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There is no evidence that antimuscarinic activity has any effect on schizo- phrenia and thioridizine has no more effect on negative symptoms than typical neuroleptics discount 2 mg artane mastercard lower back pain treatment exercise. Of course cheap artane 2mg line pain treatment center seattle wa, since clozapine is also a weaker D2 antagonist than thioridizine this automatically reduces its ability to produce EPSs anyway. This has centred primarily on 5-HT2A receptors found in the limbic cortex, which are linked to neuronal excitation and believed to mediate the hallucinogenic effects of drugs such as lysergic acid diethylamide (LSD). Generally most atypical neuroleptics have higher affinity for 5-HT2 than D2 receptors while typical ones retain a preference for the D2 receptor. There is, however, no infallible separation since chlorpromazine (typical neuroleptic) is more active at 5-HT2A 366 NEUROTRANSMITTERS, DRUGS AND BRAIN FUNCTION Figure 17. Normally the inhibitory effects of DA released from nigrostriatal afferents on to striatal neuron D2 receptors is believed to balance the excitatory effect of ACh from intrinsic neurons acting on muscarinic (M2) receptors (a). Typical neuroleptics block the inhibitory effect of DA which leaves unopposed the excitatory effect of ACh (b) leading to the augmented activity of the striatal neurons and EPSs (see Fig. An atypical neuroleptic with intrinsic antimuscarinic activity reduces this possibility by counteracting the excitatory effects of released ACh as well as the inhibitory effects of DA (c). Thus the control of striatal neurons remains balanced than D2 receptors and remoxidpride (atypical) more active at D2 than 5-HT2A. Also differences in the values for the dissociation constants between experimental studies (see later) make comparisons between D2 and 5-HT2A potency somewhat difficult. No neuroleptic has purely 5-HT2A antagonist activity and a pure 5-HT2A antagonist drug may not have neuroleptic activity. Risperidone, an atypical neuroleptic with some benefit against negative symptoms, is the most potent of all neuroleptics at 5-HT2A receptors (K1: 0. Some in vitro measurements show it to have up to 25 times more affinity for 5-HT2A than D2receptors and PET studies indicate that at therapeutic doses it displaces a 5-HT2 ligand in preference to a D2 one. Clozapine is also claimed to occupy over 80% of 5-HT2 and less than half this number of D2 receptors at clinical doses. Neuroleptics with 5-HT2 antagonist activity not only produce fewer EPSs but 5-HT2 antagonists reduce neuroleptic-induced EPSs. Fibres from 5-HT neurons in the raphe nucleus innervate and yet, despite the observed 5-HT2A receptor link with neuronal excitation, appear to inhibit DA neurons in the SN (A9). Thus antagonism of 5-HT released onto them would increase their firing and so reduce the likelihood of EPSs, although how 5-HT2A antagonists can SCHIZOPHRENIA 367 overcome the established motor side-effects of another neuroleptic is less clear if that compound has already caused a depolarising block of the neurons. The mechanism by which 5-HT2 antagonism could ameliorate schizophrenic symptoms and what effect 5-HT has on mesolimbic and mesocortical pathways through A10 neurons is even less certain. The probability that neuroleptics benefit from a particular balance of DA and 5-HT2A antagonism is developed later. The 5-HT3 receptor is found appropriately in mesocortical areas and while behavioural studies with their antagonists in rodents showed potential antipsychotic activity, they have proved ineffective in patients. They have been found to increase the extracellular concentration of DA in the frontal cortex of rats but diminish apomorphine-induced stereotypy (striatal effect). So they could be of some benefit, especially against negative symptoms, without causing EPSPs (see Chapter 9). Some, like chlorpromazine, block a1 postsynaptic receptors while clozapine (and risperidone) are as potent at a2 as D2 receptors. There is no evidence that either of these actions could influence striatal or mesolimbic function but NA is considered important for function of the prefrontal cortex and any increase in its release, achieved by blocking a2-mediated autoinhibition, might contribute to a reduction in negative symptoms and provide a further plus for clozapine (see Nutt et al. Centrally, however, most a2-receptors are found post- synaptically and their function, and the effect of blocking them, is uncertain. Glutamate Although there is no evidence that any of the neuroleptics have any significant effect on glutamate receptors, it will be of no surprise to learn that clozapine, but not pure D2 or 5-HT2 antagonists nor any typical neuroleptic, can overcome phencyclidine disruption of PPI in animals. Interestingly, the efficacy of clozapine (but not risperidone or olanzopine) is increased by the antiepileptic drug lamotrigine that has inhibition of glutamate release as one of its actions (see Chapter 16). Also glycine (and serine) have been shown to improve the negative symptoms by what is assumed (but not proven) to be a potentiation of NMDA receptor activity, but they can make positive symptoms worse. Profile of NT antagonism in neuroleptic action In deciphering the role of the different NTs, or more precisely their antagonists, in the antischizophrenic action of neuroleptic drugs it must be remembered that published binding data and calculated dissociation constants vary considerably, which, of course, affects correlation coefficients made with clinical activity. Factors to bear in mind are: (1) In vitro binding studies use different cell lines or membrane preparations and generally only yield the apparent dissociation constants for a number of antagonists obtained by comparative displacement of one labelled ligand. Unfortunately few 368 NEUROTRANSMITTERS, DRUGS AND BRAIN FUNCTION such ligands are specific for the receptor being analysed, i.
For some indi- Cognitive changes usually occur in the viduals cheap artane 2 mg mastercard key pain management treatment center, work becomes increasingly difﬁ- early stages 2mg artane overnight delivery pain and treatment center greensburg pa, with the individual at ﬁrst cult and the effort to continue working may becoming increasingly absent-minded produce a tremendous strain. For others, the volve movements of the ﬁngers, which inability to work may have a detrimental give the impression that the individual is Neuromuscular Conditions 99 ﬁdgeting. As the condition progresses, It is sometimes difﬁcult to distinguish movement and coordination continue to which behavioral symptoms are related to deteriorate, with bradykinesia (slowness the condition itself and which are related of movement) and rigidity interfering to the individual’s anxiety about having with the individual’s ability to walk. Psychotropic medications Jerky, involuntary movements (chorea) may be used to help alleviate or control are also present. Motor difﬁculty also behavioral symptoms, regardless of their affects the individual’s ability to speak cause. Behavioral changes associat- medication may also be used to control ed with the condition range from de- some of the involuntary, jerky move- lusions to impulse-control problems. A major portion of treatment is direct- Diagnosis of Huntington’s Disease ed to assisting individuals and their fam- ilies manage self-care as the condition pro- Diagnosis is usually based on the indi- gresses. Individual counseling, family coun- vidual’s symptoms and family history. In seling, and genetic counseling of family most instances extensive neurological test- members may be important interventions. Evaluation is usually done by a neurologist (physician who eval- Psychosocial Issues in uates and treats neurological disorders). Huntington’s Disease Treatment and Management of Individuals and their families must Huntington’s Disease cope with continuing losses, both physical and mental, as the condition progresses as There is no known treatment to slow well as with the knowledge that Hunting- progression or to cure Huntington’s dis- ton’s disease is a progressive condition in ease. Treatment is usually directed toward which continued deterioration can be ex- preventing complications and treating pected. Physical therapy, a major com- changes for affected individuals may make ponent of the treatment program, can it more difﬁcult for them to cope. Individ- help the individual improve or stabilize uals as well as family members may feel motor ability, prevent contractures, or helpless and hopeless. As a result, they adapt the environment to promote safe- may be reluctant to participate in activi- ty and maximum independence. Occupa- ties designed to maintain or improve their tional therapists may help individuals current level of function. Speech therapists ed to behavioral changes may result in may help individuals maximize their unsafe situations for the individual. Those speech capability as well as their ability to who are in denial about their condition swallow. In some instances cognitive and their limitations may also be exposed retraining and memory training may be to situations that could result in unsafe useful. Individuals are usually affected in cult, social interactions also become more middle or later life, with males affected difﬁcult, resulting in increasing social iso- more frequently than women. Personality changes that may pro- duce violent or hostile behaviors further Manifestations of ALS stress support systems. Because Huntington’s disease has a Symptoms of ALS depend on the area of genetic component, family members may the nervous system affected; both upper be under the additional stress of knowing and lower extremities are affected. There that they may themselves be at risk for are two primary forms of ALS: developing Huntington’s disease. Coun- • Spinal form seling, education, and support can help to • Bulbar form reduce the stress that family members may be experiencing. The spinal form of ALS is characterized by muscular weakness, muscle atrophy Vocational Issues in Huntington’s Disease (decrease in size), spasticity, and hyperac- tive reﬂexes. Individuals may ﬁrst com- Huntington’s disease is a progressive, plain of tripping, stumbling, or awk- degenerative disease; however, in the ear- wardness when walking or running. In the bulbar condition progresses and individuals have form individuals may ﬁrst notice difﬁcul- increasing difﬁculty with memory, com- ty in breathing, slurring of speech or low- munication skills, and physical ability, ered volume when speaking, or difﬁculty sheltered employment may be the most with swallowing. As the condition progresses, symptoms become worse, spreading to other parts of Amyotrophic Lateral Sclerosis the body so that eventually, whether the (ALS; Lou Gehrig’s Disease) individual ﬁrst experienced the bulbar or spinal form of ALS, he or she eventually Amyotrophic lateral sclerosis (ALS), also experiences all the symptoms. Individuals sometimes referred to as Lou Gehrig’s dis- become increasingly weak and immobile. They may experience respiratory mus- current medical theory suggests a multi- cle weakness leading to breathing factorial etiology that may include genet- problems, and in later stages of the con- ic, viral, autoimmune, and neurotoxic fac- dition they may require ventilatory assis- Neuromuscular Conditions 101 tance in order to breathe. Cognitive func- Psychosocial Issues in ALS tion, sensation, vision, hearing, and bow- el and bladder function are usually not The social, economic, and psychologi- affected. It is common for individuals with ALS to Diagnosis of ALS experience fear, anxiety, and depression, especially as the condition progresses There is no reliable laboratory test to and the individual recognizes rapid pro- detect the presence of ALS.