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Significance and remembrance: the role of neuro- 31 1mg terazosin free shipping. Pain pathways involved in fear conditioning correlated with long-term terazosin 2 mg sale, free recall of emotional information. Involvement of subcortical and cortical the human amygdala associates with later memory for individual afferents to the lateral nucleus of the amygdala in fear condition- emotional experience. Amygdala activity rently with auditory and visual conditioned stimuli. J Neurosci related to enhanced memory for pleasant and aversive stimuli. Emotional memory: what does the loid nucleus: sensory interface of the amygdala in fear condition- amygdala do? Equipotentiality of thalamo-amyg- ory: current studies in humans. The amygda- dala and thalamo-cortico-amygdala circuits in auditory fear con- loid complex. Chapter 63: Neurobiological Basis of Anxiety Disorders 923 57. A visual pathway that mediates fear- system in experiential phenomena of temporal lobe epilepsy. Neurphysiology of the perception of intentions by 78. A symptom provoca- trol of the hypothalamo-pituitary-adrenocortical axis. Trends tion study of posttraumatic stress disorder using positron emis- Neurosci 1997;20:78–84. Neuroanatomical cor- awake but not anesthetized rats resemble conditioned emotional relates of happiness, sadness, and disgust. Neuroanatomical cor- responses elicited by electrical stimulation of the amygdala cen- relates of externally and internally generated human emotion. Central noradrenergic path- involved in conditioned fear as measured with the fear-poten- ways for the integration of hypothalamic neuroendocrine and tiated startle paradigm. The effect of medial frontal cortex amnesia in rats with amygdala lesions assessed with the fear- lesions on cardiovascular conditioned emotional responses in potentiated startle paradigm. Different projections of organization of neurons in the rat medial frontal, insular and the central amygdaloid nucleus mediate autonomic and behav- olfactory cortex projecting to the solitary nucleus, olfactory ioral correlates of conditioned fear J Neurosci 1988;8: bulb, periaqueductal gray and superior colliculus. Neural correlates projections in the monkey-an anterograde tracing study. From motivation in the decision-making cognition of chronic amphetamine to action: a review of dopaminergic regulation of limbic nucleus abusers, opiate abusers, patients with focal damage to prefrontal accumbens ventral pallidum pedunculopontine nucleus circuit- cortex, and tryptophan-deleted normal volunteers: evidence for ries involved in limbic-motor integration. Columnar organization in the midbrain cortex (cingulate gyrus) in the regulation of hypothalamic-pitui- periaqueductal grey: modules for emotional expression? Dopamine neurons and their role in reward mecha- 68. Behavioral changes associated with ablation of nisms. Effect of aspiration locus coeruleus in the regulation of cognitive performance. Sci- versus neurotoxic lesions of the amygdala on emotional re- ence 1999;283:549–554. A differential neural of neglect patients overcomes their spatial deficit in visual aware- response in the human amygdala to fearful and happy facial ness. Fear and the human of the cognitive generation of affect. Functional dissociation nition of fear and anger following bilateral amygdala lesions. A functional anatomi- to the subiculum in the rat and cat. J Comp Neurol 1977;172: cal study of unipolar depression. Cingulate func- the perirhinal cortex but not of the frontal, medial prefrontal, tion in depression: a potential predictor of treatment response. N-methyl-D-aspartate lesions of the lat- cortex abnormalities in mood disorders. Nature 1997;386: eral and basolateral nuclei of the amygdaloid block fear-poten- 824–827. Arch Gen Psychiatry 1997;54: blood flow correlate with emotional self-rating: a PET study 233–237. Limbic connections of the orbital and late cortex volume in first-episode psychosis.

Academic researchers and clinical academics were based in universities and specialist research institutes discount terazosin 5 mg amex, in NHS hospital and community trusts and in specialist treatment and rehabilitation centres serving the NHS purchase 1mg terazosin with visa. As well as leading their own research and managing under- and postgraduate teaching programmes or large clinical caseloads, many had additional roles and responsibilities. Within their own organisations these included managing research strategy, building research capacity and capability, providing clinical and student supervision, and positions as heads of service and professional leads. Externally they included providing strategic leadership via active membership of networks such as the British Academy of Childhood Disability; the European Academy of Childhood Disability; NHS clinical governance networks and independent clinical advisory bodies; and organisations such as Disability Matters. A few had been members of guidance development groups for NICE. TABLE 3 Professional role of individual interview participants Role Number of individual interview participants Academic researcher based at university 9 Cliniciana based in the NHS 17 Cliniciana based in a specialist centreb 5 Private practitioner operating nationally 3 Professional body employee operating nationally 5 Total 39 a May also be a clinical academic. Of those recruited who had a therapy background, all were members of their national professional body. Within these organisations, some were members of specialist sections providing professional direction and guidance to their members, such as the Specialist Section Children, Young People and Families of the RCOT and the Association of Paediatric Chartered Physiotherapists within the CSP. Of those who were members of the RCSLT, some were voluntary specialist advisors in their field of expertise and/or members of local Clinical Excellence Networks that meet regularly to share and develop common interests and expertise. In the same way, some of the paediatricians recruited held voluntary roles within the Royal College of Paediatrics and Child Health, such as on the Specialist Advisory Committee for Neurodisability. The largest group, from the North of England, was made up of nine people from the north-east and three from the north-west. Representatives from RCOT, CSP and RCSLT worked countrywide, as did two of the private practitioners. Practitioner focus groups: sample Forty-four therapists took part in one of six focus groups. Over half of these were physiotherapists, the smallest therapy profession represented among those interviewed individually. Most worked for the NHS in the community, predominantly in the north of England. Overall, the therapies they represented, and the organisation, type of setting and locations in which they were based, are reported in Table 6. TABLE 4 Professional training of individual interview participants Type of training Number of individual interview participants Occupational therapist 12 Physiotherapist 7 Speech and language therapista 10 Paediatrician/paediatric neurologist 9 Otherb 1 Total 39 a Includes a social science academic. TABLE 5 Regional base of individual interview participants Region (based on NHS regional teams) Number of individual interview participants North of England 12 Midlands and East of England 3 London 7 South of England 7 Countrywide 8 Othera 2 Total 39 a One from Scotland and one from Wales. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 9 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. METHODS TABLE 6 Practitioner focus groups: therapists and their bases Practitioner group (n) Participant characteristics A(N = 4) B (N = 7) C (N = 15) D (N = 9) E (N = 3) F (N = 6) Total (N) Therapy OT 4 5 9 PT 2 14 9 25 SLT Other 1a 1 Organisation base NHS 7 11 9 5 32 Charitable 4 3 1 8 Private 3 3 Other 1a 1 Practice base Hospital 1 1 Community 5 10 9 5 29 Mix 2 2 1 5 Other 4b 1a 3b 9 Missing 1 Regional base (based on NHS regional teams) North 7 4 9 6 26 Midlands and East 3 3 London 2 2 South 4 1 3 8 Other 2c 2 Missing data 3 3 OT, occupational therapy; PT, physiotherapy; SLT, speech and language therapy. The practitioners had wide-ranging experience within physiotherapy, occupational therapy and speech and language therapy. The mean number of years that practitioners had been qualified was 14. Over 60% reported some previous experience of research, although this varied: investigator, involvement in delivering a programme under evaluation, research within undergraduate/postgraduate studies, service audit and/or membership of research discussion forums. These characteristics of the sample are reported in Table 7. BOX 2 Diagnostic groups represented in practitioner focus groups l Acquired brain injury. Parent focus groups: sample In total, four focus groups were conducted with 26 parents. Of these parents, 20 were mothers, five were fathers and one was a grandfather (Table 8). Within these four parent focus groups, 28 children and young people (15 boys, 13 girls) were represented. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 11 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. METHODS TABLE 8 Parents taking part in focus groups Parent group Mothers (n) Fathers (n) Grandfathers (n) Total in group (N) A B C D Total 20 6 1 26 TABLE 9 Type of parent group organisation and regional base of parents recruited Regional base of parents (based on NHS Type of organisation (n) regional teams) (n) Midlands Parent Local parent- Condition- In-house parent North of and East South of Missing group carer forum specific charity consultation group England of England England data A(N = 4) – B(N = 7) 1 1 – C(N = 6) 1 1 – D(N = 9) – 1 – Total 2 1 1 3 1 2 2 TABLE 10 Gender and age of children represented by parents attending focus groups Gender of children represented (n) Age of children (years) Parent Total number group Male Female represented (n) Mean Median A(N = 4) 3 0 3 14. The conditions reported by parents are listed in Box 3. It should be noted that, as would be expected for this population, many children had more than one diagnosis, including some degree of learning disability and/or autism and/or sensory impairment. Challenges of recruitment Whereas recruitment of the individual interview participants was straightforward, recruitment of the focus group participants proved more difficult. These challenges of recruitment are reported separately for the focus groups with practitioners, parents, and children and young people.

Role of theory of mind and executive function in explaining social intelligence generic terazosin 5mg with amex. CHAPTER 36 AUTOIMMUNE ENCEPHALITIS This is a new field discount terazosin 2mg visa. Definitions are not clear – there is concern the same condition may be known by different names, and different conditions may be known by the same name. Most important from a psychiatric perspective is a recently described condition involving antibodies to N-methyl-D-aspartate (glutamate) receptors (anti-NMDA-Rs) (Dalmau et al, 2007). But, limbic encephalitis (LE) was described half a century ago, and will be mentioned first. Site of the antigen It seems the site of the antigen may separate LE and anti-NMDA-R encephalitis and some other forms of autoimmune encephalitis. Neuronal surface antigens are frequently receptors or synaptic proteins. They are attacked by “neuronal surface antibodies” (NSAbs; Ramanathan et al, 2013). LIMBIC ENCEPHALITIS (LE) Limbic encephalitis, (Brierley et al,) was first described in 1960. Unsurprisingly, it is an inflammatory or autoimmune process predominantly involving the limbic system. It has a sub- acute onset with memory loss, confusion, agitation, hallucinations, seizures and sleep disturbance (Ramanathan et al, 2013). LE is classically described as being paraneoplastic (being associated with neoplasm), most often lung and testicular malignancies. The antigens are frequently intra-neuronal proteins. NEURONAL SURFACE ANTIBODY SYNDROMES (NSAS) Pioneering work in NSAA by Delmau et al (2007) concerned anti-NMDA-R encephalitis. New reports describe new surface antibodies (listed later). It is not clear whether these have different clinical presentations. A young Indian woman was admitted to hospital, behaving in a bizarre manner. When she was asked to write she did so in a manner we did not recognize. She suffered an autoimmune encephalopathy (with anti-NMDA-R antibodies). Recent reports of autoimmune encephalitis excited and alarmed psychiatrists. They tell of conditions which commence with “flue-like” symptoms, in which the presenting complaints are often delusions and hallucinations, accompanied or followed by odd movements of the face or limbs (dyskinesia), seizures, autonomic dysfunction and possibly death from central hypoventilation (Tidswell et al, 2013). There is progressive structural damage of the hippocampi, which may lead to severe irreversible cognitive impairment – thus, rapid diagnosis is desirable (Finke et al, 2015). Given the psychotic symptoms, it is not surprising that 30% of patients present or are admitted to psychiatric facilities. Given the possible sudden need for life support and the potential cognitive damage, it is not surprising psychiatrists are a little alarmed. The condition is more common in women (80%), particularly young (early-20s) but may occur in either gender and at any age. More common in some ethnic groups: African, Asian, Latinos. NSAS are more prevalent than LE, and less commonly paraneoplastic (Lancaster et al, 2013). Cross reactivity of antibodies against different antigens can occur (Irani and Vincent, 2012). Site and action Antibodies mainly affect the medial temporal lobes, amygdala, hippocampus and orbitofrontal cortex. There is rapid removal (reversible) of neurotransmitter receptors from synaptic sites, leading to changes in synaptic and circuit function. Autopsies demonstrate shrunken brain, however, if the individual survives, brain atrophy may be reversed (Lizuka et al, 2010). FDG-PET studies have shown cortical hypermetabolism during the acute stage and hopometabolism in later stages of the illness (Pillai et al, 2010). Therapy Removal of neoplasm when present (Lancaster, 2011).

Elevations in cytokine discount terazosin 1 mg without prescription, acute-phase pro- E cheap terazosin 1mg mastercard, in part because of its accessibility, has received greatest teins, complement, and activated microglia are all present attention among compounds in this class. Furthermore, in in Alzheimer disease brain (38,68–70). Of potential signifi- vitro cell studies in various cell culture preparations indicate cance is that the complement cascade can be activated by that vitamin E can have a protective effect on -amy- A , ultimately leading to the induction of the membrane loid–induced neurotoxicity (61). These A carefully conducted double-blind, placebo-controlled, postmortem findings are given increased meaning by epide- multicenter investigation of the effect of vitamin E and sele- miologic studies that also impute a role for inflammatory giline provided some support for the efficacy of both these mechanisms in Alzheimer disease. The use of nonsteroidal agents in altering the progression of Alzheimer disease (62). Studies of siblings mg per day of selegiline, or the combination of vitamin E with differential exposure to NSAIDs reveal a profound and selegiline. An additional treatment arm exposed patients delay in the onset of Alzheimer disease in the sibling with only to placebo. This was a 2-year trial in which the primary exposure to these agents (74–77). Chapter 87: Current and Experimental Therapeutics of Alzheimer Disease 1247 Particular interest has centered on the inhibition of epidemiologic studies showing benefit from prior exposure cyclooxygenase in Alzheimer disease. Although the inflam- to NSAIDs and treatment studies with NSAIDs could re- matory reaction in the Alzheimer brain appears quite broad, flect the period in which NSAIDs were administrated. Con- a rationale nonetheless exists for inhibition of cyclooxygen- ceivably, such drugs will have no effect, or even an adverse ase, especially cyclooxygenase 2 (Cox-2). Cox-2 levels are effect, once Alzheimer disease has developed, but they may elevated in hippocampal neurons from postmortem exami- still be effective in delaying onset by drug administration nation of patients with Alzheimer disease (78). Hence, a full test of the Cox-2 expression is up-regulated in the frontal cortex of the antiinflammatory approach in Alzheimer disease will require patient with Alzheimer disease. ESTROGEN Given these data, it is not surprising that numerous anti- inflammatory agents are being, or have been, tested in pa- As with antiinflammatory agents, the basis for estrogen ther- tients with Alzheimer disease. With the extensiveness of the apy in Alzheimer disease, in part, derives from epidemio- inflammatory response in the Alzheimer disease brain, a logic studies. One such study, the Baltimore longitudinal relatively nonspecific antiinflammatory drug such as predni- study of aging, followed 500 women, of whom half were sone seemed a rational approach to treatment. A large, mul- estrogen users, for approximately 16 years. The relative risk ticenter, double-blind study in which an initial dose of up of developing Alzheimer disease in the women who were to 20 mg of prednisone, followed by a maintenance dose taking estrogen was approximately halved (84). No evidence of efficacy result was obtained in an Italian longitudinal aging study in delaying the progression of Alzheimer disease was found. Other epidemiologic surveys have reached similar con- Indeed, patients receiving prednisone were more likely to clusions (86). The plausibility of these results are enhanced develop behavioral worsening as well as glucocorticoid- by the finding that estrogen replacement therapy was associ- related medical adverse events. Although it is conceivable ated with higher cognitive test scores in healthy elderly that a higher dose of prednisone was necessary, the adminis- women over the age of 65 years, compared with a cohort tration of such a dose would seem impossible, based on the not receiving such treatment (87,88). There is, however, medical problems encountered with relatively modest doses one large 15-year follow-up study of approximately 800 of prednisone (79). The patient withdrawal rate from the study was effect on the development of Alzheimer disease, or cognition exceedingly high, and it limited the interpretability of the in general, is supported by a series of studies investigating results. For example, Conversely, indomethacin administered in a 6-month trial ovariectomized rats treated with estrogen show preservation was reported to be efficacious, but here, too, the dropout of the integrity of hippocampal neurons and their dendritic rate was excessive, compromising both the interpretability arborization (90). Furthermore, activity of choline acetyl- of the results as well as the ultimate utility of this drug (80). Es- The most positive results obtained to date from large- trogen may also have antioxidant activity, may facilitate pro- scale studies derive from the clinical trials with propentofyl- cessing of APP toward a nonamyloidogenic pathway, and line. Hence, some role for series of studies demonstrated improvement in global func- estrogen in the therapeutics of Alzheimer disease is a reason- tioning, cognitive measures, and activities of daily living able proposition. However, the effects were Two studies examined the effect of estrogen on both exceedingly modest, and attempts to obtain approval for the course and symptoms of Alzheimer disease. Estrogen an Alzheimer disease–related indication in the European replacement therapy for 1year did not slow disease progres- community have so far been unsuccessful, because the ex- sion among women with mild to moderate Alzheimer dis- tent of drug effect has not been deemed to be sufficient to ease who had previously undergone a hysterectomy (94). In another randomized, double-blind, placebo-controlled Numerous trials with selective Cox-2 inhibitors are cur- parallel group study, no effects of estrogen on cognitive rently ongoing. Conversely, some benefit of a to date, despite the relatively compelling rationale for testing transdermal estrogen preparation was noted in an 8-week antiinflammatory agents in Alzheimer disease, results have treatment trial in a very small group of women. The apparent contradiction between more, positive results were found in a few, but not all, 1248 Neuropsychopharmacology: The Fifth Generation of Progress neuropsychological tests (96). Given the effect of estrogen cellular consequences of the various mutations associated on cholinergic parameters, of note is a retrospective analysis with Alzheimer disease supports the notion of the centrality of patients previously exposed to tacrine in the pivotal trials of amyloid production in the pathophysiology of Alzheimer leading to the approval of that drug. Specifically, regardless of whether a mutation occurs gen replacement therapy had a significantly greater response in the amyloid precursor protein gene, presenilin 1or pre- on all outcome measures than those female patients receiv- senilin 2, all mutations increase the concentrations of A 1- ing tacrine who were not receiving estrogen replacement 42 in brain, plasma, or cell culture media.

These findings document further effects of -opioid-receptor activation discount terazosin 2mg with mastercard, and the changes that the early hypothesis of the Kreek laboratory generic 2mg terazosin fast delivery, and many oth- have been observed may result exclusively from the opioid ers, that the reinforcing properties of heroin are mediated effects acting at the -opioid receptors or also secondary primarily by dopamine-independent mechanisms and prob- indirect effects on dopamine receptors. This hypothesis has These and other findings suggest that opiates may act 1496 Neuropsychopharmacology: The Fifth Generation of Progress directly to alter dopaminergic systems both in the ventrome- that is, the neuroplasticity after chronic opiate administra- dial striatum, that is, the core and shell of the nucleus ac- tion that results in impairment of normal neural integrity. Clearly, there are abundant - regulatory events may alter neural growth, development, opioid receptors as well as -opioid receptors in those re- and synapse formation, signal transduction, and overall sys- gions (26,75–77). Work from the Kreek laboratory showed tem integrity (24,79). There have been no similar expression, as well as more direct effects of enhanced tran- findings with respect to increasing -opioid-receptor den- scription factors on dynorphin gene expression, may be sity after chronic opioid administration, however. It is not again important counterregulatory events, which also repre- really known to what extent reinforcement or reward result- sent examples of profound neuroplasticity of the brain. Such ing from heroin and morphine occurs because of activation findings have also been made during binge pattern cocaine directly in these areas, especially the nucleus accumbens and administration (80,81). Enhanced dynorphin peptides, in possibly also the amygdala, as contrasted to indirect effects turn, acting at -opioid receptors, may reduce dopaminergic on the ventral tegmental area. The effects on dopamine tone in many brain regions, including those involved in in each of these different locations and also the different reward and also locomotor activity, and they may also atten- mechanisms involved have not yet been fully elucidated uate opioid withdrawal in dependent animals or humans using a model of chronic, high-dose, intermittent but evenly (6,8,9–11,16). Again, these events must be considered to spaced opiate administration, mimicking the human pattern be a direct result of neuroplasticity and are counterregula- of heroin or morphine abuse and addiction, and also after tory, the attempt to attenuate, modulate, or even brake the withdrawal, as well as during reexposure after such opiate events caused by the rapid changes in dopaminergic tone administration. During chronic binge pattern cocaine ad- brought about especially by stimulants such as cocaine, but ministration, a pattern mimicking the human condition, also to a lesser extent also by opiates. Noble edly primarily the result of the effects of chronic opioid and Cox clearly defined a role of the dopaminergic system in administration. However, because there are also significant opioid-receptor desensitization in these brain regions during changes in dopaminergic tone with enhanced signaling chronic morphine administration (39). This is a rate-limiting enzyme in the biosyn- tion of the dopaminergic neurons, as stated earlier. They also found a reduction in mean D5-type dopaminergic receptors enhance adenylyl cyclase size of the ventral tegmental area dopaminergic neurons and activity, an effect similar to that occurring in the locus ceru- decreased axonal transport to the nucleus accumbens (24, leus after chronic, but not acute, morphine administration, 79). However, there were no changes in numbers of dopa- in most strains of rodents studied, and also in the nucleus minergic neurons and no changes in the size of nondopami- accumbens in some strains of some species. Within ventral tegmental area, infusion activation of the dopaminergic D2 receptors causes a reduc- of brain-derived neurotrophic factor prevented this mor- tion in adenylyl cyclase activity, such as observed during phine-induced reduction in size of dopaminergic neurons acute morphine administration in all brain regions of strains (79). Their group also found that chronic morphine admin- and species of rodents studied, as well as in all cell systems istration resulted in an increase of other components related studied, and an effect that continues to pertain in some to signal transduction, including the extracellular signal reg- specific regions of the brain and other parts of the body ulated kinases (ERKs), which are effectors for brain-derived during chronic opioid administration. Thus, the observa- neurotrophic factor in the ventral tegmental area (24). Crain There have been only limited studies of the time course and Shen hypothesized that, although most -opioid recep- of all these dopaminergic responses during investigator-ad- tors are coupled with inhibitory Gi/oprotein, a small propor- ministered morphine or heroin on an intermittent basis, tion may be coupled at the stimulatory Gs protein, which mimicking the human pattern of heroin abuse, or during can be suppressed with small amounts of opioid antagonists. It would be assumed These findings of enhanced morphine analgesia are, in part, that possibly, as with cocaine, one sees a progressive diminu- very similar to the findings of Bohn, Caron, Lefkowitz, and tion of the responsivity, with a resultant lowering of basal colleagues, in mice with deletion of -arrestin (60). These level and stimulant-induced rise of absolute levels of dopa- researchers also showed that -arrestin is important in sev- mine (78). Numerous human studies suggest this may in- eral distinct functions, including events leading to the inter- deed happen. It has been repeatedly shown in heroin addicts nalization of an agonist bound -opioid receptor, which, that the short acting -opioid agonist heroin will cause a after the phosphorylation of the bound form, binds to - prompt increase in serum prolactin levels, resulting directly arrestin, along with binding by G-protein–receptor kinases from an abrupt lowering of dopamine levels in the tuberoin- (60). This event of -arrestin binding has been described fundibular dopaminergic systems (85). In humans, and to a as potentially part of the process that desensitizes, that is, greater extent than in rodents, prolactin release is essentially leads to G-protein uncoupling of the -opioid receptors, solely under tonic inhibition by dopaminergic tone in the as well as being actually involved in the internalization of tuberoinfundibular dopaminergic system. However, it was endogenous and some exogenous agonist-bound -opioid found that during chronic methadone treatment, there is receptors (44–52,60). The role of internalization in the de- adaptation or tolerance to this phenomenon, an attenua- velopment of tolerance and the independent process of de- tion, but not a complete removal or ablation of this response pendence remain unclear because there are many conflicting caused by dopamine lowering and resulting in elevation of results, including the finding that most exogenous opioid serum prolactin levels (85). Even during long-term metha- ligands, including morphine, that do not induce prompt done maintenance treatment, as reported in 1978, it was internalization of -opioid receptors once bound, clearly found that peak plasma levels of the -opiate agonist metha- lead to the development of both tolerance and physical de- done are related temporally to the peak plasma levels of pendence (44–52). In sharp contrast, methadone and etor- prolactin (85). These findings suggest that the long-acting phine do lead to prompt internalization of -opioid recep- opioid methadone administered orally continues to have tors, just as do all the natural endogenous opioid peptides an impact at least on the tuberoinfundibular dopaminergic such as Met-enkephalin and -endorphin (44–52). Intrigu- system, with a lowering of dopaminergic tone, resulting in ingly, in the mice with deletion at the -arrestin-2 gene, a modest increase of prolactin levels, although not exceeding enhanced morphine analgesia was seen, and further studies upper levels of normal. However, that attenuation occurs revealed that tolerance does not develop to morphine effects, suggests that there may be either a lowering of dopaminergic and yet objective signs reflecting the development of physi- levels and tone in the turberoinfundibular dopaminergic cal dependence are present after chronic morphine adminis- system of that region or, alternatively, an attenuation of tration (60). These studies again dissociated the develop- responsivity of the -opiate-receptor system. It has been ment of tolerance from the development of physical shown that the -opiate-receptor system similarly plays a dependence. The studies of the group of Crain, as well as role in modulating prolactin levels in humans (86).