predictive of antipsychotic behavior including inhibition of conditioned avoidance responding in rats and blockade of apomorphine-induced climbing behavior in mice. d-Amphetamine-induced Fos expression in rat nucleus accumbens was inhibited by PTAC, thus directly demonstrating the ability of PTAC to modulate DA activity. In electrophysiological studies in rats, PTAC acutely inhibited the firing of A10 DA cells and after chronic administration decreased the number of spontaneously firing DA cells in the A10 brain area. However, PTAC did not appreciably alter the firing of A9 DA cells. Thus, PTAC appears to have novel antipsychotic-like activity and these data suggest that muscarinic compounds such as PTAC may represent a new class of antipsychotic agents.
Article
Muscarinic receptors modulate hippocampal activity in two main ways: inhibition of synaptic activity and enhancement of excitability of hippocampal cells. Due to the lack of pharmacological tools, it has not been possible to identify the individual receptor subtypes that mediate the specific physiological actions that underlie these forms of modulation. Light and electron microscopic immunocytochemistry using subtype-specific antibodies was combined with lesioning techniques to examine the pre- and postsynaptic location of m1-m4 mAChR at identified hippocampus synapses. The results revealed striking differences among the subtypes, and suggested different ways that the receptors modulate excitatory and inhibitory transmission in distinct circuits. Complementary physiological studies using m1-toxin investigated the modulatory effects of this subtype on excitatory transmission in more detail. The implications of these data for understanding the functional roles of these subtypes are discussed.
Article
The neurochemical effects of psychostimulant exposure may depend on how these drugs are encountered. A useful method for examining this issue is to compare neurotransmitter release following response-dependent, or self-administered, drug exposure and response-independent exposure. This experiment examined the effect of active and passive cocaine administration on acetylcholine (ACh) efflux in the shell region of the nucleus accumbens (NAc) in rats. One group of rats (CSA: cocaine self-administration) was trained to lever-press for intravenous infusions of cocaine (0.42 mg/kg per infusion) on a fixed-ratio-1 schedule of reinforcement. Cocaine infusions were accompanied by the onset of a stimulus light that signaled a 20-s time-out period. Control rats received intravenous cocaine (cocaine non-contingent: CNC) or saline (SAL) in a manner that was not contingent upon their behavior. Drug infusions in these groups were determined by the lever-press behavior of the animals in the CSA group, i.e. they were yoked to rats in the self-administration group such that CNC animals received equal amounts of cocaine as CSA rats. Animals received cocaine or saline in 3-h sessions for 13 consecutive days before testing. On day 14, extracellular ACh was measured in 15-min intervals before, during and after a 3-h session of cocaine exposure using unilateral microdialysis probes located in the NAc shell coupled with HPLC. ACh efflux was significantly increased above baseline in both groups of rats that received cocaine but CSA rats had significantly higher ACh levels during the self-administration period compared to their yoked counterparts. In addition, ACh efflux remained elevated longer in CSA animals relative to CNC rats following cessation of cocaine exposure. These results demonstrate that ACh interneurons in the NAc shell are responsive to cocaine exposure. In addition, these findings suggest that the manner in which the drug is administered (i.e. either by active self-administration or passive exposure) may be relevant to the magnitude of the neural response.
Article
Groups of subjects whose primary drug of abuse was amphetamine or heroin were compared, together with age- and IQ-matched control subjects. The study consisted of a neuropsychological test battery which included both conventional tests and also computerised tests of recognition memory, spatial working memory, planning, sequence generation, visual discrimination learning, and attentional set-shifting. Many of these tests have previously been shown to be sensitive to cortical damage (including selective lesions of the temporal or frontal lobes) and to cognitive deficits in dementia, basal ganglia disease, and neuropsychiatric disorder. Qualitative differences, as well as some commonalities, were found in the profile of cognitive impairment between the two groups. The chronic amphetamine abusers were significantly impaired in performance on the extra-dimensional shift task (a core component of the Wisconsin Card Sort Test) whereas in contrast, the heroin abusers were impaired in learning the normally easier intra-dimensional shift component. Both groups were impaired in some of tests of spatial working memory. However, the amphetamine group, unlike the heroin group, were not deficient in an index of strategic performance on this test. The heroin group failed to show significant improvement between two blocks of a sequence generation task after training and additionally exhibited more perseverative behavior on this task. The two groups were profoundly, but equivalently impaired on a test of pattern recognition memory sensitive to temporal lobe dysfunction. These results indicate that chronic drug use may lead to distinct patterns of cognitive impairment that may be associated with dysfunction of different components of cortico-striatal circuitry.
Article
Morphine-dependent rats were allowed to undergo withdrawal by abrupt discontinuation of the drug. The regional expression of brain M1 muscarinic receptors was measured directly by autoradiographic determination with [(3)H] pirenzepine, and indirectly by quantifying the relative levels of M1 mRNA encoding the receptor protein. Patterns of receptor changes after morphine treatment were in general agreement using the two methods. Frontal cortical samples derived from morphine-dependent rats exhibited a 28% increase in M1 receptor mRNA measured at the end of the infusion. At the peak of the withdrawal, M1 mRNA levels for dependent rats were much lower (33.4%) than those for control rats. Hippocampal samples derived from morphine-dependent rats exhibited no changes in M1 mRNA levels after the morphine infusion. During the peak of withdrawal, however, hippocampal M1 mRNA levels were reduced (57%) compared with levels for controls. The M1 mRNA levels remained at this reduced degree of expression even after withdrawal symptoms had subsided. Addition of diisopropylflurophophate (DFP) to the morphine infusion schedule inhibited the adaptive changes in M1 mRNA levels induced by morphine. During the peak period of withdrawal, M1 mRNA levels in the hippocampus declined by only 18% as compared with 57% for the morphine control group. The adaptive decrease in hippocampal M1 receptors after withdrawal subsided may reflect prolonged heightened cholinergic activity in an area where such cholinergic innervation plays an important role in memory.
Article
Although there are increasing reports of methamphetamine use, studies examining the cognitive consequences of methamphetamine have not been performed on a population currently using the drug. To characterize this population, 65 people currently using MA regularly and 65 non-users were given a battery of cognitive tests. The battery included recall, recognition, Digit Symbol, Trail Making A & B, Stroop, Wisconsin Card Sort, backward digit span, and the FAS test of verbal fluency. The methamphetamine users were significantly more impaired on recall tasks, digit symbol, Stroop color words, and Trail Making B, but scores fell within the normal ranges on the other measures.